lithium versus valproic acid


Attention Valued Visitor: A Drug Reference Page for FDA Approved General Anesthetics is now available!
Shawn Thomas ( is working to summarize the mechanisms of action of every drug approved by the FDA for a brain- related condition. In addition, new pages with more automated content will soon replace some of the older pages on the web site. If you have suggestions about content that you would like to see, e-mail if you have anything at all to share.



(Updated 1/12/04)

Manji HK, Chen G.
PKC, MAP kinases and the bcl-2 family of proteins as long-term targets for mood stabilizers.
Mol Psychiatry 2002;7 Suppl 1:S46-56
"The complexity of the unique biology of bipolar disorder--which includes the predisposition to episodic, and often progressive, mood disturbance--and the dynamic nature of compensatory processes in the brain, coupled with limitations in experimental design, have hindered our ability to identify the underlying pathophysiology of this fascinating neuropsychiatric disorder. Although we have yet to identify the specific abnormal genes in mood disorders, recent studies have implicated critical signal transduction pathways as being integral to the pathophysiology and treatment of bipolar disorder. In particular, a converging body of preclinical data has shown that chronic lithium and valproate, at therapeutically relevant concentrations, regulate the protein kinase C signaling cascade. This has led to the investigation of the antimanic efficacy of tamoxifen (at doses sufficient to inhibit protein kinase C), with very encouraging preliminary results. A growing body of data also suggests that impairments of neuroplasticity and cellular resilience may also underlie the pathophysiology of bipolar disorder. It is thus noteworthy that mood stabilizers, such as lithium and valproate, indirectly regulate a number of factors involved in cell survival pathways--including cAMP response element binding protein, brain derived neurotrophic factor, bcl-2 and mitogen-activated protein kinases--and may thus bring about some of their delayed long-term beneficial effects via under-appreciated neurotrophic effects. The development of novel treatments, which more directly target molecules involved in critical central nervous system cell survival and cell death pathways, has the potential to enhance neuroplasticity and cellular resilience, thereby modulating the long-term course and trajectory of these devastating illnesses." [Abstract]

Wang HY, Johnson GP, Friedman E.
Lithium treatment inhibits protein kinase C translocation in rat brain cortex.
Psychopharmacology (Berl) 2001 Oct;158(1):80-6
"RATIONALE: Lithium, an effective psychotropic agent, affects membrane phospholipid metabolism, interferes with phosphoinositide signal transduction, and antagonizes the biological activity of calcium, all major factors of protein kinase C (PKC) activation. Consequently, lithium may interfere with cellular functions requiring PKC. Supporting this hypothesis, lithium was found to inhibit increased neurotransmitter release upon PKC activation and to prevent phorbol ester-mediated PKC translocation. OBJECTIVES: The present study was undertaken to determine whether the frontal cortex of rats treated with lithium exhibits altered PKC activity and translocation in response to phorbol ester, K+, or serotonin (5-HT) receptor stimulation and to determine whether specific PKC isozymes are disproportionately affected. METHODS: Rats were fed either a normal diet or one enriched with LiCl. In cerebrocortical slices or synaptosomes, cytosolic and membranous PKC activity and translocation in response to stimuli were determined after partial purification with anion exchange chromatography. RESULTS: In brain slices, lithium treatment inhibited phorbol 12-myristate, 13-acetate (PMA)-, 5-HT-, or K+-induced PKC translocation from cytosol to membrane without affecting basal membrane or cytosolic PKC activity. In synaptosomes, lithium also attenuated PMA- or K+-evoked translocation of PKC. Immunoblotting with isozyme-specific PKC antibodies revealed that chronic lithium treatment reduced basal cytosolic alphaPKC and deltaPKC but increased membrane-associated zetaPKC immunoreactivities. Stimulation with PMA, 5-HT or K+ elicited translocation of alpha, beta and gammaPKC isozymes and PMA induced translocation of delta and epsilonPKC isozymes. Stimulus-mediated translocation of PKC isozymes was attenuated in cortical tissue obtained from animals that received lithium for 6 weeks. In synaptosomes, PMA- or K+-induced PKC translocation was attenuated by in vitro lithium or chronic lithium treatment. Neither rubidium nor cesium affected PKC activities or PMA-induced translocation. Suppression of PMA-elicited translocation by lithium was partially antagonized by Ca2+. CONCLUSIONS: Lithium treatment reduces PKC translocation induced by either stimulation of a cell surface receptor or by direct enzyme stimulation with phorbol ester. This effect leads to reduced PKC-mediated phosphorylation of cellular proteins and may be responsible for the pharmacotherapeutic action of lithium." [Abstract]

Chen, G, Manji, HK, Hawver, DB, Wright, CB, Potter, WZ
Chronic sodium valproate selectively decreases protein kinase C alpha and epsilon in vitro
J Neurochem 1994 63: 2361-2364
"Valproic acid (VPA) is a fatty acid antiepileptic with demonstrated antimanic properties, but the molecular mechanism or mechanisms underlying its therapeutic efficacy remain to be elucidated. In view of the increasing evidence demonstrating effects of the first-line antimanic drug, lithium, on protein kinase C (PKC), we investigated the effects of VPA on various aspects of this enzyme. Chronic exposure (6-7 days) of rat C6 glioma cells to "therapeutic" concentrations (0.6 mM) of VPA resulted in decreased PKC activity in both membrane and cytosolic fractions and increased the cytosol/membrane ratio of PKC activity. Western blot analysis revealed isozyme-selective decreases in the levels of PKC alpha and epsilon (but not delta or zeta) in both the membrane and cytosolic fractions after chronic VPA exposure; VPA added to reaction mixtures did not alter PKC activity or 3H-phorbol ester binding. Together, these data suggest that chronic VPA indirectly lowers the levels of specific isozymes of PKC in C6 cells. Given the pivotal role of PKC in regulating neuronal signal transduction and modulating intracellular cross-talk between neurotransmitter systems, the specific decreases in PKC alpha and epsilon may play a role in the antimanic effects of VPA." [Abstract]

Anna M. Rice, and Alan C. Sartorelli
Inhibition of 20 S and 26 S Proteasome Activity by Lithium Chloride. IMPACT ON THE DIFFERENTIATION OF LEUKEMIA CELLS BY ALL-TRANS-RETINOIC ACID
J. Biol. Chem. 276: 42722-42727, November 16, 2001.
"Cleavage of the peptide substrate Suc-Leu-Leu-Val-Leu-AMC by the 20 S proteasome in the presence of 0.035% SDS resulted in fluorescence at 460 nm. 20 S proteasomes from WEHI-3B D+ cells displayed activity similar to that of commercially available rabbit 20 S proteasomes (>95% purity) (Fig. 2A). The presence of increasing concentrations of LiCl decreased the rate of chymotryptic activity of WEHI-3B D+ and rabbit 20 S proteasomes (Fig. 2, B and C). LiCl at 2.5 mM significantly reduced peptide cleavage after 1 h by WEHI-3B D+ 20 S proteasomes, whereas 10 mM LiCl reduced fluorescence in this system to background levels."

"No effect was observed on 20 S proteasome activity by the presence of 1-5 mM NaCl (Fig. 3A); however, 10 mM NaCl decreased activity slightly. In contrast, neither KCl nor ATRA significantly affected the rate of chymotryptic-like activity of 20 S proteasomes (Fig. 3, B and C). These observations suggest that LiCl has a unique effect on both WEHI-3B D+ and rabbit proteasome activity, and that this inhibitory effect probably is responsible for the observed accumulation of polyubiquitinated RAR species following exposure of WEHI-3B D+ cells to LiCl." [Full Text]

Yamada S, Hojo K, Yoshimura H, Ishikawa K.
Reaction of 20S proteasome: shift of SDS-dependent activation profile by divalent cations.
J Biochem (Tokyo) 1995 Jun;117(6):1162-9
"This study examined the effects of various divalent cations on the SDS-dependent peptidase and casein degradation activities of 20S proteasome purified from Xenopus laevis oocytes at a series of SDS concentrations and the correlation between these effects and the critical micelle concentration (CMC) of SDS. Surprisingly, it was found that divalent cations such as Mg2+ markedly shifted the SDS-dependent activation profiles to a lower concentration range." [Abstract]

Ishiura S, Nojima M, Yamamoto T, Fuchiwaki T, Okuyama T, Furuya H, Sugita H.
Effects of linoleic acid and cations on the activity of a novel high-molecular weight protease, ingensin, from human placenta.
Int J Biochem 1986;18(9):765-9
"A linoleic acid-sensitive protease, ingensin, was purified to homogeneity from human placenta. The physical properties of the placental ingensin were found to be very similar to those of skeletal muscle ingensin [Ishiura et al. (1985) FEBS Lett. 189, 119-123]. The purified ingensin was activated by linoleic acid and SDS. The linoleic acid-activated form was inhibited preferentially by divalent cations, whereas the SDS-activated form was inhibited by monovalent cations instead."

Fischer M, Hilt W, Richter-Ruoff B, Gonen H, Ciechanover A, Wolf DH.
The 26S proteasome of the yeast Saccharomyces cerevisiae.
FEBS Lett 1994 Nov 21;355(1):69-75
"20S proteasomes have been found in all eukaryotes from yeast to man. So far 26S proteasomes have only been discovered in higher eukaryotes. We now report the existence of the 26S proteasome in a lower eukaryote, the yeast Saccharomyces cerevisiae. Formation of the 26S proteasome could most effectively be induced in crude extracts of heat stressed yeast cells by incubation with ATP and Mg2+ ions." [Abstract]

Abukhdeir AM, Layden BT, Minadeo N, Bryant FB, Stubbs EB Jr, Mota de Freitas D.
Effect of chronic Li+ treatment on free intracellular Mg2+ in human neuroblastoma SH-SY5Y cells.
Bipolar Disord. 2003 Feb;5(1):6-13.
"OBJECTIVES: Previous findings have demonstrated Li+/Mg2+ competition at therapeutic intracellular Li+ levels after acute Li+ treatment in human neuroblastoma SH-SY5Y cells. In the current study, we examined whether Li+/Mg2+ competition exists at therapeutically relevant extra- and intracellular [Li+] after chronic Li+ loading times. METHODS: In human neuroblastoma cells, intracellular free Mg2+ was determined by fluorescence spectroscopy with the fluorophore furaptra. Intracellular Li+ and Mg2+ were measured by atomic absorption spectrophotometry. RESULTS: After loading of the neuroblastoma cells with 1-2 mM extracellular Li+ for 24-72 h, the observed, increased intracellular free [Mg2+] levels were significantly higher (p < 0.03) than those in matched Li+ free cells, and intracellular [Li+] was found to be at therapeutic intracellular levels (0.7-1.5 mM). CONCLUSIONS: The results demonstrate that Li+/Mg2+ competition exists after chronic treatment with Li+ at therapeutically relevant intracellular Li+ levels in neuroblastoma cells. We found differences between acute and chronic Li+ treatment effects on the extent of Li+/Mg2+ competition. Possible reasons for these differences are discussed." [Abstract]

Amari, Louis, Layden, Brian, Nikolakopoulos, Joyce, Rong, Qinfen, Mota de Freitas, Duarte, Baltazar, Graca, Castro, M. Margarida C. A., Geraldes, Carlos F. G. C.
Competition between Li+ and Mg2+ in Neuroblastoma SH-SY5Y Cells: A Fluorescence and 31P NMR Study
Biophys. J. 1999 76: 2934-2942
"Because Mg2+ and Li+ ions have similar chemical properties, we have hypothesized that Li+/Mg2+ competition for Mg2+ binding sites is the molecular basis for the therapeutic action of lithium in manic-depressive illness. By fluorescence spectroscopy with furaptra-loaded cells, the free intracellular Mg2+ concentration within the intact neuroblastoma cells was found to increase from 0.39 ± 0.04 mM to 0.60 ± 0.04 mM during a 40-min Li+ incubation in which the total intracellular Li+ concentration increased from 0 to 5.5 mM. Our fluorescence microscopy observations of Li+-free and Li+-loaded cells also indicate an increase in free Mg2+ concentration upon Li+ incubation. By 31P NMR, the free intracellular Mg2+ concentrations for Li+-free cells was 0.35 ± 0.03 mM and 0.80 ± 0.04 mM for Li+-loaded cells (final total intracellular Li+ concentration of 16 mM). If a Li+/Mg2+ competition mechanism is present in neuroblastoma cells, an increase in the total intracellular Li+ concentration is expected to result in an increase in the free intracellular Mg2+ concentration, because Li+ displaces Mg2+ from its binding sites within the nerve cell. The fluorescence spectroscopy, fluorescence microscopy, and 31P NMR spectroscopy studies presented here have shown this to be the case." [Full Text]

Rick A. Finch, Jianming Li, T-C. Chou, and Alan C. Sartorelli
Maintenance of retinoic acid receptor alpha pools by granulocyte colony-stimulating factor and lithium chloride in all-trans retinoic acid-treated WEHI-3B leukemia cells: relevance to the synergistic induction of terminal differentiation
Blood 96: 2262-2268, September 2000.
"Interestingly, both G-CSF and LiCl were capable of protecting RAR pools in ATRA-treated cells by what appeared to be a nontranscriptional mechanism while producing synergistic terminal differentiation of the leukemia cells."
[Full Text]

Yuan, Peixiong, Chen, Guang, Manji, Husseini K.
Lithium Activates the c-Jun NH2-Terminal Kinases In Vitro and in the CNS In Vivo
J Neurochem 1999 73: 2299-2309
"Lithium also increased cJun-mediated reporter gene expression in a dose-dependent manner, with significant effects observed at therapeutically relevant concentrations. Lithium's effects on cJun-mediated reporter gene expression in SH-SY5Y cells were more pronounced in the absence of myo-inositol and were blocked by protein kinase C (PKC) inhibitors and by cotransfection with a PKC alpha dominant-negative mutant."

"It is quite likely that the initial lithium-induced PKC activation may result in increased AP-1 DNA binding activity, which persists even after the down-regulation of PKC alpha and epsilon. Indeed, evidence from various sources has shown that long-term neuronal changes can be maintained by effectors that themselves only transiently maintain the active conformation." [Abstract]

Coleman ES, Wooten MW.
Nerve growth factor-induced differentiation of PC12 cells employs the PMA-insensitive protein kinase C-zeta isoform.
J Mol Neurosci 1994 Spring;5(1):39-57
"To elucidate the role of protein kinase C (PKC) in nerve growth factor (NGF)-induced differentiation, PMA downregulation of pheochromocytoma (PC12) cells was undertaken. Prolonged treatment (2 d) of PC12 cells with PMA (1 microM) resulted in depleting the cells of alpha, beta, delta, and epsilon-PKC isoforms, but had no effect on the expression of the atypical PKC isoform zeta." [Abstract] [Note that PMA is a PKC activator.]

Cho Y, Tighe AP, Talmage DA.
Retinoic acid induced growth arrest of human breast carcinoma cells requires protein kinase C alpha expression and activity.
J Cell Physiol 1997 Sep;172(3):306-13
"Retinoic acid inhibits proliferation of hormone-dependent, but not hormone-independent breast cancer cells. Retinoic acid-induced changes in cellular proliferation and differentiation are associated with disturbances in growth factor signaling and frequently with changes in protein kinase C expression. PKC delta, epsilon, and zeta are expressed in both hormone-dependent (T-47D) and hormone-independent (MDA-MB-231) cell lines. Retinoic acid arrested T-47D proliferation, induced PKC alpha expression and concomitantly repressed PKC zeta expression. The changes in PKC alpha and PKC zeta reflect retinoic acid-induced changes in mRNA. In contrast, retinoic acid had no effect on growth, or PKC expression in MDA-MB-231 cells. Growth arrest and the induction of PKC alpha, but not the reduction in PKC zeta, resulted from selective activation of RAR alpha. In total, these results support an important role for PKC alpha in mediating the anti-proliferative action of retinoids on human breast carcinoma cells." [Abstract]

Cho Y, Talmage DA.
Protein kinase Calpha expression confers retinoic acid sensitivity on MDA-MB-231 human breast cancer cells.
Exp Cell Res 2001 Sep 10;269(1):97-108
"Retinoic acid activation of retinoic acid receptor alpha (RARalpha) induces protein kinase Calpha (PKCalpha) expression and inhibits proliferation of the hormone-dependent T-47D breast cancer cell line. Retinoic acid has no effect on proliferation or PKCalpha expression in a hormone-independent, breast cancer cell line (MDA-MB-231). To test the role of PKCalpha in retinoic acid-induced growth arrest of human breast cancer cells we established MDA-MB-231 cell lines stably expressing PKCalpha. Constitutive expression of PKCalpha did not affect proliferation of MDA-MB-231 cells but did result in partial retinoic acid sensitivity. Retinoic acid treatment of PKCalpha-MDA-MB-231 cells decreased proliferation (by approximately 40%) and inhibited serum activation of MAP kinases and induction of c-fos. Similar results were seen in MDA-MB-231 cells in which transcription of the transfected PKCalpha cDNA was reversibly induced by isopropyl beta-d-thiogalactoside. Expression of RARalpha in PKCalpha expressing MDA-MB-231 cells resulted in even greater retinoic acid responses, as measured by effects on cell proliferation, inhibition of serum signaling, and transactivation of an RARE-CAT reporter plasmid. In summary, PKCalpha synergizes with activated RARalpha to disrupt serum growth factor signaling, ultimately arresting proliferation of MDA-MB-231 cells." [Abstract]


Anna Radominska-Pandya, Guangping Chen, Piotr J. Czernik, Joanna M. Little, Victor M. Samokyszyn, Charleata A. Carter, and Graz·yna Nowak
Direct Interaction of All-trans-retinoic Acid with Protein Kinase C (PKC). IMPLICATIONS FOR PKC SIGNALING AND CANCER THERAPY
J. Biol. Chem. 275: 22324-22330, July 2000.
"These results let us hypothesize that in vivo, pharmacological concentrations of atRA may hamper binding of PS to PKC alpha and prevent PKC alpha activation." [Full Text]

Watson DG, Wainer BH, Lenox RH.
Phorbol ester- and retinoic acid-induced regulation of the protein kinase C substrate MARCKS in immortalized hippocampal cells.
J Neurochem 1994 Nov;63(5):1666-74
"MARCKS protein expression was also down-regulated in a dose-dependent manner on exposure of HN33 cells to retinoic acid." [Abstract]

Chen M, Antoni L, Tazi-Ahnini R, Cork M, Ward S, Bavik C.
Identification of known and novel genes whose expression is regulated by endogenous retinoic acid during early embryonic development of the mouse.
Mech Dev 2002 Jun;114(1-2):205
"The utility of the method is exemplified by our finding that several genes in the Wnt signaling pathway are vitamin A regulated in day 9.0 post coitum (p.c.) embryos." [Abstract]

Mora A, Sabio G, Risco AM, Cuenda A, Alonso JC, Soler G, Centeno F.
Lithium blocks the PKB and GSK3 dephosphorylation induced by ceramide through protein phosphatase-2A.
Cell Signal 2002 Jun;14(6):557-62
"Since lithium inhibits in vivo the observed protein phosphatase-2A (PP2A) activation induced by ceramide, we hypothesise that the neuroprotective action of lithium may be due to the inhibition of the PP2A activation by apoptotic stimuli." [Abstract]

Galadari S, Hago A, Patel M.
Effects of cations on ceramide-activated protein phosphatase 2A.
Exp Mol Med 2001 Dec 31;33(4):240-4
"In this study, we investigated the effects of metal ions and chelators on ceramide-activated PP2A (CAPP). Our study demonstrates that at 0.5 mM concentration, Mg2+ appears to have no significant effect on either basal or ceramide-stimulated phosphatase activities, whereas Ca2+ stimulated the basal phosphatase activity, but was inhibitory towards CAPP. Moreover, the divalent cations Cr2+, Mn2+, Fe2+, Ni2+, Cu2+ and Zn2+ were tested and all were found to be inhibitory towards both CAPP and basal phosphatase activities. By contrast, Cs+ and Li+ had almost no effect on CAPP, although both stimulated basal phosphatase activity." [Abstract]

I Tawara, M Nishikawa, K Morita, K Kobayashi, H Toyoda, SB Omay, H Shima, M Nagao, T Kuno, and C Tanaka
Down-regulation by retinoic acid of the catalytic subunit of protein phosphatase type 2A during granulocytic differentiation of HL-60 cells.
FEBS Lett, Apr 1993; 321(2-3): 224-8.
"The decreased phosphatase activity may be mainly due to a decrease in the expression of the PP2A protein. The mRNA level of PP2A beta was markedly decreased within 5 h after addition of ATRA, but there was only a slight increase in the mRNA level of PP2A alpha. Selective down-regulation of PP2A beta mRNA clearly preceded the cell differentiation induced by ATRA treatment. Thus, PP2A is down-regulated during ATRA-induced differentiation of HL-60 cells into granulocytes." [Abstract]

Ruvolo PP, Clark W, Mumby M, Gao F, May WS.
A functional role for the B56 alpha-subunit of protein phosphatase 2A in ceramide-mediated regulation of Bcl2 phosphorylation status and function.
J Biol Chem 2002 Jun 21;277(25):22847-52
"Recently it has been shown that the potent apoptotic agent ceramide activates a mitochondrial protein phosphatase 2A (PP2A) and promotes dephosphorylation of the anti-apoptotic molecule Bcl2 (Ruvolo, P. P., Deng, X., Ito, T., Carr, B. K., and May, W. S. (1999) J. Biol. Chem. 274, 20296-20300). In cells expressing Bcl2, dephosphorylation of Bcl2 appears to be required for ceramide-induced cell death because treatment of cells with low doses of the PP2A inhibitor okadaic acid blocks Bcl2 dephosphorylation and promotes cell survival."

Dimmeler, Stefanie, Breitschopf, Kristin, Haendeler, Judith, Zeiher, Andreas M.
Dephosphorylation Targets Bcl-2 for Ubiquitin-dependent Degradation: A Link between the Apoptosome and the Proteasome Pathway
J. Exp. Med. 1999 189: 1815-1822
"Finally, inhibition of Bcl-2 degradation either by suppressing ubiquitin-dependent proteasomal degradation or by mimicking continuous phosphorylation of the putative MAP kinase sites in the Bcl-2 protein confers resistance against induction of apoptosis." [Full Text]

Jiandi Zhang, Nejemie Alter, John C. Reed, Christoph Borner, Lina M. Obeid, and Yusuf A. Hannun
Bcl-2 interrupts the ceramide-mediated pathway of cell death
PNAS 93: 5325-5328, May 1996.
"Overexpression of bcl-2 prevented apoptosis in response to ceramide, suggesting that bcl-2 acts at a point downstream of ceramide." [Abstract/Full Text]

M Lam, G Dubyak, L Chen, G Nunez, RL Miesfeld, and CW Distelhorst
Evidence that BCL-2 Represses Apoptosis by Regulating Endoplasmic Reticulum-Associated Ca2+ Fluxes
PNAS 91: 6569-6573, 1994.
"By reducing ER Ca2+ efflux, BCL-2 interfered with a signal for "capacitative" entry of extracellular Ca2+, preventing a sustained increase of cytosolic Ca2+ in TG-treated cells. These findings suggest that BCL-2 either directly or indirectly regulates the flux of Ca2+ across the ER membrane, thereby abrogating Ca2+ signaling of apoptosis." [Article]

Peter P. Ruvolo, Xingming Deng, Boyd K. Carr, and W. Stratford May
A Functional Role for Mitochondrial Protein Kinase C in Bcl2 Phosphorylation and Suppression of Apoptosis
J. Biol. Chem. 273: 25436-25442, September 1998.
"Thus, if it can be demonstrated that the chemotherapy-resistant leukemic cells also contain relatively high levels of mitochondrial PKC alpha and phosphorylated Bcl2, one novel therapeutic strategy for translational research might involve the selective inhibition of PKC alpha and blockade of Bcl2 phosphorylation prior to institution of induction-remission chemotherapy."
[Full Text]

Bosetti F, Seemann R, Rapoport SI.
Chronic lithium chloride administration to rats decreases brain protein level of epsilon (epsilon) subunit of eukaryotic initiation factor-2B.
Neurosci Lett 2002 Jul 12;327(1):71-3
"The eukaryotic initiation factor-2B (eIF-2B) can regulate translation and protein synthesis. We used Western blot analysis to quantify the protein level of the catalytic epsilon (epsilon) subunit of eIF-2B in brains of rats fed lithium chloride (LiCl) for 6 weeks so as to produce a brain lithium concentration that is therapeutically effective in bipolar disorder. The ratio of eIF-2B (epsilon) to actin protein was significantly reduced (P<0.01) in LiCl-fed rats, 0.86+/-0.06 (SE) compared to 1.2+/-0.07 in control rats. These results suggest that a therapeutic level of lithium may downregulate the synthesis of proteins whose translation depends on eIF-2B." [Abstract]

Xingming Deng, Lei Xiao, Wenhua Lang, Fengqin Gao, Peter Ruvolo, and W. Stratford May, Jr.
Novel Role for JNK as a Stress-activated Bcl2 Kinase
J. Biol. Chem. 276: 23681-23688, June 2001.
Furthermore, low dose okadaic acid (OA), a potent protein phosphatase 1 and 2A inhibitor, can activate the mitogen-activated protein kinases JNK1 and ERK1/2, but not p38 kinase, to induce Bcl2 phosphorylation and prolong cell survival in factor-deprived cells. [Full Text]

Bosetti F, Rintala J, Seemann R, Rosenberger TA, Contreras MA, Rapoport SI, Chang MC.
Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E(2) concentration in rat brain.
Mol Psychiatry 2002;7(8):845-50
"Rats treated with lithium chloride for 6 weeks have been reported to demonstrate reduced turnover of arachidonic acid (AA) in brain phospholipids, and decreases in mRNA and protein levels, and enzyme activity, of AA-selective cytosolic phospholipase A(2)(cPLA(2)). We now report that chronic lithium administration to rats significantly reduced the brain protein level and enzyme activity of cyclooxygenase-2 (COX-2), without affecting COX-2 mRNA. Lithium also reduced the brain concentration of prostaglandin E(2) (PGE(2)), a bioactive product of AA formed via the COX reaction. COX-1 and the Ca(2+)-independent iPLA(2) (type VI) were unaffected by lithium. These and prior results indicate that lithium targets a part of the AA cascade that involves cPLA(2) and COX-2. This effect may contribute to lithium's therapeutic action in bipolar disorder."

Chang MC, Contreras MA, Rosenberger TA, Rintala JJ, Bell JM, Rapoport SI.
Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizers.
J Neurochem 2001 May;77(3):796-803
"Both (Li(+)) and valproic acid (VPA) are effective in treating bipolar disorder, but the pathway by which either works, and whether it is common to both drugs, is not agreed upon. We recently reported, using an in vivo fatty acid model, that Li(+) reduces the turnover rate of the second messenger arachidonic acid (AA) by 80% in brain phospholipids of the awake rat, without changing turnover rates of docosahexaenoic or palmitic acid. Reduced AA turnover was accompanied by down-regulation of gene expression and protein levels of an AA-specific cytosolic phospholipase A(2) (cPLA(2)). To see if VPA had the same effect on AA turnover, we used our in vivo fatty acid model in rats chronically administered VPA (200 mg/kg, i.p. for 30 days). Like Li(+), VPA treatment significantly decreased AA turnover within brain phospholipids (by 28-33%), although it had no effect on cPLA(2) protein levels. Thus, both mood stabilizers, Li(+) and VPA have a common action in reducing AA turnover in brain phospholipids, albeit by different mechanisms." [Abstract]

Weerasinghe GR, Seemann R, Rapoport SI, Bosetti F.
Lithium chloride, administered chronically to rats, does not affect the fractional phosphorylation of brain cytosolic phospholipase A(2), while reducing its net protein level.
Brain Res Bull 2003 Jan 15;59(4):303-6
"Lithium, used to treat bipolar disorder, has been reported to decrease rat brain mRNA and protein levels of cytosolic phospholipase A(2) (cPLA(2)), an enzyme that selectively hydrolyzes arachidonic acid from the stereospecifically numbered (sn)-2 position of membrane phospholipids, and to decrease PLA(2) activity. cPLA(2) can be activated by being phosphorylated at its Ser-228, Ser-505, and Ser-727 sites. In this study, we show that the percent phosphorylated cPLA(2) protein in rat brain is unaffected by lithium. Male Fischer-344 rats were fed lithium chloride for 6 weeks, so as to produce a therapeutically equivalent brain lithium concentration; control rats were fed lithium-free chow under parallel conditions. cPLA(2) was immunoprecipitated from brain homogenate and phosphorylated cPLA(2) protein was quantified using an anti-phosphoserine antibody, and compared to net cPLA(2) protein. The mean ratio of phosphorylated/total cPLA(2) was not changed significantly in the lithium-treated compared to the control group. Thus, decreased brain PLA(2) enzyme activity caused by chronic lithium is likely a consequence only of lithium's downregulation of cPLA(2) transcription." [Abstract]

Giroux, Melanie, Descoteaux, Albert
Cyclooxygenase-2 Expression in Macrophages: Modulation by Protein Kinase C-{alpha}
J Immunol 2000 165: 3985-3991 [Full Text]

Wang, Hui Qin, Kim, Michael P., Tiano, Howard F., Langenbach, Robert, Smart, Robert C.
Protein Kinase C-{alpha} Coordinately Regulates Cytosolic Phospholipase A2 Activity and the Expression of Cyclooxygenase-2 through Different Mechanisms in Mouse Keratinocytes
Mol Pharmacol 2001 59: 860-866 [Full Text]

Subbaramaiah, Kotha, Cole, Philip A., Dannenberg, Andrew J.
Retinoids and Carnosol Suppress Cyclooxygenase-2 Transcription by CREB-binding Protein/p300-dependent and -independent Mechanisms
Cancer Res 2002 62: 2522-2530
"Treatment with retinoic acid (RA) or carnosol, two structurally unrelated compounds with anticancerproperties, inhibited phorbol ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. The induction of COX-2 transcription by PMA was mediated by increased binding of AP-1 to the cyclic AMP response element (CRE) of the COX-2 promoter. Inhibition of the histone acetyltransferase activity of CREB- binding protein (CBP)/p300 blocked the induction of COX-2 by PMA. Treatment with carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter. Because AP-1 binding was unaffected by RA, we investigated whether RA inhibited COX-2 transcription via effects on the coactivator CBP/p300. Treatment with RA stimulated an interaction between RA receptor-alpha and CBP/p300; a corresponding decrease in the interaction between CBP/p300 and c-Jun was observed. Importantly, overexpressing CBP/p300 or dominant-negative RA receptor-alpha relieved the suppressive effect of RA on PMA-mediated stimulation of the COX-2 promoter. To elucidate the mechanism by which carnosol inhibited COX-2 transcription, its effects on protein kinase C (PKC) signaling were determined. Carnosol but not RA inhibited the activation of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase. Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of carnosol on PMA-mediated stimulation of COX-2 promoter activity. Thus, RA acted by a receptor-dependent mechanism to limit the amount of CBP/p300 that was available for AP-1-mediated induction of COX-2. By contrast, carnosol inhibited the induction of COX-2 by blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter. Taken together, these results show that small molecules can block the activation of COX-2 transcription by distinct mechanisms." [Abstract]

Qihe Xu, Tsuneo Konta, Akira Furusu, Kenji Nakayama, Javier Lucio-Cazana, Leon G. Fine, and Masanori Kitamura
Transcriptional induction of MKP-1 by retinoids: Selective roles of nuclear receptors and contribution to the anti-apoptotic effect
JBC Papers in Press published on August 16, 2002 as 10.1074/jbc.M207095200
"Among the three RAR subtypes, RARalpha and RARgamma, but not RARbeta, mediated the t-RA-induced MKP-1 expression. The anti-apoptotic effect of t-RA on H2O2-induced apoptosis in several cell types was correlated with the inducibility of MKP-1 by t-RA. Inhibition of MKP-1 by vanadate enhanced JNK phosphorylation and attenuated the anti-apoptotic effect of t-RA. Furthermore, over-expression of MKP-1 inhibited H2O2-induced JNK phosphorylation and apoptosis." [Abstract/Full Text]

Schroer K, Zhu Y, Saunders MA, Deng WG, Xu XM, Meyer-Kirchrath J, Wu KK.
Obligatory role of cyclic adenosine monophosphate response element in cyclooxygenase-2 promoter induction and feedback regulation by inflammatory mediators.
Circulation 2002 Jun 11;105(23):2760-5
"CREB-2 and c-Fos binding was increased by phorbol 12-myristate 13-acetate but not tumor necrosis factor-alpha. The binding assay and chromatin immunoprecipitation revealed binding of P300 coactivator to the COX-2 promoter region. CONCLUSIONS: CRE plays an obligatory role in COX-2 promoter activation by diverse stimuli. CREB-2 and ATF-2 bound to CRE serve as an anchor for P300 interaction with upstream transactivators and downstream transcription machinery." [Abstract]

Zoltán H. Németh, Edwin A. Deitch, Csaba Szabó, Zoltán Fekete, Carl J. Hauser, and György Haskó
Lithium Induces NF-kappaB Activation and Interleukin-8 Production in Human Intestinal Epithelial Cells
J. Biol. Chem. 277: 7713-7719, March 8, 2002.
"Incubation of human intestinal epithelial cells with lithium induced both enhanced NF-kappaB DNA binding and NF-kappaB-dependent transcriptional activity. In addition, lithium stimulated activation of both the p38 and p42/44 MAP kinases." [Abstract]

Maria Torcia, Giovanna De Chiara, Lucia Nencioni, Serena Ammendola, Danilo Labardi, Maria Lucibello, Paolo Rosini, Lionel N. J. L. Marlier, Paolo Bonini, Persio Dello Sbarba, Anna Teresa Palamara, Nicola Zambrano, Tommaso Russo, Enrico Garaci, and Federico Cozzolino
Nerve Growth Factor Inhibits Apoptosis in Memory B Lymphocytes via Inactivation of p38 MAPK, Prevention of Bcl-2 Phosphorylation, and Cytochrome c Release
J. Biol. Chem. 276: 39027-39036, October 2001. [Full Text]

Hedgepeth CM, Conrad LJ, Zhang J, Huang HC, Lee VM, Klein PS.
Activation of the Wnt signaling pathway: a molecular mechanism for lithium action.
Dev Biol 1997 May 1;185(1):82-91
"Using a novel assay for GSK-3 beta in oocytes, we show that lithium inhibits GSK-3 beta from species as diverse as Dictyostelium discoideum and Xenopus laevis, providing a biochemical mechanism for the action of lithium on the development of these organisms. Lithium treatment also leads to activation of an AP-1-luciferase reporter in Xenopus embryos, consistent with previous observations that GSK-3 beta inhibits c-jun activity. Activation of the wnt pathway with a dominant negative form of GSK-3 beta is inhibited by myo-inositol, similar to the previously described effect of coinjecting myo-inositol with lithium. The mechanism by which myo-inositol inhibits both dominant negative GSK-3 beta and lithium remains uncertain." [Abstract]

Ren-Wu Chen, and De-Maw Chuang
Long Term Lithium Treatment Suppresses p53 and Bax Expression but Increases Bcl-2 Expression. A PROMINENT ROLE IN NEUROPROTECTION AGAINST EXCITOTOXICITY
J. Biol. Chem. 274: 6039-6042, March 1999. [Full Text]

Scotto, Christian, Delphin, Christian, Deloulme, Jean Christophe, Baudier, Jacques
Concerted Regulation of Wild-Type p53 Nuclear Accumulation and Activation by S100B and Calcium-Dependent Protein Kinase C
Mol. Cell. Biol. 1999 19: 7168-7180 [Full Text]

Mora, Alfonso, Sabio, Guadalupe, Gonzalez-Polo, Rosa A., Cuenda, Ana, Alessi, Dario R., Alonso, Juan C., Fuentes, Jose M., Soler, German, Centeno, Francisco
Lithium inhibits caspase 3 activation and dephosphorylation of PKB and GSK3 induced by K+ deprivation in cerebellar granule cells
J Neurochem 2001 78: 199-206
"As lithium did not inhibit caspase 3 activity in vitro, these results suggest that this ion inhibits an upstream component that is required for caspase 3 activation."

King TD, Bijur GN, Jope RS.
Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3beta and attenuated by lithium.
Brain Res 2001 Nov 16;919(1):106-14 [Abstract]

Ghribi O, Herman MM, Spaulding NK, Savory J.
Lithium inhibits aluminum-induced apoptosis in rabbit hippocampus, by preventing cytochrome c translocation, Bcl-2 decrease, Bax elevation and caspase-3 activation.
J Neurochem 2002 Jul;82(1):137-45 [Abstract]

Wang HY, Friedman E.
Lithium inhibition of protein kinase C activation-induced serotonin release.
Psychopharmacology (Berl) 1989;99(2):213-8
"In parietal cortical slices, PMA elicited increase in K+-evoked [3H]NE release was prevented in slices taken from lithium-treated (3 weeks) animals. Lithium treatment did not affect the activity and distribution of protein kinase C in cortical tissue. However, 3 weeks of treatment reduced the PMA-induced translocation of the enzyme. These results suggest that lithium treatment interferes with serotonin and norepinephrine release facilitation which results from the stimulation of PKC by phorbol esters. These actions of the ion may be mediated by its ability to inhibit PMA induced PKC translocation." [Abstract]

Shaldubina A, Agam G, Belmaker RH.
The mechanism of lithium action: state of the art, ten years later.
Prog Neuropsychopharmacol Biol Psychiatry 2001 May;25(4):855-66
"Inhibition of 5HT autoreceptors by lithium is supported by biochemical and behavioral data in rats but would seem more related to lithium's antidepressant than to its antimanic or prophylactic effects. Lithium induces increases in levels of the anti-apoptotic factor Bcl-2. This effect could be most relevant for treatment of neurodegenerative disorders. Lithium inhibits glycogen synthase kinase-3, which is involved in a wide range of signal transduction pathways. However, this lithium effect occurs at high concentrations and may be more relevant for its toxic effect." [Abstract]

Chen, G, Yuan, PX, Jiang, YM, Huang, LD, Manji, HK
Lithium increases tyrosine hydroxylase levels both in vivo and in vitro
J Neurochem 1998 70: 1768-1771 [Abstract]

Kumer, SC, Vrana, KE
Intricate regulation of tyrosine hydroxylase activity and gene expression
J Neurochem 1996 67: 443-462 [Abstract]

Kim SJ, Im DS, Kim SH, Ryu JH, Hwang SG, Seong JK, Chun CH, Chun JS.
Beta-catenin regulates expression of cyclooxygenase-2 in articular chondrocytes.
Biochem Biophys Res Commun 2002 Aug 9;296(1):221-6
"Inhibition of beta-catenin degradation by the treatment of cells with LiCl or proteasome inhibitor stimulated expression of COX-2, indicating that transcriptionally active beta-catenin is sufficient to induce COX-2 expression. This was demonstrated further by the observation that ectopic expression of transcriptionally competent beta-catenin stimulated expression of COX-2." [Abstract]

Li, X, Jope, RS
Selective inhibition of the expression of signal transduction proteins by lithium in nerve growth factor-differentiated PC12 cells
J Neurochem 1995 65: 2500-2508
"This investigation examined if lithium, the primary therapeutic treatment for bipolar affective disorder, modulated the levels of selected signal transduction proteins in PC12 cells. Nerve growth factor (NGF) induced differentiation of PC12 cells, and after 12 days of NGF treatment there were large increases in the levels of the heterotrimeric G protein subunits alpha o1, alpha i1, beta, and alpha s, small increases in those of alpha i2 and alpha q, and a slight decrease in that of alpha o2. Lithium (1 mM, equivalent to the therapeutic concentration) selectively reduced NGF-induced increases in levels of G protein subunits, generally having the greatest inhibition on those that were increased the most by NGF. Lithium at 5 mM had greater inhibitory effects than 1 mM lithium on NGF-induced increases in levels of G proteins, but neither concentration of lithium affected the induction of the cytoskeletal protein beta-tubulin. Examination of other proteins involved in signal transduction revealed that 12 days of NGF treatment increased the level of protein kinase C-alpha, but not those of the beta, epsilon, or zeta subtypes, and did not alter the levels of beta, gamma, or delta phospholipase C. Pretreatment with lithium inhibited the increase in content of protein kinase C-alpha induced by NGF but had little effect on the proteins not responsive to NGF except for decreasing the levels of protein kinase C-epsilon. The inhibitory effect of lithium was found not to be due to inhibition of NGF-induced tyrosine phosphorylation, which was unaffected by 5 mM lithium, or to inositol depletion. In summary, use of the dynamic system of NGF-induced PC12 cell differentiation provided a sensitive model in which to identify signal transduction proteins that were influenced by lithium treatment. The large changes caused by a therapeutically equivalent concentration of lithium lend support to the proposal that the selective inhibitory effects of lithium on subtypes of G proteins and protein kinase C may be important therapeutic targets." [Abstract]

Peter Schotte, Geert Van Loo, Isabelle Carpentier, Peter Vandenabeele, and Rudi Beyaert
Lithium Sensitizes Tumor Cells in an NF-kappaB-independent Way to Caspase Activation and Apoptosis Induced by Tumor Necrosis Factor (TNF). EVIDENCE FOR A ROLE OF THE TNF RECEPTOR-ASSOCIATED DEATH DOMAIN PROTEIN
J. Biol. Chem. 276: 25939-25945, July 2001.
"So far, the underlying mechanism for TNF/lithium synergism is still unclear." [Full Text]

Natalie J. Avdi, Malcolm, Kenneth C, Nick, Jerry A, and G. Scott Worthen
p38 mitogen-activated protein kinase-mediated regulation of the c-Jun NH2 terminal kinase pathway in human neutrophils: A role for PP2A
JBC Papers in Press published on August 16, 2002 as 10.1074/jbc.M204455200
The studies described here demonstrate functional crosstalk between the p38 and JNK pathways in TNF alpha-stimulated neutrophils, whereby p38 MAPk acts to limit the activation of JNK by PP2A-mediated inhibition of MKK4 (Fig. 10)." [Abstract/Full Text]

Zhen X, Torres C, Friedman E.
Lithium regulates protein tyrosine phosphatase activity in vitro and in vivo.
Psychopharmacology (Berl) 2002 Aug;162(4):379-84
"Lithium stimulated protein tyrosine phosphatase (PTPase) activity in a dose- and time-dependent manner in PC12 cells. A maximal stimulation of 87% was observed after 6 h of incubation with 3 mM LiCl. In contrast, protein serine phosphatase (PSPase) activity was not changed by lithium. The stimulatory effect on PTPase was not due to a direct action of the ion on the enzymes, but its selectivity was noted since treatment of cells with other monovalent cations exhibited no effect on PTPase activity. Lithium appeared to target specific PTPase(s) as it stimulated membrane-associated PTPase activity without affecting cytosolic or nuclear enzymatic activities. Moreover, the stimulation of PTPase activity in PC12 cells by lithium is independent of de novo protein synthesis. In the rat, 3 weeks of lithium treatment significantly elevated PTPase activity in hippocampus, striatum and cortex." [Abstract]

Moorman JM, Leslie RA.
Paradoxical effects of lithium on serotonergic receptor function: an immunocytochemical, behavioural and autoradiographic study.
Neuropharmacology 1998;37(3):357-74
"Treatment of rats with chronic lithium significantly enhanced DOI-induced locomotor activity and Fos-like immunoreactivity throughout the cerebral cortex. This elevation in Fos-like immunoreactivity was completely abolished by prior treatment with ritanserin. In contrast, chronic lithium treatment had no effect on the density of [3H]ketanserin binding to 5-HT2A receptors in any brain region examined. The results of the time-course experiment demonstrated that the enhancing effect of lithium on 5-HT2A/2C receptor-mediated Fos expression was short-lived such that Fos-like immunoreactivity returned to untreated levels within 48 h. In the acute lithium experiment, administration of lithium to rats 12 or 24 h before DOI resulted in a similar elevation of Fos-like immunoreactivity to that seen in chronically treated animals. Administration of acute lithium 36 or 48 h before DOI had no effect. The effects of lithium on 5-HT2A/2C receptor function thus appear to be complex. In particular, the results of this study indicate that the enhancing effects of lithium on DOI-induced locomotor activity and Fos-like immunoreactivity are not accompanied by any alteration in the density of 5-HT2A receptor binding sites. If changes in receptor numbers therefore do not account for the physiological effect of chronic lithium, other explanations must be sought. The study also suggests that the inositol depletion hypothesis of lithium's therapeutic action does not adequately explain the mechanism of action of lithium in man." [Abstract]

Lopez-Coronado JM, Belles JM, Lesage F, Serrano R, Rodriguez PL.
A novel mammalian lithium-sensitive enzyme with a dual enzymatic activity, 3'-phosphoadenosine 5'-phosphate phosphatase and inositol-polyphosphate 1-phosphatase.
J Biol Chem 1999 Jun 4;274(23):16034-9
"We report the molecular cloning in Rattus norvegicus of a novel mammalian enzyme (RnPIP), which shows both 3'-phosphoadenosine 5'-phosphate (PAP) phosphatase and inositol-polyphosphate 1-phosphatase activities. This enzyme is the first PAP phosphatase characterized at the molecular level in mammals, and it represents the first member of a novel family of dual specificity enzymes. The phosphatase activity is strictly dependent on Mg2+, and it is inhibited by Ca2+ and Li+ ions. Lithium chloride inhibits the hydrolysis of both PAP and inositol-1,4-bisphosphate at submillimolar concentration; therefore, it is possible that the inhibition of the human homologue of RnPIP by lithium ions is related to the pharmacological action of lithium." [Full Text]

Patel S, Yenush L, Rodriguez PL, Serrano R, Blundell TL.
Crystal structure of an enzyme displaying both inositol-polyphosphate-1-phosphatase and 3'-phosphoadenosine-5'-phosphate phosphatase activities: a novel target of lithium therapy.
J Mol Biol. 2002 Jan 25;315(4):677-85.
"Lithium cations exert profound and selective psychopharmacological effects on ameliorate manic-depressive psychosis. Although lithium is an effective drug for both treatment and prophylaxis of bipolar disorder, the precise mechanism of action is not well understood. Lithium acts as both an uncompetitive and non-competitive inhibitor of several lithium- sensitive phosphatases with regard to substrate and magnesium cofactor, respectively. In this work, we report the crystal structure and reaction mechanism of Rattus norvegicus 3'-phosphoadenosine 5'-phosphate and inositol 1,4-bisphosphate phosphatase (RnPIP), a recently identified target of lithium therapy. This Li(+)-sensitive enzyme plays a crucial role in several cellular processes, such as RNA processing, sulphation reactions and probably inositol recycling. RnPIP specifically removes the 3'-phosphate group of 3'-phosphoadenosine 5'-phosphate (PAP) and the 1'-phosphate group of inositol 1,4-bisphosphate (I(1),(4)P(2)) producing AMP and inositol 4'-phosphate, respectively. The crystal structure of RnPIP complexed with AMP, Pi and magnesium ions at 1.69 A resolution provides insight into the reaction mechanism of the hydrolysis of PAP. The core fold of the enzyme is equivalent to that found in other Li(+)-sensitive phosphatases, such as inositol monophosphatase, but molecular modelling of I(1),(4)P(2) in the RnPIP active site reveals important structural determinants that accommodate this additional substrate. RnPIP is potently inhibited by lithium and, as the accumulation of PAP inhibits a variety of proteins, including sulphotransferases and RNA processing enzymes, this dual specificity enzyme represents a potential target of lithium action, in addition to inositol monophosphatases." [Abstract]

Agam G, Shaltiel G.
Possible role of 3'(2')-phosphoadenosine-5'-phosphate phosphatase in the etiology and therapy of bipolar disorder.
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Aug;27(5):723-7.
"Bipolar affective disorder (BPD) is a multifactorial, severe, chronic and disabling illness with 50% heritability that affects 1-2% of the population. Lithium ions (Li) are the drug of choice for BPD. Yet, 20-40% of patients fail to respond to Li. Although numerous biochemical and cellular effects have been attributed to Li, its therapeutic mechanism of action has not been elucidated. This review presents the possible involvement of 3'(2')-phosphoadenosine-5'-phosphate (PAP) phosphatase in the etiology of bipolar disorder and the mechanism of action of Li. Of the enzymes inhibited by Li, PAP phosphatase is inhibited with the lowest Ki (0.3 mM). At therapeutic concentrations of Li (0.5-1.5 mM), inhibition is greater than 80%. Therefore, PAP phosphatase is a strong candidate for Li's therapeutic mechanism of action. In yeast, a PAP phosphatase knockout mutation leads to the accumulation of PAP, which affects ribosomal-, transfer- and small nucleolar-RNA processing. PAP accumulation in the mammalian brain following Li inhibition of PAP phosphatase may very well account for the observed effects of Li on gene expression and behavior. Furthermore, we have reported significant changes in PAP phosphatase levels in postmortem frontal cortex of bipolar patients." [Abstract]

Agam G, Shatiel G, Kozlovsky N, Shimon H, Belmaker RH.
Lithium inhibitable enzymes in postmortem brain of bipolar patients.
J Psychiatr Res. 2003 Sep-Oct;37(5):433-42.
"Despite considerable ongoing efforts at the epidemiological, genetic and molecular level, the etiology of bipolar disorder had not yet been elucidated. To study possible contributing components to the pathophysiology of this disorder, we have hypothesized that levels of enzymes inhibited by therapeutically relevant lithium ion concentrations in the brain of patients may differ from those in normal controls and may be involved in the etiology of the disorder. Three Li-inhibitable enzymes were studied in postmortem brain samples of bipolar patients and normal controls. The expression and function of the two enzymes that are obviously involved in signaling cascades, IMPase, involved in the second messenger system of the phosphatidylinositol cycle, and GSK-3, a mediator of an array of signaling cascades, were not found to be different in postmortem frontal and occipital cortex of bipolar patients and normal controls. Only PAP phosphatase protein levels, but not its mRNA levels or enzymatic activity, were found to be significantly decreased in frontal cortex of bipolar patients compared with normal controls." [Abstract]

Gould TD, Chen G, Manji HK.
In Vivo Evidence in the Brain for Lithium Inhibition of Glycogen Synthase Kinase-3.
Neuropsychopharmacology. 2003 Aug 27 [Epub ahead of print].
"There is considerable interest in the possibility that small-molecule glycogen synthase kinase-3 inhibitors may have utility in the treatment of bipolar disorder, since glycogen synthase kinase-3 is a target of lithium. Although the in vitro inhibition of glycogen synthase kinase-3 by lithium occurs with a K(i) of 1-2 mM, the degree of inhibition of this enzyme in the mammalian brain at therapeutically relevant concentrations has not fully been established. The transcription factor beta-catenin is an established marker of glycogen synthase kinase-3 inactivation because cytoplasmic levels are increased by inhibition of the enzyme. In this study, we measured beta-catenin protein levels after treatment with therapeutically relevant doses of lithium, valproate, and carbamazepine. Western blot revealed that 9 days of treatment with lithium and valproate, but not carbamazepine, increased beta-catenin protein levels in soluble fractions from the frontal cortex. The level of beta-catenin in the particulate fraction, which is not directly regulated by glycogen synthase kinase-3, did not change with any of the three drugs. Furthermore, real-time PCR revealed that lithium significantly decreased beta-catenin mRNA levels, which may represent compensation for an increase in beta-catenin stability. These results strongly suggest that lithium significantly inhibits brain glycogen synthase kinase-3 in vivo at concentrations relevant for the treatment of bipolar disorder." [Abstract]

Vreugdenhil M, Wadman WJ.
Modulation of sodium currents in rat CA1 neurons by carbamazepine and valproate after kindling epileptogenesis.
Epilepsia 1999 Nov;40(11):1512-22
"PURPOSE: To determine the modulation of sodium currents in hippocampal CA1 neurons by carbamazepine (CBZ) and valproate (VPA), before and after kindling epileptogenesis. METHODS: Voltage-dependent sodium current was measured in isolated hippocampal CA1 neurons, by using the whole-cell voltage-clamp technique. CBZ (15-100 microM) or VPA (0.5-5 mM) was applied by bath perfusion. Cells from fully kindled rats were compared with controls, 1 day and 5 weeks after the tenth generalized seizure. RESULTS: CBZ did not affect sodium current activation but selectively shifted the voltage dependence of steady-state inactivation to more hyperpolarized potentials. One day after the last kindled generalized seizure, the shift induced by 15 microM CBZ was 2.1+/-0.5 mV (mean +/- SEM; n = 20) compared with 4.3+/-0.3 mV (n = 16; p<0.001) in matched controls. The EC50 of the concentration-effect relation was 57+/-6 microM compared with 34+/-2 microM (p<0.01) in controls. Five weeks after kindling, these values had recovered to a level not different from control. VPA induces at a relatively high concentration a similar but smaller shift in voltage dependence of inactivation than does CBZ. After kindling, the shift induced by 2 mM VPA (2.8+/-0.6 mV; n = 19) was not different from controls (3.0+/-0.5 mV; n = 22). The EC50 for VPA was 2.6+/-0.3 mM compared with 2.5+/-0.4 mM in controls. CONCLUSIONS: Both CBZ and VPA selectively modulate the voltage dependence of sodium current steady-state inactivation and as a consequence reduce cellular excitability. The effect of CBZ was reduced immediately after kindling epileptogenesis, apparently by a reduced affinity of its receptor. In contrast, the shift induced by VPA was not different at any stage after kindling epileptogenesis. The change in CBZ sensitivity after kindling is related to epileptic activity rather than to the epileptic state, because it almost completely recovers in a period without seizures." [Abstract]

Yatham, Lakshmi N., Liddle, Peter F., Lam, Raymond W., Shiah, I-Shin, Lane, Carol, Stoessl, A. Jon, Sossi, Vesna, Ruth, Thomas J.
PET Study of the Effects of Valproate on Dopamine D2 Receptors in Neuroleptic- and Mood-Stabilizer-Naive Patients With Nonpsychotic Mania
Am J Psychiatry 2002 159: 1718-1723
"OBJECTIVE: A previous study reported a higher than normal density of dopamine D2 receptors in psychotic mania but not in nonpsychotic mania. The purpose of this study was to further examine D2 receptor density in a larger sample of nonpsychotic manic patients by using positron emission tomography (PET) and [11C]raclopride. METHOD: Thirteen neuroleptic- and mood- stabilizer-naive patients with DSM-IV mania without psychotic features and 14 healthy comparison subjects underwent [11C]raclopride PET scans. Of the 13 patients, 10 were treated with divalproex sodium monotherapy. PET scans were repeated 2–6 weeks after commencement of divalproex sodium. D2 receptor binding potential was calculated by using a ratio method with the cerebellum as the reference region. RESULTS: The [11C]raclopride D2 binding potential was not significantly different in manic patients than in the comparison subjects in the striatum. Treatment with divalproex sodium had no significant effect on the [11C]raclopride D2 binding potential in manic patients. There was no correlation between the D2 binding potential and manic symptoms before or after treatment. CONCLUSIONS: These results suggest that D2 receptor density is not altered in nonpsychotic mania and that divalproex sodium treatment does not affect D2 receptor availability." [Abstract]

V Asghari, JF Wang, JS Reiach, and LT Young
Differential effects of mood stabilizers on Fos/Jun proteins and AP-1 DNA binding activity in human neuroblastoma SH-SY5Y cells.
Brain Res Mol Brain Res, Jul 1998; 58(1-2): 95-102.
"At therapeutically relevant concentrations, both drugs acutely (<24 h) induced c-Fos immunoreactivity and AP-1 binding. In contrast to lithium, chronic (1 week) treatment with VPA led to continued induction of c-Fos, in addition to induction of c-Jun immunoreactivity and a 33-35 kDa band previously identified as chronic FRA. AP-1 DNA binding activity was also increased after 1 week VPA treatment. These findings suggest that both these mood stabilizers may have an effect on neuronal gene expression of target genes containing the AP-1 consensus sequence in their promoter regions after acute treatment." [Abstract]

Jin C, Li H, Murata T, Sun K, Horikoshi M, Chiu R, Yokoyama KK.
JDP2, a repressor of AP-1, recruits a histone deacetylase 3 complex to inhibit the retinoic acid-induced differentiation of F9 cells.
Mol Cell Biol 2002 Jul;22(13):4815-26
"Up-regulation of the c-jun gene is a critical event in the retinoic acid (RA)-mediated differentiation of embryonal carcinoma F9 cells. Activating transcription factor 2 (ATF-2) and p300 cooperate in the activation of transcription of the c-jun gene during the differentiation of F9 cells. We show here that the overexpression of Jun dimerization protein 2 (JDP2), a repressor of AP-1, inhibits the transactivation of the c-jun gene by ATF-2 and p300 by recruitment of the histone deacetylase 3 (HDAC3) complex, thereby repressing the RA-induced transcription of the c-jun gene and inhibiting the RA-mediated differentiation of F9 cells. Moreover, chromatin immunoprecipitation assays showed that the JDP2/HDAC3 complex, which binds to the differentiation response element within the c-jun promoter in undifferentiated F9 cells, was replaced by the p300 complex in response to RA, with an accompanying change in the histone acetylation status of the chromatin, the initiation of transcription of the c-jun gene, and the subsequent differentiation of F9 cells. These results suggest that JDP2 may be a key factor that controls the commitment of F9 cells to differentiation and shed new light on the mechanism by which an AP-1 repressor functions." [Abstract]

Christopher J. Phiel, Fang Zhang, Eric Y. Huang, Matthew G. Guenther, Mitchell A. Lazar, and Peter S. Klein
Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen
J. Biol. Chem. 276: 36734-36741, September 2001.
"At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and endogenous promoters. Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription." [Full Text]

Rickard KL, Gibson PR, Wilson NJ, Mariadason JM, Phillips WA.
Short-chain fatty acids reduce expression of specific protein kinase C isoforms in human colonic epithelial cells.
J Cell Physiol 2000 Feb;182(2):222-31
"LIM1215 colon cancer cells were used as a model of human colonic epithelium to examine the effects of butyrate on protein kinase C (PKC) activity and isoform expression. On Western blot analysis, LIM1215 cells express the PKC isoforms alpha, beta, varepsilon, zeta, and lambda, but not gamma, straight theta, or micro. Treatment with 2 mM butyrate for 48 h reduced cellular PKC activity up to 50% and specifically reduced the expression of PKCalpha and PKCvarepsilon. Similar results were obtained using Caco-2 colon cancer cells. These effects were neither a consequence of the induction of differentiation itself nor the result of direct or indirect activation of PKC. Although dependent on gene transcription and protein synthesis, the effect was not due to a reduction in the synthesis of PKC protein. Butyrate's effect was independent of its beta-oxidation but was mimicked, at least in part, by trichostatin A, an inhibitor of histone deacetylase." [Abstract]

Chung, Yih-Lin, Lee, Yan-Hwa Wu, Yen, Sang-Hue, Chi, Kwan-Hwa
A Novel Approach for Nasopharyngeal Carcinoma Treatment Uses Phenylbutyrate as a Protein Kinase C Modulator: Implications for Radiosensitization and EBV-targeted Therapy
Clin Cancer Res 2000 6: 1452-1458
"Sodium phenylbutyrate (NaPB) represent a new non-toxic class of compounds with antiproliferative activities to different tumors and has been shown to modulate many gene expressions by inhibiting histone deacetylation and DNA methylation as the major mechanism. Butyrate and other protein kinase C (PKC) activators have been reported to be able to activate virus enzymes. The present work investigates whether NaPB has an antiproliferative effect or modulatory effects on EBV-associated nasopharyngeal carcinoma (NPC) and whether EBV thymidine kinase gene can be activated to make cells susceptible to ganciclovir (GCV) therapy. NaPB treatment displayed a dose- and time-dependent antiproliferative effect on the NPC cell line CNE2. Cell cycle analysis revealed an inhibitory effect of NaPB on G1-S-phase progression. Shortly after NaPB treatment, we found that PKC activity was activated rapidly but also decreased rapidly. Down-regulation of PKC-alpha and translocation of PKC-alpha from the cytosol to membrane were seen by Western blot. The decrease in PKC activity by NaPB corresponds to an enhanced response to radiation on CEN2 cells. Moreover, NaPB up-regulated EBV thymidine kinase activity to render EBV-associated Daudi cells susceptible to killing by GCV. Based on the observations of NaPB as a PKC modulator, the combination of NaPB, GCV, and radiation may provide a potential novel approach for treatment of EBV-associated NPC." [Full Text]

Chen, Ying, Sharma, Rajiv P., Costa, Robert H., Costa, Erminio, Grayson, Dennis R.
On the epigenetic regulation of the human reelin promoter
Nucl. Acids. Res. 2002 30: 2930-2939
"Retinoic acid (RA)-induced differentiation of NT2 cells to hNT neurons was accompanied by increased reelin expression and by the appearance of three DNase I hypersensitive sites 5' to the RNA start site. RA-induced differentiation was also associated with demethylation of the reelin promoter. To test if methylation silenced reelin expression, we methylated the promoter in vitro prior to transfection. In addition, we treated NT2 cells with the methylation inhibitor aza-2'-deoxycytidine and observed a 60-fold increase in reelin mRNA levels. The histone deacetylase inhibitors trichostatin A (TSA) and valproic acid also induced expression of the endogenous reelin promoter, although TSA was considerably more potent. These findings indicate that one determinant responsible for regulating reelin expression is the methylation status of the promoter. Our data also raise the interesting possibility that the down-regulation of reelin expression documented in psychiatric patients might be the consequence of inappropriate promoter hypermethylation." [Abstract]

Tremolizzo L, Carboni G, Ruzicka WB, Mitchell CP, Sugaya I, Tueting P, Sharma R, Grayson DR, Costa E, Guidotti A.
An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability.
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17095-100. Epub 2002 Dec 12.
"Reelin and glutamic acid decarboxylase (GAD)67 expressed by cortical gamma-aminobutyric acid-ergic interneurons are down-regulated in schizophrenia. Because epidemiological studies of schizophrenia fail to support candidate gene haploinsufficiency of Mendelian origin, we hypothesize that epigenetic mechanisms (i.e., cytosine hypermethylation of CpG islands present in the promoter of these genes) may be responsible for this down-regulation. Protracted l-methionine (6.6 mmolkg for 15 days, twice a day) treatment in mice elicited in brain an increase of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl-methionine, and a marked decrease of reelin and GAD67 mRNAs in both WT and heterozygous reeler mice. This effect of l-methionine was associated with an increase in the number of methylated cytosines in the CpG island of the reelin promoter region. This effect was not observed for GAD65 or neuronal-specific enolase and was not replicated by glycine doses 2-fold greater than those of l-methionine. Prepulse inhibition of startle declined at a faster rate as the prepulsestartle interval increased in mice receiving l-methionine. Valproic acid (2 mmolkg for 15 days, twice a day) reverted l-methionine-induced down-regulation of reelin and GAD67 in both WT and heterozygous reeler mice, suggesting an epigenetic action through the inhibition of histone deacetylases. The same dose of valproate increased acetylation of histone H3 in mouse brain nearly 4-fold. This epigenetic mouse model may be useful in evaluating drug efficacy on schizophrenia vulnerability. Hence the inhibition of histone deacetylases could represent a pharmacological intervention mitigating epigenetically induced vulnerability to schizophrenia in individuals at risk." [Full Text]

Benkoussa M, Brand C, Delmotte MH, Formstecher P, Lefebvre P.
Retinoic acid receptors inhibit AP1 activation by regulating extracellular signal-regulated kinase and CBP recruitment to an AP1-responsive promoter.
Mol Cell Biol 2002 Jul;22(13):4522-34
"Here we show that transcriptional activation of an AP1-regulated gene through the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) pathway (MAPK(ERK)) is characterized, in intact cells, by a switch from a fra2-junD dimer to a junD-fosB dimer loading on its promoter and by simultaneous recruitment of ERKs, CREB-binding protein (CBP), and RNA polymerase II. All-trans-retinoic acid (atRA) receptor (RAR) was tethered constitutively to the AP1 promoter. AP1 transrepression by retinoic acid was concomitant to glycogen synthase kinase 3 activation, negative regulation of junD hyperphosphorylation, and to decreased RNA polymerase II recruitment. Under these conditions, fra1 loading to the AP1 response element was strongly increased. Importantly, CBP and ERKs were excluded from the promoter in the presence of atRA." [Abstract]

Philippe Lefebvre, Arnaud Mouchon, Bruno Lefebvre, and Pierre Formstecher
Binding of Retinoic Acid Receptor Heterodimers to DNA. A ROLE FOR HISTONES NH2 TERMINI
J. Biol. Chem. 273: 12288-12295, May 1998.
"However, histone tails removal by limited proteolysis and histone hyperacetylation yielded nucleosomal RAREs able to bind to hRXR alpha/hRAR alpha heterodimers. These data establish therefore the role of histones NH2 termini as a major impediment to retinoid receptors access to DNA, and identify histone hyperacetylation as a potential physiological regulator of retinoid-induced transcription."
[Full Text]

L Nagy, HY Kao, D Chakravarti, RJ Lin, CA Hassig, DE Ayer, SL Schreiber, and RM Evans
Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase.
Cell, May 1997; 89(3): 373-80.
"The transcriptional corepressors SMRT and N-CoR function as silencing mediators for retinoid and thyroid hormone receptors. Here we show that SMRT and N-CoR directly interact with mSin3A, a corepressor for the Mad-Max heterodimer and a homolog of the yeast global-transcriptional repressor Sin3p. In addition, we demonstrate that the recently characterized histone deacetylase 1 (HDAC1) interacts with Sin3A and SMRT to form a multisubunit repressor complex. Consistent with this model, we find that HDAC inhibitors synergize with retinoic acid to stimulate hormone-responsive genes and differentiation of myeloid leukemia (HL-60) cells. This work establishes a convergence of repression pathways for bHLH-Zip proteins and nuclear receptors and suggests this type of regulation may be more widely conserved than previously suspected."

Marie-Hélène Delmotte, Ali Tahayato, Pierre Formstecher, and Philippe Lefebvre
Serine 157, a Retinoic Acid Receptor Residue Phosphorylated by Protein Kinase C in Vitro, Is Involved in RXR·RAR Heterodimerization and Transcriptional Activity
J. Biol. Chem. 274: 38225-38231, December 1999.
"We demonstrate that PKC isoforms alpha and gamma are able to phosphorylate human RAR alpha (hRAR alpha) in vitro on a single serine residue located in the extended DNA binding domain (T box). The introduction of a negative charge at this position (serine 157) strongly decreased hRAR alpha transcriptional activity, whereas a similar mutation at other PKC consensus phosphorylation sites had no effect. The effect on transcriptional activation was correlated with a decrease in the capacity of hRAR alpha to heterodimerize with hRXR." [Full Text]

Tabata H, Nakajima K.
Neurons tend to stop migration and differentiate along the cortical internal plexiform zones in the Reelin signal-deficient mice.
J Neurosci Res 2002 Sep 15;69(6):723-30
"The Reelin molecule plays a fundamental role in corticogenesis. After Reelin binds to its receptors, the Reelin signal is transduced through tyrosine phosphorylation of the intracellular adaptor protein disabled 1 (Dab1)." [Abstract]

Haas, Carola A., Dudeck, Oliver, Kirsch, Matthias, Huszka, Csaba, Kann, Gunda, Pollak, Stefan, Zentner, Josef, Frotscher, Michael
Role for Reelin in the Development of Granule Cell Dispersion in Temporal Lobe Epilepsy
J. Neurosci. 2002 22: 5797-5802
"The reelin signaling pathway plays a crucial role during the development of laminated structures in the mammalian brain. Reelin, which is synthesized and secreted by Cajal-Retzius cells in the marginal zone of the neocortex and hippocampus, is proposed to act as a stop signal for migrating neurons. Here we show that a decreased expression of reelin mRNA by hippocampal Cajal-Retzius cells correlates with the extent of migration defects in the dentate gyrus of patients with temporal lobe epilepsy. These results suggest that reelin is required for normal neuronal lamination in humans, and that deficient reelin expression may be involved in migration defects associated with temporal lobe epilepsy."

Edwin J. Weeber, Uwe Beffert, Chris Jones, Jill M. Christian, Eckart Förster, J. David Sweatt, and Joachim Herz
Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning
JBC Papers in Press published on August 7, 2002 as 10.1074/jbc.M205147200 [Abstract/Full Text]

Dietze EC, Caldwell LE, Marcom K, Collins SJ, Yee L, Swisshelm K, Hobbs KB, Bean GR, Seewaldt VL.
Retinoids and retinoic acid receptors regulate growth arrest and apoptosis in human mammary epithelial cells and modulate expression of CBP/p300.
Microsc Res Tech 2002 Oct 1;59(1):23-40
"To assess the role of retinoids and RARs in regulating growth arrest and apoptosis in benign and malignant mammary epithelial cells, two model systems were developed: 1) RAR function was suppressed in retinoid-sensitive normal human mammary epithelial cells (HMECs) by the dominant-negative retinoic acid receptor, RARalpha403 (DNRAR), and 2) retinoid-resistant MCF-7 breast cancer cells were transduced with a functional RARbeta2. Inhibition of RAR function by the DNRAR in HMECs resulted in retinoid-resistance, increased proliferation, and dysregulated growth when cells were cultured in reconstituted extracellular matrix (rECM). Expression of RARbeta2 in MCF-7 cells resulted in sensitivity to retinoid-induced growth arrest and apoptosis. The CREB-binding protein (CBP) and the homologous protein p300 are tightly regulated, rate-limiting integrators of diverse signaling pathways and are recruited during retinoid-mediated transcriptional activation. The relationship between retinoid receptor expression, growth regulation, and transcriptional regulation of CBP/p300 is poorly understood. Inhibition of RAR function in HMECs by DNRAR suppressed expression of CBP/p300 and expression of RARbeta2 in MCF-7 cells promoted induction of CBP/p300 when cells were treated with 1.0 &mgr;M all-trans-retinoic acid (ATRA)." [Abstract]

Mora, Alfonso, Gonzalez-Polo, Rosa A., Fuentes, Jose M., Soler, German, Centeno, Francisco
Different mechanisms of protection against apoptosis by valproate and Li+
Eur J Biochem 1999 266: 886-891
"Acute treatment with valproate and Li+ was found to protect cultured cerebellar granule cells against apoptosis induced by low K+ (5 mM). Because the protection was unaffected by MK801 (N-methyl-D-aspartate receptor inhibitor), an increase in glutamate release cannot be responsible for the observed neuroprotection. Insulin also protects against low-K+-induced apoptosis of cerebellar granule cells. This protection is totally dependent on LY294002 (a phosphatidylinositol 3-kinase inhibitor). These results suggest a role for phosphatidylinositol 3-kinase in the neuroprotection induced by insulin. Likewise, and in contrast with the results observed with Li+, the protection induced by valproate is also dependent on insulin and LY294002. Moreover, valproate (a branched-chain fatty acid) does not change the plasma membrane microviscosity under physiological conditions. These results suggest that valproate protects against low-K+-induced apoptosis by acting in the phosphatidylinositol 3-kinase/protein kinase B pathway. The protection by Li+ is independent of this transduction pathway." [Full Text]

De Sarno P, Li X, Jope RS.
Regulation of Akt and glycogen synthase kinase-3beta phosphorylation by sodium valproate and lithium.
Neuropharmacology 2002 Dec;43(7):1158-64
"This study tested if sodium valproate or lithium, two agents used to treat bipolar mood disorder, altered the regulatory phosphorylations of Akt or glycogen synthase kinase-3beta (GSK3beta) in human neuroblastoma SH-SY5Y cells. Treatment with sodium valproate caused a gradual but relatively large increase in the activation-associated phosphorylation of Akt on Ser-473, and a similarly gradual but more modest increase in the inhibition-associated phosphorylation of GSK3beta on Ser-9. Two other inhibitors of histone deacetylase, a recently identified target of sodium valproate, also caused gradual increases in the phosphorylation of Akt and GSK3beta. Lithium treatment increased the Ser-9 phosphorylation of GSK3beta both in cells and in mouse brain after chronic administration, but did not alter the phosphorylation of Akt. These results identify novel effects of sodium valproate on the Akt/GSK3beta signaling pathway, indicating that histone deacetylase inhibition is linked to activation of Akt, and show that two anti-bipolar agents have a common action, the increased inhibitory phosphorylation of Ser-9-GSK3beta. The latter finding, along with previous reports that lithium directly inhibits GSK3beta, reveals the possibly unique situation where a single target, GSK3beta, is inhibited by two independent mechanisms, directly and by phosphorylation following lithium administration, and further, that two mood stabilizers have inhibitory effects on GSK3beta." [Abstract]

Hall AC, Brennan A, Goold RG, Cleverley K, Lucas FR, Gordon-Weeks PR, Salinas PC.
Valproate regulates GSK-3-mediated axonal remodeling and synapsin I clustering in developing neurons.
Mol Cell Neurosci 2002 Jun;20(2):257-70
"Valproate (VPA) and lithium have been used for many years in the treatment of manic depression. However, their mechanisms of action remain poorly understood. Recent studies suggest that lithium and VPA inhibit GSK-3beta, a serine/threonine kinase involved in the insulin and WNT signaling pathways. Inhibition of GSK-3beta by high concentrations of lithium has been shown to mimic WNT-7a signaling by inducing axonal remodeling and clustering of synapsin I in developing neurons. Here we have compared the effect of therapeutic concentrations of lithium and VPA during neuronal maturation. VPA and, to a lesser extent, lithium induce clustering of synapsin I. In addition, lithium and VPA induce similar changes in the morphology of axons by increasing growth cone size, spreading, and branching. More importantly, both mood stabilizers decrease the level of MAP-1B-P, a GSK-3beta-phosphorylated form of MAP-1B in developing neurons, suggesting that therapeutic concentrations of these mood stabilizers inhibit GSK-3beta. In vitro kinase assays show that therapeutic concentrations of VPA do not inhibit GSK-3beta but that therapeutic concentrations of lithium partially inhibit GSK-3beta activity. Our results support the idea that both mood stabilizers inhibit GSK-3beta in developing neurons through different pathways." [Abstract]

Chen, Guang, Huang, Li-Dong, Jiang, Yi-Ming, Manji, Husseini K
The Mood-Stabilizing Agent Valproate Inhibits the Activity of Glycogen Synthase Kinase-3
J Neurochem 2000 72: 1327-1330
"In conclusion, we have demonstrated that VPA, like lithium, exerts significant inhibitory effects on the activity of GSK-3ß both directly in vitro and also on endogenous GSK-3ß in intact human neuroblastoma SY5Y cells. Significant inhibitory effects are clearly observed at concentrations of VPA approximating those attained clinically in the treatment of BD. Furthermore, addition of lithium at therapeutic concentrations results in additive inhibitory effects to that of VPA." [Abstract]

Agam G, Shatiel G, Kozlovsky N, Shimon H, Belmaker RH.
Lithium inhibitable enzymes in postmortem brain of bipolar patients.
J Psychiatr Res. 2003 Sep-Oct;37(5):433-42.
"Despite considerable ongoing efforts at the epidemiological, genetic and molecular level, the etiology of bipolar disorder had not yet been elucidated. To study possible contributing components to the pathophysiology of this disorder, we have hypothesized that levels of enzymes inhibited by therapeutically relevant lithium ion concentrations in the brain of patients may differ from those in normal controls and may be involved in the etiology of the disorder. Three Li-inhibitable enzymes were studied in postmortem brain samples of bipolar patients and normal controls. The expression and function of the two enzymes that are obviously involved in signaling cascades, IMPase, involved in the second messenger system of the phosphatidylinositol cycle, and GSK-3, a mediator of an array of signaling cascades, were not found to be different in postmortem frontal and occipital cortex of bipolar patients and normal controls. Only PAP phosphatase protein levels, but not its mRNA levels or enzymatic activity, were found to be significantly decreased in frontal cortex of bipolar patients compared with normal controls." [Abstract]

Beasley C, Cotter D, Everall I.
An investigation of the Wnt-signalling pathway in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder.
Schizophr Res 2002 Nov 1;58(1):63
"The Wnt-signalling pathway has been implicated in a variety of processes including cortical development and plasticity. We have previously demonstrated a reduction in glycogen synthase kinase-3beta (GSK-3beta) levels in the prefrontal cortex in schizophrenia and aimed to further elucidate the abnormalities of the Wnt-signalling pathway in this and other psychiatric disorders. Immunoblotting was performed to quantify the levels of three members of the Wnt-signalling pathway, GSK-3beta, beta-catenin and dishevelled-2 (Dvl-2), in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder and in matched controls. We found no significant differences between the disease and control groups for any of the proteins studied, and therefore, cannot confirm our earlier findings of abnormalities of GSK-3beta in schizophrenia." [Abstract]

Wolfson M, Bersudsky Y, Zinger E, Simkin M, Belmaker RH, Hertz L.
Chronic treatment of human astrocytoma cells with lithium, carbamazepine or valproic acid decreases inositol uptake at high inositol concentrations but increases it at low inositol concentrations.
Brain Res 2000 Feb 7;855(1):158-61
"Inositol uptake was measured at concentrations of 25, 40 and 50 microM in human astrocytoma cell cultures treated for 1-3 weeks with pharmacologically relevant concentrations of LiCl, valproic acid or carbamazepine as well as in control cultures that had not been treated with any drug. After at least 2 weeks of treatment, each of these 3 conventional anti-bipolar drugs increased the uptake significantly at 25 microM inositol, had no effect at 40 microM, and decreased it at 50 microM inositol. Reduction of the drug concentrations by 50% abolished the stimulation of uptake at 25 microM inositol by lithium and valproic acid and reduced that by carbamazepine. These findings may contribute to an understanding of the mechanisms of action for anti-bipolar medication, and explain the controversy in the literature whether or not brain inositol is reduced after chronic administration of lithium." [Abstract]

Jenab S, Inturrisi CE.
Retinoic acid regulation of mu opioid receptor and c-fos mRNAs and AP-1 DNA binding in SH-SY5Y neuroblastoma cells.
Brain Res Mol Brain Res 2002 Feb 28;99(1):34-9 [Abstract]

Gottlicher, Martin, Minucci, Saverio, Zhu, Ping, Kramer, Oliver H., Schimpf, Annemarie, Giavara, Sabrina, Sleeman, Jonathan P., Lo Coco, Francesco, Nervi, Clara, Pelicci, Pier Giuseppe, Heinzel, Thorsten
Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells
EMBO J. 2001 20: 6969-6978 [Abstract]

Espinos, Estelle, Thai, Agathe Le Van, Pomies, Christelle, Weber, Michel J.
Cooperation between Phosphorylation and Acetylation Processes in Transcriptional Control
Mol. Cell. Biol. 1999 19: 3474-3484 [Full Text]

Vivat-Hannah V, You D, Rizzo C, Daris JP, Lapointe P, Zusi FC, Marinier A, Lorenzi MV, Gottardis MM.
Synergistic cytotoxicity exhibited by combination treatment of selective retinoid ligands with taxol (Paclitaxel).
Cancer Res 2001 Dec 15;61(24):8703-11
"Examination of pathways common to Taxol and retinoid signaling revealed that this synergy was related in part to effects on Bcl-2 expression/phosphorylation as well as the activity of the c-Jun NH(2)-terminal kinase and activator protein-1. In contrast, the tubulin polymerization induced by Taxol was not further affected by cotreatment with a variety of retinoid receptor ligands. These observations indicate that potent RAR alpha/beta selective agonists may be of therapeutic benefit in combination with Taxol therapy." [Abstract]

Chen, Guang, Zeng, Wei-Zhang, Yuan, Pei-Xiong, Huang, Li-Dong, Jiang, Yi-Ming, Zhao, Zhen-Hua, Manji, Husseini K.
The Mood-Stabilizing Agents Lithium and Valproate Robustly Increase the Levels of the Neuroprotective Protein bcl-2 in the CNS
J Neurochem 1999 72: 879-882 [Abstract]

Li R, El-Mallahk RS.
A novel evidence of different mechanisms of lithium and valproate neuroprotective action on human SY5Y neuroblastoma cells: caspase-3 dependency.
Neurosci Lett 2000 Nov 24;294(3):147-50
"Our results suggest that lithium and valproate share a common neuroprotective action against potassium efflux-induced cell apoptosis with different mechanisms." [Abstract]

Mora A, Sabio G, Alonso JC, Soler G, Centeno F.
Different dependence of lithium and valproate on PI3K/PKB pathway.
Bipolar Disord 2002 Jun;4(3):195-200
"These results suggest that VPA protects against low K(+)-induced apoptosis by acting on the PI3K/PKB pathway; however, VPA does not affect the increase of PKB activity caused by insulin in these cells. The protection by Li+ is independent of this transduction pathway. Moreover, Li+ blocks the caspase 3 activation induced by low K+, whereas neither VPA nor insulin affects this activation." [Abstract]

Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA.
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.
Nature 1995 Dec 21-28;378(6559):785-9
"Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase." [Abstract

Burgering BM, Coffer PJ.
Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction.
Nature 1995 Aug 17;376(6541):599-602
"Finally, we show that a constructed Gag-PKB fusion protein, homologous to the v-akt oncogene, displays significantly increased ligand-independent kinase activity. Furthermore, this activity is sufficient to activate the p70 S6-kinase (p70S6K)." [Abstract]

Ding D, Greenberg ML.
Lithium and valproate decrease the membrane phosphatidylinositol/phosphatidylcholine ratio.
Mol Microbiol 2003 Jan;47(2):373-81
"Lithium and valproate, two structurally different anti-bipolar drugs, cause decreased intracellular inositol in the yeast Saccharomyces cerevisiae and an in-crease in expression of a structural (INO1) and a regulatory (INO2) gene for phospholipid synthesis that responds to inositol depletion (Vaden, D., Ding, D., Peterson, B., and Greenberg, M.L., 2001, J Biol Chem 276: 15466-15471). We report here that both drugs decrease the relative rate of membrane phosphatidylinositol synthesis and, to a lesser but still significant degree, the steady state relative phosphatidylinositol composition. In addition, both drugs increase the rate of phosphatidylcholine (PC) synthesis. Finally, valproate, but not lithium, increases expression of phosphatidylcholine pathway genes CHO1 and OPI3. The overall effect on membrane phospholipid composition is a reduction in the phosphatidylinositol/phosphatidylcholine ratio by both drugs. Because maintenance of the appropriate phosphatidylinositol/phosphatidylcholine ratio is required for secretory vesicle formation, a decrease in this ratio may have far-reaching implications for understanding the therapeutic mechanisms of action of these drugs." [Abstract]

Wang, Le, Liu, Xingge, Lenox, Robert H.
Transcriptional down-regulation of MARCKS gene expression in immortalized hippocampal cells by lithium
J Neurochem 2001 79: 816-825 [Abstract]

Watson, David G., Watterson, Jeannette M., Lenox, Robert H.
Sodium Valproate Down-regulates the Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) in Immortalized Hippocampal Cells: A Property of Protein Kinase C-Mediated Mood Stabilizers
J Pharmacol Exp Ther 1998 285: 307-316
"Of particular note, carbamazepine, an anticonvulsant that has also been used in the treatment of mania in patients with bipolar disorder, did not have an effect on MARCKS regulation. It is of interest that carbamazepine has not been shown to be as effective overall as lithium or VPA across clinical studies, particularly in a prophylactic role as a mood stabilizer (Keck et al., 1992), nor has it been approved by the Food and Drug Administration for this application." [Full Text]

John F. Dixon, and Lowell E. Hokin
The antibipolar drug valproate mimics lithium in stimulating glutamate release and inositol 1,4,5-trisphosphate accumulation in brain cortex slices but not accumulation of inositol monophosphates and bisphosphates
PNAS 94: 4757-4760, April 1997.
"Unlike lithium, valproate does not increase accumulation of inositol monophosphates, inositol bisphosphates, or inositol 1,3,4-trisphosphate. This is additional evidence against the "inositol depletion" hypothesis, which states that, by trapping inositol in the form of inositol monophosphates and certain inositol polyphosphates, lithium exerts its antimanic action by inhibiting resynthesis of phosphoinositides with resultant blunting of Ins(1,4,5)P3 signaling."
[Full Text]

Vadnal R, Parthasarathy R.
Myo-inositol monophosphatase: diverse effects of lithium, carbamazepine, and valproate.
Neuropsychopharmacology 1995 Jul;12(4):277-85
"The therapeutic molecular sites of action for the mood-stabilizing medications are unknown. Myo-inositol monophosphatase (E.C. is a major enzyme of the inositol signaling system that has previously been shown to be inhibited by clinically relevant concentrations of lithium, implicating this enzyme as a potential therapeutic site of action in manic-depressive disorder. Inhibition of myo-inositol monophosphatase (IMPase), which converts myo-inositol monophosphates to myo-inositol, results in increased levels of myo-inositol monophosphates and decreased myo-inositol available for the resynthesis of inositol phospholipids. In addition to lithium, carbamazepine and valproate are also used medically to treat manic-depressive disorder. It is of considerable interest to determine whether inhibition of IMPase activity is a common unifying mechanism for mood-stabilizing medications. Using a partially purified myo-inositol monophosphatase preparation derived from bovine brain, we examined the effects of lithium, carbamazepine, and valproate on the IMPase reaction. These results demonstrate that (1) lithium inhibited IMPase activity in the low millimolar range, (2) carbamazepine stimulated the IMPase reaction beginning in the low-micromolar range, and (3) valproate did not demonstrate any stimulation or inhibition of IMPase. We conclude that inhibition of IMPase is not a common neurochemical mechanism for mood-stabilizing medications." [Abstract]

Parthasarathy LK, Seelan RS, Wilson MA, Vadnal RE, Parthasarathy RN.
Regional changes in rat brain inositol monophosphatase 1 (IMPase 1) activity with chronic lithium treatment.
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Feb;27(1):55-60.
"Myo-inositol monophosphatase 1 (IMPase 1) is one of the targets for the mood-stabilizing action of lithium. Inhibition of IMPase is the basis for the "inositol depletion hypothesis" for the molecular action of lithium. To better understand the precise action of chronic (up to 4 weeks) lithium treatment on IMPase 1 activity, we measured IMPase 1 activity using both a colorimetric and a radiometric assay in rats (53-58 days old) fed a diet containing 0.2% lithium carbonate. Our results show that IMPase 1 activity increases substantially in the various brain regions analyzed, even doubling in some regions in the following order, after chronic treatment: hippocampus>cerebellum>striatum>cerebral cortex>brain stem. Both the qualitative and quantitative increases of IMPase 1 activity by chronic lithium treatment were substantiated by Western blot analysis of hippocampal and cerebral cortex regions. We conclude that the increased IMPase 1 activity is an adaptational response to chronic lithium treatment, and may involve direct or indirect stimulation of IMPA1 (which encodes IMPase 1) and/or turnover of the enzyme. The increased enzyme activity may alter critical neurochemical processes involving either free myo-inositol, the precursor of inositol based signaling system or other metabolic pathways, since IMPase 1 also utilizes selective sugar phosphates, such as galactose-1-phosphate, as substrates. One or more of these signal and metabolic pathways may be associated with lithium's psychotherapeutic mood-stabilizing action." [Abstract]

Shaltiel G, Shamir A, Nemanov L, Yaroslavsky Y, Nemets B, Ebstein RP, Belmaker RH, Agam G.
Inositol monophosphatase activity in brain and lymphocyte-derived cell lines of bipolar patients.
World J Biol Psychiatry 2001 Apr;2(2):95-8
"BACKGROUND: Inositol monophosphatase (IMPase) activity was reported to be low in lymphocyte-derived cell lines of bipolar patients. METHODS: IMPase activity was measured spectrophotometrically as inorganic phosphate liberated from inositol-1-phosphate. RESULTS: The previously reported reduction was replicated in a new, small group of bipolar patients. The reduction is not present in cell lines of unipolar or schizophrenic patients. IMPase activity in postmortem frontal and occipital cortical samples of unipolar, bipolar and schizophrenic patients was not different from controls. CONCLUSIONS: A reduction in lymphocyte-derived IMPase activity without a parallel reduction in cortical IMPase activity could be due to the fact that most leukocyte IMPase activity is the product of the IMPA-2 gene." [Abstract]

Sjoholt G, Ebstein RP, Lie RT, Berle J, Mallet J, Deleuze JF, Levinson DF, Laurent C, Mujahed M, Bannoura I, Murad I, Molven A, Steen VM.
Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder.
Mol Psychiatry. 2003 Dec 23 [Epub ahead of print].
"Manic-depressive (bipolar) illness is a serious psychiatric disorder with a strong genetic predisposition. The disorder is likely to be multifactorial and etiologically complex, and the causes of genetic susceptibility have been difficult to unveil. Lithium therapy is a widely used pharmacological treatment of manic-depressive illness, which both stabilizes the ongoing episodes and prevents relapses. A putative target of lithium treatment has been the inhibition of the myo-inositol monophosphatase (IMPase) enzyme, which dephosphorylates myo-inositol monophosphate in the phosphatidylinositol signaling system. Two genes encoding human IMPases have so far been isolated, namely myo-inositol monophosphatase 1 (IMPA1) on chromosome 8q21.13-21.3 and myo-inositol monophosphatase 2 (IMPA2) on chromosome 18p11.2. In the present study, we have scanned for DNA variants in the human IMPA1 and IMPA2 genes in a pilot sample of Norwegian manic-depressive patients, followed by examination of selected polymorphisms and haplotypes in a family-based bipolar sample of Palestinian Arab proband-parent trios. Intriguingly, two frequent single-nucleotide polymorphisms (-461C>T and -207T>C) in the IMPA2 promoter sequence and their corresponding haplotypes showed transmission disequilibrium in the Palestinian Arab trios. No association was found between the IMPA1 polymorphisms and bipolar disorder, neither with respect to disease susceptibility nor with variation in lithium treatment response. The association between manic-depressive illness and IMPA2 variants supports several reports on the linkage of bipolar disorder to chromosome 18p11.2, and sustains the possible role of IMPA2 as a susceptibility gene in bipolar disorder." [Abstract]

Yoshikawa T, Padigaru M, Karkera JD, Sharma M, Berrettini WH, Esterling LE, Detera-Wadleigh SD.
Genomic structure and novel variants of myo-inositol monophosphatase 2 (IMPA2).
Mol Psychiatry 2000 Mar;5(2):165-71
"Recently, we cloned the human myo-inositol monophosphatase 2 (IMPA2) cDNA and established its map location to chromosome 18p11.2, a region previously implicated in bipolar disorder. Because the myo-inositol monophosphatase enzyme has been shown to be inhibited by lithium, an effective therapeutic agent for bipolar disorder, IMPA2 is a plausible positional and functional candidate gene. To permit comprehensive screening for variants we characterized the genomic structure and isolated the potential promoter of IMPA2. The gene was found to encode eight exons spanning;27 kb. The proximal 1-kb 5' flanking region did not contain an obvious TATA box but multiple potential binding sites for Sp1 and consensus motifs for AP2 and other transcription factors were evident. Sequencing of the coding region and splice junctions in unrelated bipolar disorder patients detected novel variants. A missense mutation in exon 2, His76Tyr, was found in one patient. His76 is evolutionarily conserved and replacement with Tyr introduces a potential site for phosphorylation. The other polymorphisms included an RsaI polymorphism, IVS1-15G>A, and a T --> C silent mutation in the third nucleotide of codon 53 in exon 2. By Fisher's exact test the silent mutation showed a trend for association (P = 0.051) with bipolar disorder suggesting that further scrutiny of this gene is warranted." [Abstract]

Sjoholt G, Gulbrandsen AK, Lovlie R, Berle JO, Molven A, Steen VM.
A human myo-inositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients.
Mol Psychiatry 2000 Mar;5(2):172-80
"For several decades, lithium has been the drug of choice in the long-term treatment of manic-depressive illness, but the molecular mechanism(s) mediating its therapeutic effects remain to be determined. The enzyme myo-inositol monophosphatase (IMPase) in the phospholipase C signaling system is inhibited by lithium at therapeutically relevant concentrations, and is a candidate target of lithium's mood-stabilizing action. Two genes encoding human IMPases have so far been isolated, namely IMPA1 on chromosome 8q21. 13-21.3 and IMPA2 on chromosome 18p11.2. Interestingly, several studies have indicated the presence of a susceptibility locus for bipolar disorder on chromosome 18p11.2. IMPA2 is therefore a candidate for genetic studies on both etiology and lithium treatment of manic-depressive illness. Here we report that the genomic structure of IMPA2 is composed of eight exons, ranging in size from 46 bp to 535 bp. The promoter region contains several Sp1 elements and lacks a TATA-box, features typical for housekeeping genes. By a preliminary polymorphism screening of exons 2-8 in a sample of 23 Norwegian bipolar patients, we have identified nine single nucleotide polymorphisms (SNPs). Seven of the polymorphisms were located in the introns, one was a silent transition in exon 2 (159T>C) and one was a transition in exon 5 (443G>A) resulting in a predicted amino acid substitution (R148Q). Our data show that even in a small sample of bipolar patients, several variants of the IMPA2 gene can be identified. IMPA2 is therefore an intriguing candidate gene for future association studies of manic-depressive illness." [Abstract]

Patel S, Yenush L, Rodriguez PL, Serrano R, Blundell TL.
Crystal structure of an enzyme displaying both inositol-polyphosphate-1-phosphatase and 3'-phosphoadenosine-5'-phosphate phosphatase activities: a novel target of lithium therapy.
J Mol Biol. 2002 Jan 25;315(4):677-85.
"Lithium cations exert profound and selective psychopharmacological effects on ameliorate manic-depressive psychosis. Although lithium is an effective drug for both treatment and prophylaxis of bipolar disorder, the precise mechanism of action is not well understood. Lithium acts as both an uncompetitive and non-competitive inhibitor of several lithium- sensitive phosphatases with regard to substrate and magnesium cofactor, respectively. In this work, we report the crystal structure and reaction mechanism of Rattus norvegicus 3'-phosphoadenosine 5'-phosphate and inositol 1,4-bisphosphate phosphatase (RnPIP), a recently identified target of lithium therapy. This Li(+)-sensitive enzyme plays a crucial role in several cellular processes, such as RNA processing, sulphation reactions and probably inositol recycling. RnPIP specifically removes the 3'-phosphate group of 3'-phosphoadenosine 5'-phosphate (PAP) and the 1'-phosphate group of inositol 1,4-bisphosphate (I(1),(4)P(2)) producing AMP and inositol 4'-phosphate, respectively. The crystal structure of RnPIP complexed with AMP, Pi and magnesium ions at 1.69 A resolution provides insight into the reaction mechanism of the hydrolysis of PAP. The core fold of the enzyme is equivalent to that found in other Li(+)-sensitive phosphatases, such as inositol monophosphatase, but molecular modelling of I(1),(4)P(2) in the RnPIP active site reveals important structural determinants that accommodate this additional substrate. RnPIP is potently inhibited by lithium and, as the accumulation of PAP inhibits a variety of proteins, including sulphotransferases and RNA processing enzymes, this dual specificity enzyme represents a potential target of lithium action, in addition to inositol monophosphatases." [Abstract]

José M. López-Coronado, José M. Bellés, Florian Lesage, Ramón Serrano, and Pedro L. Rodríguez
A Novel Mammalian Lithium-sensitive Enzyme with a Dual Enzymatic Activity, 3'-Phosphoadenosine 5'-Phosphate Phosphatase and Inositol-polyphosphate 1-Phosphatase
J. Biol. Chem. 274: 16034-16039.
"We report the molecular cloning in Rattus norvegicus of a novel mammalian enzyme (RnPIP), which shows both 3'-phosphoadenosine 5'-phosphate (PAP) phosphatase and inositol-polyphosphate 1-phosphatase activities. This enzyme is the first PAP phosphatase characterized at the molecular level in mammals, and it represents the first member of a novel family of dual specificity enzymes. The phosphatase activity is strictly dependent on Mg2+, and it is inhibited by Ca2+ and Li+ ions. Lithium chloride inhibits the hydrolysis of both PAP and inositol-1,4-bisphosphate at submillimolar concentration; therefore, it is possible that the inhibition of the human homologue of RnPIP by lithium ions is related to the pharmacological action of lithium. We propose that the PAP phosphatase activity of RnPIP is crucial for the function of enzymes sensitive to inhibition by PAP, such as sulfotransferase and RNA processing enzymes. Finally, an unexpected connection between PAP and inositol-1,4-bisphosphate metabolism emerges from this work." [Full Text]

Yatham, Lakshmi N., Liddle, Peter F., Shiah, I-Shin, Lam, Raymond W., Ngan, Elton, Scarrow, Gayle, Imperial, Miguel, Stoessl, Jon, Sossi, Vesna, Ruth, Thomas J.
PET Study of [18F]6-Fluoro-L-Dopa Uptake in Neuroleptic- and Mood-Stabilizer-Naive First-Episode Nonpsychotic Mania: Effects of Treatment With Divalproex Sodium
Am J Psychiatry 2002 159: 768-774
"Although presynaptic dopamine function as reflected by [18F]DOPA uptake is not altered in mania, presynaptic dopamine function in manic patients was lower after treatment with divalproex sodium." [Abstract]

CU Johannessen
Mechanisms of action of valproate: a commentatory.
Neurochem Int, August 1, 2000; 37(2-3): 103-10. [Abstract]

Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilisers
Br J Psychiatry 2001 178: 107-119 [Full Text]

Chen, Guang, Hasanat, Khondakar A., Bebchuk, Joseph M., Moore, Gregory J., Glitz, Debra, Manji, Husseini K.
Regulation of Signal Transduction Pathways and Gene Expression by Mood Stabilizers and Antidepressants
Psychosom Med 1999 61: 599-617 [Full Text]

Chen G, Yuan P, Hawver DB, Potter WZ, Manji HK.
Increase in AP-1 transcription factor DNA binding activity by valproic acid.
Neuropsychopharmacology 1997 Mar;16(3):238-45
"VPA did not affect CREB DNA binding activity, but concentration- and time-dependently increased AP-1 DNA binding activity. The activity was raised at 2 hours (the shortest time examined) and remained high after 6 days (the longest time used) of continuing VPA treatment." [Abstract]

Mai, Lian, Jope, Richard S., Li, Xiaohua
BDNF-mediated signal transduction is modulated by GSK3beta and mood stabilizing agents
J Neurochem 2002 82: 75-83
"Overexpression of GSK3ß did not affect BDNF-induced phosphorylation of Akt, ERK1/2, or FKHRL1, but abolished CREB phosphorylation induced by BDNF. This inhibition of BDNF-induced CREB phosphorylation in GSK3ß-overexpressing SH-SY5Y cells was blocked by treatment with lithium. In contrast to lithium, sodium valproate and lamotrigine did not affect BDNF-mediated signaling, whereas carbamazepine induced a rapid and prolonged phosphorylation of ERK1/2 and CREB in the absence or the presence of BDNF. Therefore, increased GSK3ß selectively attenuates BDNF-induced CREB phosphorylation, and lithium and carbamazepine can facilitate activation of CREB." [Abstract]

Grimes, Carol A., Jope, Richard S.
CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium
J Neurochem 2001 78: 1219-1232
"The inhibitory effects due to overexpressed GSK3ß were reversed by treatment with lithium and with another GSK3ß inhibitor, sodium valproate." [Abstract]

Hashimoto, Ryota, Hough, Christopher, Nakazawa, Takanobu, Yamamoto, Tadashi, Chuang, De-Maw
Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation
J Neurochem 2002 80: 589-597
"Significant protection was observed at the therapeutic and subtherapeutic concentration of 0.2–1.6 mm LiCl with almost complete protection at 1 mm. Neuroprotection was also elicited by valproate, another major mood-stabilizer. The neuroprotective effects of lithium coincided with inhibition of NMDA receptor-mediated calcium influx. Lithium pre-treatment did not alter total protein levels of NR1, NR2A and NR2B subunits of NMDA receptors. However, it did markedly reduce the level of NR2B phosphorylation at Tyr1472 and this was temporally associated with its neuroprotective effect. Because NR2B tyrosine phosphorylation has been positively correlated with NMDA receptor-mediated synaptic activity and excitotoxicity, the suppression of NR2B phosphorylation by lithium is likely to result in the inactivation of NMDA receptors and contributes to neuroprotection against excitotoxicity. This action could also be relevant to its clinical efficacy for bipolar patients."

Peter S. Klein, and Douglas A. Melton
A molecular mechanism for the effect of lithium on development
PNAS 93: 8455-8459, August 1996.
"We show here that complete inhibition of IMPase has no effect on the morphogenesis of Xenopus embryos and present a different hypothesis to explain the broad action of lithium. Our results suggest that lithium acts through inhibition of glycogen synthase kinase-3 (GSK-3), which regulates cell fate determination in diverse organisms including Dictyostelium, Drosophila, and Xenopus. Lithium potently inhibits GSK-3 activity (Ki = 2 mM), but is not a general inhibitor of other protein kinases." [Abstract/Full Text]

Liangyou Rui, Tracey L. Fisher, Jeffrey Thomas, and Morris F. White
Regulation of Insulin/Insulin-like Growth Factor-1 Signaling by Proteasome-mediated Degradation of Insulin Receptor Substrate-2
J. Biol. Chem. 276: 40362-40367, October 2001.
"In summary, insulin and IGF-1 stimulate substantial degradation of IRS-2 mediated by the ubiquitin/proteasome system in multiple cell types, leading to an inhibition of insulin/IGF-1 signaling. The PI 3-kinase -> Akt -> mTOR pathway is required for insulin/IGF-1-induced degradation of IRS-2. We propose that the ubiquitin/proteasome-mediated degradation of IRS-2 is a component of negative feedback inhibition modulating the action of insulin and IGF-1. Inhibitors of 26 S proteasome significantly improve insulin sensitivity, suggesting that these types of agents might have clinical value in the treatment of patients with type 2 diabetes." [Full Text]

Kobayashi_Y, Pang_T, Iwamoto_T, Wakabayashi_S, Shigekawa_M
Lithium activates mammalian Na^+/H^+ exchangers: Isoform specificity and inhibition by genistein
"Thus, externally added Li^+ activates NHE1 and NHE2 via a mechanism possibly involving a tyrosine kinase, causing an increase in cytoplasmic pH that could potentially affect various cell functions." [Abstract]

Yuan PX, Chen G, Huang LD, Manji HK.
Lithium stimulates gene expression through the AP-1 transcription factor pathway.
Brain Res Mol Brain Res 1998 Jul 15;58(1-2):225-30 [Abstract]

Ozaki, N, Chuang, DM
Lithium increases transcription factor binding to AP-1 and cyclic AMP- responsive element in cultured neurons and rat brain
J Neurochem 1997 69: 2336-2344 [Abstract]

Mori S, Zanardi R, Popoli M, Smeraldi E, Racagni G, Perez J.
Inhibitory effect of lithium on cAMP dependent phosphorylation system.
Life Sci 1996;59(9):PL99-104
"The results show that lithium, but not rubidium, at therapeutic and high concentrations significantly decreases the cAMP stimulated MAP2 endogenous phosphorylation in microtubule fraction." [Abstract]

Mirjana Andjelkovic, Teresa Jakubowicz, Peter Cron, Xiu-Fen Ming, Jeung-Whan Han, and Brian A. Hemmings
Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors
PNAS 93: 5699-5704, 1996.
"Treatment of RAC-PK in vitro with protein phosphatase 2A led to kinase inactivation and an increase in electrophoretic mobility." [Abstract/Full Text]

Elzbieta Chalecka-Franaszek, and De-Maw Chuang
Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons
PNAS 96: 8745-8750, July 1999.
"In contrast, lithium treatment activates Akt-1 by enhancing phosphorylation triggered by PI 3-K signaling. This conclusion is based on our findings that the enhanced Akt-1 activity is blocked by selective PI 3-K inhibitors and that lithium treatment rapidly increases PI 3-K activity. The activation of PI 3-K under our experimental conditions suggests that lipid second messengers such as PI-3,4,5-P3 or PI-3,4-P2, or both, are generated in response to lithium treatment. The mechanisms by which lithium activates PI 3-K are unclear." [Full Text]

Chi-Wu Chiang, Gregory Harris, Cindy Ellig, Shane C. Masters, Romesh Subramanian, Shirish Shenolikar, Brian E. Wadzinski, and Elizabeth Yang
Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin- 3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation
Blood 97: 1289-1297, March 2001. [Full Text]

Mori S, Tardito D, Dorigo A, Zanardi R, Smeraldi E, Racagni G, Perez J.
Effects of lithium on cAMP-dependent protein kinase in rat brain.
Neuropsychopharmacology 1998 Sep;19(3):233-40 [Abstract]

Nonaka, Shigeyuki, Katsube, Nobuo, Chuang, De-Maw
Lithium Protects Rat Cerebellar Granule Cells against Apoptosis Induced by Anticonvulsants, Phenytoin and Carbamazepine
J Pharmacol Exp Ther 1998 286: 539-547
"However, we found that supplement of excess myoinositol does not affect lithium's protective effect, and a potent IMPase inhibitor, L-690,330, fails to mimic the protective action (fig. 5). Thus, the neuroprotective mechanism apparently is independent of inhibition of PI turnover by blocking IMPase." [Full Text]
(High doses of the anticonvulsants induced apoptosis.)

Cordeiro, Mara L., Umbach, Joy A., Gundersen, Cameron B.
Lithium Ions Enhance Cysteine String Protein Gene Expression In Vivo and In Vitro.
J Neurochem 2000 74: 2365-2372 [Abstract]

Phiel, Christopher J, Klein, Peter S
Annu. Rev. Pharmacol. Toxicol. 2001 41: 789-813
"A number of enzymes have been proposed as potential targets of lithium action, including inositol monophosphatase, a family of structurally related phosphomonoesterases, and the protein kinase glycogen synthase kinase-3. These potential targets are widely expressed, require metal ions for catalysis, and are generally inhibited by lithium in an uncompetitive manner, most likely by displacing a divalent cation." [Abstract]

JD York, JW Ponder, and PW Majerus
Definition of a Metal-Dependent/Li+-Inhibited Phosphomonoesterase Protein Family Based Upon a Conserved Three-Dimensional Core Structure
PNAS 92: 5149-5153, 1995.
"Inositol polyphosphate 1-phosphatase, inositol monophosphate phosphatase, and fructose 1,6-bisphosphatase share a sequence motif, Asp-Pro-(Ile or Leu)-Asp-(Gly or Ser)-(Thr or Ser), that has been shown by crystallographic and mutagenesis studies to bind metal ions and participate in catalysis." [Abstract/Full Text]

Wang X, Janmaat M, Beugnet A, Paulin FE, Proud CG.
Evidence that the dephosphorylation of Ser535 in the epsilon-subunit of eukaryotic initiation factor 2B is insufficient for the activation of eIF2B by insulin.
Biochem J 2002 Jul 22;Pt [epub ahead of print]
"Treatment of cells with LiCl or with either of two recently developed GSK3 inhibitors, SB-415286 and SB-216763, brought about the dephosphorylation of Ser535, strongly indicating this site is indeed a target for GSK3 in vivo. However, these compounds did not elicit significant activation of eIF2B, indicating, consistent with conclusions from an earlier study, that additional inputs are required for the activation of eIF2B." [Abstract]

Ito, Kazuhiro, Barnes, Peter J., Adcock, Ian M.
Glucocorticoid Receptor Recruitment of Histone Deacetylase 2 Inhibits Interleukin-1beta -Induced Histone H4 Acetylation on Lysines 8 and 12
Mol. Cell. Biol. 2000 20: 6891-6903 [Full Text]

Seung Kim HF, Weeber EJ, Sweatt JD, Stoll AL, Marangell LB.
Inhibitory effects of omega-3 fatty acids on protein kinase C activity in vitro.
Mol Psychiatry 2001 Mar;6(2):246-8
"Preliminary clinical data indicate that omega-3 fatty acids may be effective mood stabilizers for patients with bipolar disorder. Both lithium and valproic acid are known to inhibit protein kinase C (PKC) activity after subchronic administration in cell culture and in vivo. The current study was undertaken to determine the effects of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on protein kinase C phosphotransferase activity in vitro. Various concentrations of DHA, EPA, and arachidonic acid (AA) were incubated with the catalytic domain of protein kinase C beta from rat brain. Protein kinase C activity was measured by quantifying incorporation of (32)P-PO(4) into a synthetic peptide substrate. Both DHA and EPA, as well as the combination of DHA and EPA, inhibited PKC activity at concentrations as low as 10 micromol l(-1). In contrast, arachidonic acid had no effect on PKC activity. Thus, PKC represents a potential site of action of omega-3 fatty acids in their effects on the treatment of bipolar disorder." [Abstract]

Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB.
Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.
Arch Gen Psychiatry 1999 May;56(5):407-12
"BACKGROUND: Omega3 fatty acids may inhibit neuronal signal transduction pathways in a manner similar to that of lithium carbonate and valproate, 2 effective treatments for bipolar disorder. The present study was performed to examine whether omega3 fatty acids also exhibit mood-stabilizing properties in bipolar disorder. METHODS: A 4-month, double-blind, placebo-controlled study, comparing omega3 fatty acids (9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30 patients with bipolar disorder. RESULTS: A Kaplan-Meier survival analysis of the cohort found that the omega3 fatty acid patient group had a significantly longer period of remission than the placebo group (P = .002; Mantel-Cox). In addition, for nearly every other outcome measure, the omega3 fatty acid group performed better than the placebo group. CONCLUSION: Omega3 fatty acids were well tolerated and improved the short-term course of illness in this preliminary study of patients with bipolar disorder." [Abstract]

Jones-Brando L, Torrey EF, Yolken R.
Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii.
Schizophr Res. 2003 Aug 1;62(3):237-44.
"The exact mechanisms of action of some antipsychotics and mood stabilizers have not been elucidated. Response to these medications can vary among individuals. Recent studies indicate that infection with the parasite Toxoplasma gondii may contribute to the symptoms of schizophrenia in some individuals. We investigated commonly used antipsychotic and mood stabilizing medications for their ability to inhibit the replication of this organism.We employed a system for testing compounds for in vitro activity against T. gondii. Human fibroblasts (HFF) were treated with test compounds and then exposed to Toxoplasma that has been genetically modified to express cytoplasmic beta-galactosidase. Inhibition by the drugs was determined by spectrophotometric analysis of colorimetric reactions.We tested 12 neuroleptic compounds and found that of these, the antipsychotic haloperidol and the mood stabilizer valproic acid most effectively inhibit Toxoplasma growth in vitro. Valproic acid inhibited the parasite at a concentration below that found in the cerebrospinal fluid and blood of individuals being treated with this medication and displayed synergistic activity with haloperidol and with trimethoprim, an antibiotic commonly used to treat Toxoplasma infections.Several medications used to treat schizophrenia and bipolar disorder have the ability to inhibit the in vitro replication of T. gondii." [Abstract]

->Back to Home<- //->Back to Bipolar Disorder Index<-