NMDA antagonist neurotoxicity


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Low SJ, Roland CL
Review of NMDA antagonist-induced neurotoxicity and implications for clinical development.
Int J Clin Pharmacol Ther. 2004 Jan;42(1):1-14.
NMDA receptor antagonists have been investigated for many years as therapeutic agents for the treatment of neurological disorders such as stroke, epilepsy, pain and Parkinson's disease. It has been discovered, however, that many of these compounds cause adverse behavioral (psychotomimetic) effects and can produce neurotoxicity characterized by neuronal vacuolization, induction of heat-shock protein, neuronal/axonal degeneration and regional brain cell death in several animal species. It is unknown whether NMDA antagonists induce neurotoxicity in humans. The mechanism of NMDA antagonist-induced neurotoxicity is not completely known, but some evidence suggests disinhibition of GABAergic inputs to the affected neurons. Several classes of compounds have been shown to prevent NMDA antagonist-induced neurotoxicity. The extent of neurotoxicity produced by NMDA antagonists is affected by many factors, including type of antagonist, dose, length of exposure, age, sex and species. While there are no published regulatory guidelines regarding how NMDA antagonist compounds should be evaluated, sponsors and investigators of these compounds should make every effort to assess the potential for neurotoxicity. NMDA receptor antagonists, as well as other CNS-active compounds need to be analyzed for neurotoxicity through careful experimental design, adequate tissue sampling and through the use of a sensitive method of detection. [Abstract]

Farber NB, Kim SH, Dikranian K, Jiang XP, Heinkel C.
Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity.
Mol Psychiatry. 2002;7(1):32-43.
"NMDA glutamate receptor antagonists are used in clinical anesthesia, and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease and schizophrenia. Thus, understanding the mechanism underlying NRHypo-induced neurotoxicity and psychosis could have significant clinically relevant benefits. NRHypo neurotoxicity can be prevented by several classes of agents (e.g. antimuscarinics, non-NMDA glutamate antagonists, and alpha(2) adrenergic agonists) suggesting that the mechanism of neurotoxicity is complex. In the present study a series of experiments was undertaken to more definitively define the receptors and complex neural circuitry underlying NRHypo neurotoxicity. Injection of either the muscarinic antagonist scopolamine or the non-NMDA antagonist NBQX directly into the cortex prevented NRHypo neurotoxicity. Clonidine, an alpha(2) adrenergic agonist, protected against the neurotoxicity when injected into the basal forebrain. The combined injection of muscarinic and non-NMDA Glu agonists reproduced the neurotoxic reaction. Based on these and other results, we conclude that the mechanism is indirect, and involves a complex network disturbance, whereby blockade of NMDA receptors on inhibitory neurons in multiple subcortical brain regions, disinhibits glutamatergic and cholinergic projections to the cerebral cortex. Simultaneous excitotoxic stimulation of muscarinic (m(3)) and glutamate (AMPA/kainate) receptors on cerebrocortical neurons appears to be the proximal mechanism by which the neurotoxic and psychotomimetic effects of NRHypo are mediated." [Abstract]

Li, Qiang, Clark, Suzanne, Lewis, Darrell V., Wilson, Wilkie A.
NMDA Receptor Antagonists Disinhibit Rat Posterior Cingulate and Retrosplenial Cortices: A Potential Mechanism of Neurotoxicity
J. Neurosci. 2002 22: 3070-3080
"NMDA receptor antagonists produce region-specific neurodegeneration by an undetermined mechanism, but one proposed mechanism involves disinhibition. In certain areas of the brain, NMDA receptors mediate excitatory drive onto inhibitory interneurons. Thus, NMDA receptor/channel antagonists may reduce inhibition (i.e., produce "disinhibition"). If a sufficient level of disinhibition is produced, enhanced vulnerability to excitotoxicity may result. Furthermore, if there are region-specific differences in NMDA antagonist-induced disinhibition, this could underlie region-specific NMDA antagonist-induced neurotoxicity. In the present study, we tested this hypothesis by exposing rat brain slices to the NMDA receptor antagonist dizocilpine maleate (MK-801) and measuring MK-801-induced disinhibition in areas of higher and lower vulnerability to neurodegeneration [posterior cingulate/retrosplenial cortices (PCC/RSC) and parietal cortex, respectively]. Using whole-cell patch-clamp techniques, bicuculline-sensitive GABA(A) receptor-mediated IPSCs were measured in biocytin-labeled pyramidal neurons in the PCC/RSC and parietal cortex. In the PCC/RSC, bath-applied MK-801 (10-40 microm) produced disinhibition, shown as a concentration-dependent decrease in spontaneous IPSC frequency and amplitude; MK-801 (40 microm) also reduced evoked IPSC amplitudes. In parietal cortex, MK-801 produced significantly less disinhibition. To determine whether disinhibition is caused by presynaptic or postsynaptic mechanisms, we tested the effects of MK-801 (40 microm) against miniature IPSC (mIPSC) frequency and amplitude in tetrodotoxin (TTX; 0.5 microm)-treated slices and found that MK-801 did not alter mIPSC frequency or amplitude. Taken together, these results suggest that NMDA receptors regulate activity of inhibitory interneurons and, consequently, GABA release in certain cortical areas. This region-specific reduction in inhibitory input to pyramidal cells could underlie the region-specific neurotoxicity of NMDA antagonists." [Full Text]

Kathleen A. Haberny , Merle G. Paule , Andrew C. Scallet , Frank D. Sistare , David S. Lester , Joseph P. Hanig , and William Slikker, Jr.
Ontogeny of the N-Methyl-D-Aspartate (NMDA) Receptor System and Susceptibility to Neurotoxicity
Toxicol. Sci. 68: 9-17. 2002.
"The NMDA receptor has been widely investigated in recent years as a target for the pharmacological management of seizures, pain and a variety of neurological disorders. Its role in normal central nervous system (CNS) activity and development, as well as in the development of CNS abnormalities and neurodegeneration has also been of interest. The NMDA receptor is one of three pharmacologically distinct subtypes of ionotropic receptor channels that are sensitive to the endogenous excitatory amino acid, L-glutamate. The ontogeny of the NMDA receptor, a multiple tetrameric and heteromeric channel complex with at least six known subunits, is controlled by three gene families and varies in developmental profile with species and regional brain area. NMDA receptors play a role in excitatory synaptic transmission, in the activity-dependent synaptic plasticity underlying learning and memory, and in pre- and postnatal CNS development, including brain cell differentiation, axonal growth and degeneration of unused neurons. The results of recent studies suggest that sustained alteration of NMDA receptor activation during critical periods of development may have deleterious effects on normal CNS development and function. Neonatal rats administered the NMDA receptor antagonists 2-amino-5-phosphonovalerate (AP5) and MK-801 during the first two weeks of life develop abnormal axonal arborization in the retinal connections to the superior colliculus, interfering with normal visual responses. Results from monkey studies suggest that chronic developmental exposure to high doses of a NMDA antagonist, remacemide, has pronounced and long-lasting effects on learning. Recent findings indicate that if NMDA receptors are blocked during a specific period in neonatal life (first two weeks postnatally in the rat), massive apoptotic neurodegeneration results, due not to excitotoxic overstimulation of neurons but to deprivation of stimulation. These observations require further laboratory evidence and support in order to establish their relevance to drug-induced human neurodevelopmental concerns. It is necessary to investigate the relevance of these findings in other animal species in addition to the rat, most notably, nonhuman primates, where neuronal cytoarchitecture and development are significantly different than the rodent but more like the human." [Abstract]

Zajaczkowski W, Hetman M, Nikolaev E, Quack G, Danysz W, Kaczmarek L.
Behavioural evaluation of long-term neurotoxic effects of NMDA receptor antagonists.
Neurotox Res. 2000 Apr;1(4):299-310.
"High doses of NMDA antagonists e.g. (+)MK-801 evoke neurodegeneration in retrosplenial cortex in rodents. To assess functional consequences of such treatment, three paradigms of two-way active avoidance learning (with visual or auditory conditioned stimuli) and additionally a spatial learning paradigm - radial maze - were used. Female rats were treated i.p. with 5 mg/kg of (+)MK-801. Recumbence, severe hypothermia and loss of body weight were observed for 3-7 days. Despite that, there were no statistically significant differences in performance of avoidance reaction between saline and (+)MK-801 treated animals trained 10-40 days after the drug administration. However, in the radial maze test (+)MK-801 impaired reference (but not working) memory in the experiment that started 8 days after the treatment. Similar effect was observed on reversal learning. The clinically used NMDA receptor antagonist memantine at the doses of 20 and 40 mg/kg had also no such long term negative effect on working memory during training (even positive effect was seen at 20 mg/kg) but at 40 mg/kg impaired learning on the first day of reversal. This indicates that (+)MK-801 neurotoxicity in the retrosplenial cortex is connected with subtle alterations in the learning performance that may be seen in some tests only. Moreover, memantine doses greatly exceeding therapeutically relevant range produce minimal functional alteration. An additional experiment revealed that the same dose of memantine results in two fold higher serum levels of the antagonist in female than male rats. Hence, considering that profiling studies are done in male rats, a safety factor of over 16 fold can be calculated for memantine." [Abstract]

Farber NB, Jiang X, Dikranian K, Nemmers B.
Muscimol prevents NMDA antagonist neurotoxicity by activating GABAA receptors in several brain regions.
Brain Res. 2003 Dec 12; 993(1-2): 90-100.
"N-Methyl-D-aspartate (NMDA) glutamate receptor antagonists are being developed as therapeutic agents for several clinical conditions. However, the ability of these agents to produce neurotoxicity and psychosis can compromise their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state may play a role in neurodegenerative and psychotic disorders. A better understanding of the mechanism underlying these adverse effects should allow for the safer use of these agents and might clarify mechanisms underlying certain clinical disorders. NRHypo neurotoxicity is mediated by a complex disinhibition mechanism in which NMDA antagonists abolish GABAergic inhibition, resulting in the simultaneous excessive release of acetylcholine and glutamate onto the vulnerable retrosplenial cortex (RSC) neurons. Systemically administered GABAergic agents are potent protectors against NRHypo neurotoxicity. To determine where in brain GABAergic agents could be acting to protect against NRHypo neurotoxicity, we injected the GABAergic agonist, muscimol, into different brain regions of rats treated systemically with a neurotoxic dose of the potent NMDA antagonist, MK-801. We report that muscimol injections into the anterior thalamus or diagonal band of Broca provide substantial protection, suggesting that disinhibition of neurons in these regions underlies NRHypo neurotoxicity. Muscimol injections into the RSC also provide substantial protection possibly by directly inhibiting the vulnerable RSC neuron. Injections of muscimol into other areas known to project to the RSC (ventral orbital cortex, anterior cingulate cortex and subiculum) provide only minimal protection. We conclude that GABAergic agents prevent NRHypo neurotoxicity mainly by activating GABA receptors in the anterior thalamus, diagonal band of Broca and RSC." [Abstract]

Jevtovic-Todorovic V, Wozniak DF, Powell S, Olney JW.
Propofol and sodium thiopental protect against MK-801-induced neuronal necrosis in the posterior cingulate/retrosplenial cortex.
Brain Res. 2001 Sep 21;913(2):185-9.
"N-Methyl-D-aspartate (NMDA) antagonists act by an anti-excitotoxic action to provide neuroprotection against acute brain injury, but these agents can also cause toxic effects. In low doses they induce reversible neuronal injury, but in higher doses they cause irreversible degeneration of cerebrocortical neurons. GABAmimetic drugs protect against the reversible neurotoxic changes in rat brain. Here we show that two GABAmimetic anesthetic agents--propofol and sodium thiopental--protect against the irreversible neurodegenerative reaction induced by the powerful NMDA antagonist, MK-801." [Abstract]

Ortiz GG, Guerrero JM, Reiter RJ, Poeggeler BH, Bitzer-Quintero OK, Feria-Velasco A.
Neurotoxicity of dextrorphan.
Arch Med Res. 1999 Mar-Apr;30(2):125-7.
"BACKGROUND: The noncompetitive NMDA antagonists phencyclidine (PCP) and dizocilpine (MK-801) have been considered for use as neuroprotective therapeutic agents, although both produce injury in neurons of cingulate and retrosplenial cortices in rodents. The low-affinity, noncompetitive NMDA antagonist dextrorphan has been considered for use as a neuroprotective therapeutic drug. The aim of the present work was to evaluate the neurotoxicity of dextrorphan. METHODS: Sprague-Dawley male rats were used and injected with either saline or dextrorphan (30 mg/kg i.p.). The animals were sacrificed 30 min later, and the brain was examined for histopathological changes. RESULTS: After systemic administration of the drug, hyperchromatic and shrunken nuclei with chromatin condensation and disruption were observed. Also, granular and vacuolated cytoplasm was apparent in pyramidal neurons in the retrosplenial (posterior cingulate) cortex. Status spongiosus (spongy degeneration) of the neuropil was also detected. CONCLUSIONS: Morphological changes are similar to those described previously, which are induced by high-affinity, noncompetitive NMDA antagonists, such as MK-801." [Abstract]

Raboisson P, Flood K, Lehmann A, Berge OG.
MK-801 neurotoxicity in the guinea pig cerebral cortex: susceptibility and regional differences compared with the rat.
J Neurosci Res. 1997 Aug 1;49(3):364-71.
"N-methyl-D-aspartate (NMDA) receptor antagonists induce transient vacuole formation in neurons of the retrosplenial cortex and, after higher doses, necrosis in the same region. To our knowledge, all studies demonstrating these effects have been carried out in rats or mice. The present study investigated whether vacuolization occurs in the guinea pig, rats being used as controls. Female Dunkin-Hartley guinea pigs (age 15-18 weeks) were given a single subcutaneous injection of saline or the non-competitive NMDA antagonist dizocilpine maleate [(+)-MK-801; 1, 4, or 12 mg/kg]. Female Sprague-Dawley rats (age 16 weeks) received saline or MK-801 (1 mg/kg). Whatever the dose of MK-801, guinea pigs showed only occasional vacuolated neurons in the retrosplenial cortex. However, affected neurons (mainly large pyramidal cells of layer V) were found in the frontoparietal neocortex. The reaction was limited after 1 mg/kg, and seemed to reach a maximum at 4 mg/kg. Rats injected with 1 mg/kg MK-801 showed an intense vacuole reaction in neurons from layers III-IV of the retrosplenial cortex, but no affected neurons were noted in neocortical areas. We conclude that there are significant species differences in susceptibility to, and location of, vacuolization induced by NMDA receptor antagonists." [Abstract]

Roland N. Auer
Effect of Age and Sex on N-Methyl-D-Aspartate Antagonist-Induced Neuronal Necrosis in Rats
Stroke 27: 743-746
"BACKGROUND AND PURPOSE: Although N-methyl-D-aspartate (NMDA) antagonism may be a useful therapeutic approach in stroke treatment, it has been found that these pharmacological agents cause neuronal necrosis in restricted cortical regions of the rodent brain. METHODS: To test the hypothesis that age and sex influence NMDA antagonist-induced neuronal necrosis, male and female rats were studied at 2 months (young), 12 months (middle-aged), and 24 months (old) of age. A dose of 5 mg/kg MK-801 was administered, followed by quantitation of neuronal necrosis at nine coronal levels in the cingulate and retrosplenial cortex at 1 week of survival. RESULTS: Mortality was dependent on age but not sex and was higher in the old rats (P<.01). The number of necrotic neurons per hemisphere was greater in female than in male rats at all ages (P<.0001). Female rats also showed increasing neuronal necrosis with age (P<.05). CONCLUSIONS: The results indicate a major sex difference in neuronal cytotoxicity caused by NMDA antagonists and a minor increase in susceptibility with increasing age in females. The findings may be relevant to development of drugs with NMDA antagonist properties for use in human stroke." [Full Text]

Farber NB, Wozniak DF, Price MT, Labruyere J, Huss J, St Peter H, Olney JW.
Age-specific neurotoxicity in the rat associated with NMDA receptor blockade: potential relevance to schizophrenia?
Biol Psychiatry. 1995 Dec 15;38(12):788-96.
"Agents that block the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor induce a schizophrenialike psychosis in adult humans and injure or kill neurons in several corticolimbic regions of the adult rat brain. Susceptibility to the psychotomimetic effects of the NMDA antagonist, ketamine is minimal or absent in children and becomes maximal in early adulthood. We examined the sensitivity of rats at various ages to the neurotoxic effects of the powerful NMDA antagonist, MK-801. Vulnerability was found to be age dependent, having onset at approximately puberty (45 days of age) and becoming maximal in early adulthood. This age-dependency profile (onset of susceptibility in late adolescence) in the rat is similar to that for ketamine-induced psychosis or schizophrenia in humans. These findings suggest that NMDA receptor hypofunction, the mechanism underlying the neurotoxic and psychotomimetic actions of NMDA antagonists, may also play a role in schizophrenia." [Abstract]

Noguchi KK, Nemmers B, Farber NB
Age has a similar influence on the susceptibility to NMDA antagonist-induced neurodegeneration in most brain regions.
Brain Res Dev Brain Res. 2005 Aug 8;158(1-2):82-91.
NMDA antagonists are of potential therapeutic benefit for several conditions. However, their ability to produce neurotoxicity and psychosis has hampered their clinical use. A better understanding of these side effects and the mechanism underlying them could result in their safer use and in improving our understanding of psychotic illnesses. By disinhibiting certain multisynaptic circuits, moderate doses of NMDA antagonists produce reversible neurotoxicity in the retrosplenial cortex in rats older than 1 month. Higher doses of these same agents result in the death of neurons in the retrosplenial cortex and several other brain regions. It is unknown whether susceptibility to this irreversible neurodegeneration has a similar age dependency profile. We, therefore, examined the sensitivity of rats of various ages (PND20-60) to the irreversible neurodegenerative effect of the selective NMDA antagonist, MK-801. Quantification of the severity of neurodegeneration with stereology revealed that the retrosplenial cortex, induseum griseum, and dentate gyrus had decreasing amounts of damage with decreasing age and onset of sensitivity around PND30. The piriform cortex also displayed a decreased amount of degeneration in younger age groups. However, a low level of degeneration continued to occur in the posterior piriform cortex in the PND20-25 animals. The stage of degeneration appeared to be more advanced, suggesting that these neurons were dying by a different mechanism. We conclude that for most neuronal populations, susceptibility to the irreversible and reversible neurodegenerative effects of NMDA antagonists has a similar age dependency profile, consistent with the proposal that the same disinhibitory mechanism underlies both neurotoxicities. [Abstract]

Auer RN.
Assessing structural changes in the brain to evaluate neurotoxicological effects of NMDA receptor antagonists.
Psychopharmacol Bull. 1994;30(4):585-91.
"Like all pharmacologic agents known, N-methyl-D-aspartate (NMDA) antagonist compounds have side effects. It is expected that neuroactive molecules have effects, including side effects, in the central nervous system (CNS). With NMDA antagonists in rodents, these side effects are remarkably focal in the cingulate and retrosplenial cortex. The salient features of NMDA antagonist neurotoxicity which should be underscored are hypermetabolism, lactate accumulation, neuronal vacuolization in aldehyde fixed material, and neuronal death in older rodents. The scope of this phenomenon must urgently be determined in non-rodent species, specifically primates. This is important from both a regulatory and neurotherapeutic point of view, since effective molecules having potential in human disease states may also have NMDA antagonist properties." [Abstract]

Bueno A, De Olmos S, Heimer L, De Olmos J.
NMDA-antagonist MK-801-induced neuronal degeneration in Wistar rat brain detected by the Amino-Cupric-Silver method.
Exp Toxicol Pathol. 2003 Mar; 54(4): 319-34.
"The neurotoxic effect following a single intraperitoneal injection of MK-801 (10 mg/kg) in adult female Wistar rats at different survival times was studied with the 1994 version of de Olmos' Amino-Cupric-Silver (A-Cu-Ag) technique for detection of neural degeneration. In addition to the well documented somatodendritic degeneration observable in cortical olfactory structures, dentate gyrus, retrosplenial and sensory cortices, we detected this type of neuronal degeneration also in the main olfactory bulb, motor and anterior cingulate cortices, thalamus and cerebellum. Terminal degeneration, not reported by previous authors, was detected in cortical olfactory structures, hippocampal formation, sensory, infralimbic, prelimbic, agranular insular, ectorhinal, perirhinal and lateral orbital cortices. These results demonstrate that the A-Cu-Ag procedure is more efficient than other silver methods for detecting the degeneration induced by MK-801. In fact, the use of the A-Cu-Ag method has made it possible to infer the connectional relations between the damaged cell bodies and corresponding terminal degeneration. Our results also indicate that the A-Cu-Ag technique may be a suitable method for the staining of neurons undergoing apoptotic-like degeneration. The probable degenerative mechanism of MK-801 in the main olfactory system is discussed." [Abstract]

Tomitaka M, Tomitaka S, Rajdev S, Sharp FR.
Fluoxetine prevents PCP- and MK801-induced HSP70 expression in injured limbic cortical neurons of rats.
Biol Psychiatry. 2000 May 1;47(9):836-41.
"BACKGROUND: N-Methyl-D-aspartate (NMDA) receptor antagonists, including phencyclidine (PCP) and dizocilpine (MK801), cause schizophrenialike psychosis in humans, and produce vacuolated neurons in the cingulate and retrosplenial cortices of the rat brain. Since psychotically depressed patients and schizophrenic depressed patients may require treatment with selective serotonin reuptake inhibitors (SSRIs), it is of interest to examine the relationship between SSRIs and NMDA antagonist neurotoxicity. METHODS: The neurotoxicity of PCP and MK801 was assessed using heat shock protein (HSP70) immunocytochemistry and HSP70 Western blots because HSP70 is expressed in the injured, vacuolated neurons. Female rats were given fluoxetine (0, 5, 10, and 20 mg/kg IP) followed 1 hour later by MK801 (1 mg/kg IP) or PCP (50 mg/kg IP). RESULTS: Pretreatment with fluoxetine (20 mg/kg IP) 1 hour before MK801 prevented the induction of HSP70 by MK801 in the cingulate and retrosplenial cortices. Pretreatment with fluoxetine (10 or 20 mg/kg IP) 1 hour before PCP also prevented the HSP70 induction by PCP. CONCLUSIONS: Fluoxetine prevents the neurotoxicity of NMDA receptor antagonists in rat brain." [Abstract]

Meoni P, Tortella FC, Bowery NG.
An autoradiographic study of dextromethorphan high-affinity binding sites in rat brain: sodium-dependency and colocalization with paroxetine.
Br J Pharmacol. 1997 Apr;120(7):1255-62.
"1. The distribution and some pharmacological properties of centrally located dextromethorphan high-affinity binding sites were investigated by in vitro autoradiography. 2. Sodium chloride (50 mM) induced a 7 to 12 fold increase in dextromethorphan binding to rat brain in all areas tested. The effect of sodium was concentration-dependent with a higher dose (120 mM) exerting a smaller effect on binding. 3. [3H]-dextromethorphan binding in the presence of sodium was inhibited in the presence of the anticonvulsant phenytoin at a concentration of 100 microM, while the sigma ligand (+)-3-(-3-hydroxyphenyl)-N-(1-propyl)pipendine ((+)-PPP) had no effect on the binding, suggesting an interaction with the DM2 site. 4. The distribution of the sodium-dependent binding identified in this study correlated significantly with the distribution of the selective 5-HT uptake inhibitor [3H]-paroxetine, and paroxetine and dextromethorphan mutually displaced their binding at concentrations in the low nanomolar range. 5. These data show that dextromethorphan and paroxetine share a sodium-dependent high affinity binding site in rat brain, and suggest that dextromethorphan might interact, in the presence of sodium, with the 5-HT uptake mechanism in rat brain." [Abstract]

Henderson MG, Fuller RW.
Dextromethorphan antagonizes the acute depletion of brain serotonin by p-chloroamphetamine and H75/12 in rats.
Brain Res. 1992 Oct 30;594(2):323-6.
"A role for calcium in p-chloroamphetamine-induced neurotoxicity has been inferred previously from protective effects of dextromethorphan. We found that dextromethorphan reduces rat brain concentrations of 5-hydroxyindoleacetic acid and blocks the acute, non-neurotoxic depletion of brain serotonin by p-chloroamphetamine and by H75/12. Inhibition of the membrane transporter on brain serotonin neurons by dextromethorphan in vivo might explain its protective effect against p-chloroamphetamine neurotoxicity." [Abstract]

Zhou GZ, Musacchio JM.
Computer-assisted modeling of multiple dextromethorphan and sigma binding sites in guinea pig brain.
Eur J Pharmacol. 1991 Apr 25;206(4):261-9.
"Computer-assisted, simultaneous analysis of self- and cross-displacement experiments demonstrated the existence of several binding sites in guinea pig brain for dextromethorphan, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), and 1,3-di-o-tolyl guanidine (DTG). Dextromethorphan binds with high affinity to two sites (R1 Kd 50-83 and R2 Kd 8-19 nM) and with low affinity to two additional sites (R3 and R4). (+)-3-PPP binds to one high-affinity (R1 Kd 24-36 nM), to one intermediate-affinity (R3 Kd 210-320 nM), and to two (R2 and R4) low-affinity sites. DTG binds with almost identical high affinity to two different sites (R1 Kd 22-24 and R3 Kd 13-16 nM). These results confirm that dextromethorphan, (+)-3-PPP, and DTG bind to the common DM1/sigma 1 site (R1). The binding of DTG to two different sites with identical affinities precludes the use of this compound as a specific marker for sigma receptors. Besides, haloperidol displaces labeled ligands from both high-affinity DTG sites (R1 and R3) with high affinity. Thus, haloperidol sensitivity should not be used as the single criterion to identify a putative receptor. The resolution of these novel sites also may provide new insights into the multiple effects of antipsychotic drugs. In addition, this investigation has important implications regarding the methods that must be applied to characterize multiple binding sites and their relations with putative receptors." [Abstract]

Avenet P, Leonardon J, Besnard F, Graham D, Depoortere H, Scatton B.
Antagonist properties of eliprodil and other NMDA receptor antagonists at rat NR1A/NR2A and NR1A/NR2B receptors expressed in Xenopus oocytes.
Neurosci Lett. 1997 Feb 21;223(2):133-6.
"We have studied the effects of a variety of N-methyl-D-aspartate (NMDA) antagonists acting at different sites of the NMDA receptor complex on NMDA-induced currents in Xenopus oocytes expressing heteromeric NR1A/NR2 and NR1A/NR2B receptors. The polyamine site antagonists eliprodil (IC50 = 3.0 microM) and ifenprodil (IC50 = 0.27 microM) antagonized NMDA responses at NR1A/NR2B receptors but not at NR1A/NR2A receptors (IC50 > 100 microM). The channel blockers dizocilpine, memantine and phencyclidine (PCP) were equally potent antagonists at both receptor subtypes whereas dextromethorphan was four times more potent at NR1A/NR2A receptors." [Abstract]

Jevtovic-Todorovic V, Wozniak DF, Powell S, Nardi A, Olney JW.
Clonidine potentiates the neuropathic pain-relieving action of MK-801 while preventing its neurotoxic and hyperactivity side effects.
Brain Res. 1998 Jan 19;781(1-2):202-11.
"Antagonists of NMDA glutamate receptors have been shown to alleviate neuropathic pain in rats and humans. However, NMDA antagonists can cause significant side effects ranging from behavioral disturbances to injury of neurons in the posterior cingulate/retrosplenial (PC/RS) cortex. We have found that alpha-2 adrenergic agonists prevent the PC/RS neurotoxic side effects of NMDA antagonists. In the present study of adult female rats subjected to sciatic nerve ligation (Bennett neuropathic pain model) and tested for paw withdrawal latency (PWL) following a thermal stimulus, we evaluated the ability of the NMDA antagonist, MK-801, to alleviate neuropathic pain either by itself or when administered together with the alpha-2 adrenergic agonist, clonidine. We found that MK-801, at a dose (0.05 mg/kg s.c.) that is known to cause mild hyperactivity but is subthreshold for producing PC/RS neurotoxic changes, relieved the neuropathic pain state associated with sciatic nerve ligation. However, the relief at this dose was very transient, and no neuropathic pain-relieving effect was observed at a lower dose (0. 025 mg/kg s.c.) of MK-801. Clonidine, at a dose (0.05 mg/kg s.c.) that prevents the cerebrocortical neurotoxic effects of MK-801, decreased sensitivity to the thermal stimulus equally under all conditions (ligated, sham ligated, unoperated), but did not specifically relieve neuropathic pain in the ligated limb. Combining this dose of clonidine with an ineffective dose (0.025 mg/kg s.c.) of MK-801 provided specific, complete and long lasting (up to 4 h) relief from neuropathic pain. Rats receiving this drug combination did not display hyperactivity or any other behavioral disturbance typically associated with MK-801 treatment, nor show neurotoxic changes in cerebrocortical neurons. In separate experiments on normal unoperated rats, we found that clonidine (0.05 mg/kg s.c.) counteracted the hyperactivity induced by MK-801 (0.05 mg/kg s.c.) and returned activity levels to a normal range. These findings signify that clonidine, which does not specifically relieve neuropathic pain, can potentiate the neuropathic pain-relieving action of MK-801, while also protecting against neurotoxicity and hyperactivity side effects of MK-801. The potentiation is of a sufficient magnitude that it permits cutting the MK-801 dose requirement in half, thereby achieving prolonged neuropathic pain relief while doubling the margin of safety against any type of side effect that might be mediated by blockade of NMDA receptors." [Abstract]

Farber NB, Foster J, Duhan NL, Olney JW.
alpha 2 adrenergic agonists prevent MK-801 neurotoxicity.
Neuropsychopharmacology. 1995 Jul;12(4):347-9.
"Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor are of considerable interest for various neurotherapeutic purposes, including preventing neuronal degeneration in stroke and CNS trauma, suppressing neuropathic pain and preventing the development of tolerance to opiate analgesics. Unfortunately, NMDA antagonists can cause potentially serious side effects, including acute neurodegenerative changes in corticolimbic regions of the adult rat brain and psychotic reactions in adult humans. We have been investigating the mechanisms underlying the neuropathological changes in rat brain and exploring methods of suppressing or preventing such changes. Here we report that alpha 2 adrenergic agonists can prevent NMDA antagonist neurotoxicity. Therefore, administering alpha 2 adrenergic agonists together with NMDA antagonists may be a valuable strategy for preventing adverse side effects of NMDA antagonists and making these agents safer for various neurotherapeutic purposes." [Abstract]

Farber NB, Foster J, Duhan NL, Olney JW.
Olanzapine and fluperlapine mimic clozapine in preventing MK-801 neurotoxicity.
Schizophr Res. 1996 Jul;21(1):33-7.
"Antagonists of the N-methyl-D-Aspartate (NMDA) subtype of glutamate receptor (e.g., phencyclidine, ketamine, MK-801) cause a schizophrenia-like psychosis in humans and neurotoxicity in the adult rat brain. We report here that clozapine and structurally related agents (olanzapine, fluperlapine, loxapine, amoxapine) can prevent NMDA antagonist neurotoxicity in the rat with a rank order corresponding to their ability to mimic the antipsychotic properties of clozapine."

Nakki R, Nickolenko J, Chang J, Sagar SM, Sharp FR.
Haloperidol prevents ketamine- and phencyclidine-induced HSP70 protein expression but not microglial activation.
Exp Neurol. 1996 Feb;137(2):234-41.
"Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, inclu ding ketamine and phencyclidine (PCP), produce abnormal intracellular vacuoles in posterior cingulate and retrosplenial cortical neurons in the rat. Ketamine also induces 70-kDa heat shock protein (HSP70) expression in pyramidal neurons in the posterior cingulate and retrosplenial cortex and, as shown by this study, activates microglia in the retrosplenial cortex of the rat. Whereas HSP70 protein expression was induced with ketamine doses of 40 mg/kg (ip) and higher, doses of 80 mg/kg and higher were required to activate microglia. HSP70-positive neurons were observed in 30- to 90-day-old rats but not in younger, 10- to 20- day old animals following ketamine (80 mg/kg, ip). Pretreatment with the antipsychotic drug haloperidol at doses of 1.0 mg/kg and above abolished all HSP70 immunostaining produced by ketamine (80 mg/kg). However, a single dose of haloperidol (5 mg/kg, im) did not decrease the number of microglia activated in retrosplenial cortex by ketamine (80-140 mg/kg). Similarly, PCP (10 and 50 mg/kg, ip)-induced microglial activation in the posterior cingulate and retrosplenial cortex of adult rats was not blocked by haloperidol (10 mg/kg, im, 1 h prior to PCP). These results suggest that ketamine and PCP injure neurons in the posterior cingulate and retrosplenial cortex of adults rats. Though haloperidol may afford some protection against this injury since it inhibits induction of HSP70 expression, the failure to prevent microglial activation suggests that single doses of haloperidol do not completely protect neurons from NMDA antagonist toxicity."

Farber NB, Nemmers B, Noguchi KK
Acute D(2)/D(3) Dopaminergic Agonism but Chronic D(2)/D(3) Antagonism Prevents NMDA Antagonist Neurotoxicity.
Biol Psychiatry. 2006 Apr 7;
BACKGROUND: Antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor, most likely by producing disinhibtion in complex circuits, acutely produce psychosis and cognitive disturbances in humans, and neurotoxicity in rodents. Studies examining NMDA Receptor Hypofunction (NRHypo) neurotoxicity in animals, therefore, may provide insights into the pathophysiology of psychotic disorders. Dopaminergic D(2) and/or D(3) agents can modify psychosis over days to weeks, suggesting involvement of these transmitter system(s). METHODS: We studied the ability of D(2)/D(3) agonists and antagonists to modify NRHypo neurotoxicity both after a one-time acute exposure and after chronic daily exposure. RESULTS: Here we report that D(2)/D(3) dopamine agonists, probably via D(3) receptors, prevent NRHypo neurotoxicity when given acutely. The protective effect with D(2)/D(3) agonists is not seen after chronic daily dosing. In contrast, the antipsychotic haloperidol does not affect NRHypo neurotoxicity when given acutely at D(2)/D(3) doses. However, after chronic daily dosing of 1, 3, or 5 weeks, haloperidol does prevent NRHypo neurotoxicity with longer durations producing greater protection. CONCLUSIONS: Understanding the changes that occur in the NRHypo circuit after chronic exposure to dopaminergic agents could provide important clues into the pathophysiology of psychotic disorders. [Abstract]

Olney JW, Farber NB.
Efficacy of clozapine compared with other antipsychotics in preventing NMDA-antagonist neurotoxicity.
J Clin Psychiatry. 1994 Sep;55 Suppl B:43-6.
"The focus of this article will be on toxic symptoms associated with blockade of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor. We have been studying two parallel phenomena: NMDA-antagonist neurotoxicity (NAN) in rats and NMDA-antagonist psychotogenicity (NAP) in humans. These phenomena have a common denominator--NMDA receptor hypofunction, which is putatively a mechanism operative in schizophrenia. We have found that the NAN reaction in rats can be prevented by specific drugs that prevent NAP in humans and by certain antipsychotic agents, including clozapine, that ameliorate symptoms in schizophrenia. By studying mechanisms by which clozapine prevents the NAN reaction in rats, we hope to gain insight into mechanisms by which clozapine or other atypical antipsychotics ameliorate symptoms in schizophrenia." [Abstract]

Farber NB, Heinkel C, Dribben WH, Nemmers B, Jiang X
In the adult CNS, ethanol prevents rather than produces NMDA antagonist-induced neurotoxicity.
Brain Res. 2004 Nov 26;1028(1):66-74.
Single doses of an NMDA antagonist cause an adult or a prepubertal form of neurodegeneration, depending on the age of the animal. Single doses of ethanol (EtOH) by blocking NMDA receptors produce apoptotic neurodegeneration in young animals. This capability could account, in part, for the ability of EtOH to produce the fetal alcohol syndrome. We investigated whether EtOH could produce NMDA antagonist-induced neurotoxicity (NAN), a different neurotoxicity that is seen only in adult animals. In spite of producing blood EtOH levels (30 to 600 mg/dl) known to block NMDA receptors, EtOH was unable to produce neurotoxicity in the adult central nervous system (CNS). Moreover, EtOH in a dose-dependent fashion (ED(50)=138 mg/dl) prevented the selective and powerful NMDA antagonist, MK-801, from producing NAN in adult animals, suggesting that activity at another site might be negating the neurotoxic effect of EtOH's inherent NMDA antagonistic activity. Because GABA(A) agonism and non-NMDA glutamate antagonism, properties which EtOH possesses, can prevent NAN, we proceeded to study whether GABA(A) antagonists (or agents capable of reversing EtOH's GABAergic effects) and non-NMDA agonists could reverse EtOH's protective effect. Bicuculline, Ro15-4513, finasteride, kainic acid or AMPA, alone or in combination, did not significantly reverse EtOH's protective effect. Given that EtOH has effects on a wide range of ion channels and receptors, determining the precise mechanism of EtOH's protective effect will take additional effort. The inability of EtOH to acutely produce NAN in the adult CNS indicates that, in contrast to fetuses, brief exposure of the adult CNS to EtOH is non-toxic for neurons. [Abstract]

Farber NB, Jiang XP, Heinkel C, Nemmers B.
Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity.
Mol Psychiatry. 2002;7(7):726-33.
"N-methyl-D-aspartate (NMDA) glutamate receptor antagonists are used in clinical anesthesia and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease, bipolar disorder and schizophrenia. Thus, developing pharmacological means of preventing these NRHypo-induced effects could have significant clinically relevant benefits. NRHypo neurotoxicity appears to be mediated by a complex disinhibition mechanism that results in the excessive stimulation of certain vulnerable neurons. Here we report our findings that five agents (phenytoin, carbamazepine, valproic acid, lamotrigine, and riluzole), thought to possess anticonvulsant activity because they inhibit voltage-gated sodium channels, prevent NRHypo neurotoxicity. The ability of tetrodotoxin, a highly selective inhibitor of voltage-gated sodium channels, to prevent the same neurotoxicity suggests that inhibition of this ion channel is the likely mechanism of action of these five agents. We also found that three other anticonvulsants (felbamate, gabapentin and ethosuximide), whose mechanism is less clear, also prevent NRHypo neurotoxicity, suggesting that inhibition of voltage-gated sodium channels is not the only mechanism via which anticonvulsants can act to prevent NRHypo neurotoxicity. Several of these agents have been found to be of clinical use in bipolar disorder. It would be of interest to determine whether these agents might have therapeutic benefits for conditions in which a NRHypo state may exist." [Abstract]

Tomitaka SI, Hashimoto K, Narita N, Minabe Y, Tamura A.
Regionally different effects of scopolamine on NMDA antagonist-induced heat shock protein HSP70.
Brain Res. 1997 Jul 25;763(2):255-8.
"Using immunohistochemical technique, we investigated the regionally different roles of muscarinic receptors in the induction of HSP-70 by NMDA receptor antagonists. The administration of memantine and phencyclidine induced HSP-70 in the retrosplenial cortex of rat brain. Pretreatment with the muscarinic receptor antagonist scopolamine (0.1-1 mg/kg) blocked induction of HSP-70 in layer III of the retrosplenial cortex. However, induction of HSP-70 in layer V was augmented by scopolamine. These results suggest a regional difference in the mechanism of neurotoxicity induced by NMDA receptor antagonists." [Abstract]

Jevtovic-Todorovic V, Kirby CO, Olney JW.
Isoflurane and propofol block neurotoxicity caused by MK-801 in the rat posterior cingulate/retrosplenial cortex.
J Cereb Blood Flow Metab. 1997 Feb;17(2):168-74.
"In acute brain injury syndromes, the potent N-methyl-D-aspartate (NMDA) antagonist, MK-801, can prevent neuronal degeneration, and the general anesthetics, isoflurane and propofol, may also provide neuroprotective benefits. An obstacle to the use of NMDA antagonists for neuroprotective purposes is that they can cause a neurotoxic vacuole reaction in cerebrocortical neurons. This study demonstrates the ability of isoflurane and propofol to prevent the neurotoxic vacuole reaction induced by MK-801. Low sedative doses of inhaled isoflurane (1%) or intravenous (i.v.) propofol (7.5 mg/kg/h) were as effective as higher general anesthetic doses. Thus, in the clinical management of acute brain injury conditions such as stroke and brain trauma, administration of one of these anesthetic agents together with an NMDA antagonist may be an excellent formula for obtaining optimal neuroprotection while eliminating serious side effects." [Abstract]

Ishimaru M, Fukamauchi F, Olney JW.
Halothane prevents MK-801 neurotoxicity in the rat cingulate cortex.
Neurosci Lett. 1995 Jun 23;193(1):1-4.
"Subcutaneous administration of the N-methyl-D-aspartic acid (NMDA) antagonist, MK-801, to adult rats causes a toxic vacuole reaction in neurons of the posterior cingulate cortex which is readily detected in histological sections 4 h following MK-801 administration. Certain drugs that facilitate neurotransmission at gamma-aminobutyric acidA (GABAA) receptors block this neurotoxic action of MK-801. The anesthetic actions of halothane (fluothane) are thought to be due, at least in part, to an interaction with GABAA receptors. In the present study, we investigated the effect of halothane on MK-801 neurotoxicity. When halothane was administered for either 1 or 2 h, then terminated immediately prior to MK-801 treatment, the vacuole reaction detected 4 h later was almost as severe as in controls not exposed to halothane. Administration of halothane for 1 h after MK-801 injection postponed but did not prevent a relatively full vacuole reaction. However, when rats were kept under halothane anesthesia continuously throughout the 4 h period following MK-801 administration, the vacuole reaction was completely prevented. We postulate that halothane blocks MK-801 neurotoxicity by a facilitative action at GABAA receptors. Because halothane's duration of action is fleeting compared to the very long duration of action of MK-801, the efficacy of halothane in blocking MK-801 neurotoxicity varies in direct proportion to the length of time following MK-801 treatment that the rat brain is exposed to halothane." [Abstract]

Farber NB, Hanslick J, Kirby C, McWilliams L, Olney JW.
Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity.
Neuropsychopharmacology. 1998 Jan;18(1):57-62. [Abstract]

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Recent NMDA Antagonist Neurotoxicity Research

1) Inta D, Filipovic D, Lima-Ojeda JM, Dormann C, Pfeiffer N, Gasparini F, Gass P
The mGlu5 receptor antagonist MPEP activates specific stress-related brain regions and lacks neurotoxic effects of the NMDA receptor antagonist MK-801: significance for the use as anxiolytic/antidepressant drug.
Neuropharmacology. 2012 Apr;62(5-6):2034-9.
Glutamatergic agents have been conceptualized as powerful, fast-acting alternatives to monoaminergic-based antidepressants. NMDA receptor antagonists such as ketamine or MK-801 are therapeutically effective, but their clinical use is hampered by psychotomimetic effects, accompanied by neurotoxicity in the retrosplenial and cingulate cortex. Antagonists of metabotropic mGlu5 receptors like MPEP elicit both robust antidepressant and anxiolytic effects; however, the underlying mechanisms are yet unknown. mGlu5 receptors closely interact with NMDA receptors, but whether MPEP induces neurotoxicity similar to NMDA receptor antagonists has not been elucidated. We show here using c-Fos brain mapping that MPEP administration results in a restricted activation of distinct stress-related brain areas, including the bed nucleus of stria terminalis (BNST), central nucleus of the amygdala, and paraventricular nucleus of the hypothalamus (PVNH), in a pattern similar to that induced by classical antidepressants and anxiolytics. Unlike the NMDA antagonist MK-801, MPEP does not injure the adult retrosplenial cortex, in which it fails to induce heat shock protein 70 (Hsp70). Moreover, MPEP does not elicit to the same extent as MK-801 apoptosis in cortical areas at perinatal stages, as revealed by caspase 3 expression. These data identify new cellular targets for the anxiolytic and antidepressant effect of MPEP, indicating also in addition that in contrast to MK-801, it lacks the cortical neurotoxicity associated with psychotomimetic side-effects. [PubMed Citation] [Order full text from Infotrieve]

2) Iravani MM, Jenner P
Mechanisms underlying the onset and expression of levodopa-induced dyskinesia and their pharmacological manipulation.
J Neural Transm. 2011 Dec;118(12):1661-90.
A significant proportion of patients with Parkinson's disease (PD) receiving dopamine replacement therapy in the form of levodopa develop dyskinesia that becomes a major complicating factor in treatment. Dyskinesia can only be effectively treated by a reduction in drug dose, which limits efficacy, by co-administration of the weak NMDA antagonist amantadine or by surgical treatment (pallidotomy, DBS). This raises the important question of why dyskinesia occurs in PD and how it can be avoided or suppressed by pharmacological treatment. This review assesses some of the mechanisms that underlie dyskinesia induction and expression from presynaptic changes in dopaminergic neurones to postsynaptic alterations in basal ganglia function and examines potential approaches to prevention and treatment. These include glutamatergic approaches where agents that directly or indirectly alter glutamatergic neurotransmission modify the intracellular influx of Ca(2+) and reduce the formation of nitric oxide by neuronal nitric oxide synthase that may form an integral component of the complex cascade of events leading to dyskinesia. There is increasing evidence for the role of serotoninergic neurones in dyskinesia induction related to non-physiological formation and release of dopamine and serotoninergic agonists can modify dyskinesia expression. Similarly, noradrenergic receptors may serve to alter dyskinesia intensity and ?-2-adrenoceptor antagonists alter the expression of levodopa-induced dyskinesia in both experimental models of PD and in man. Finally, other potential approaches to dyskinesia treatment based on manipulation of opiate, cannabinoid, adenosine and histamine receptors are considered. The conclusion is that the cause of levodopa-induced dyskinesia remains to be fully elucidated and that new approaches to treatment through non-dopaminergic mechanisms are required to control the onset and expression of involuntary movements. [PubMed Citation] [Order full text from Infotrieve]

3) Morgan TE, Davis DA, Iwata N, Tanner JA, Snyder D, Ning Z, Kam W, Hsu YT, Winkler JW, Chen JC, Petasis NA, Baudry M, Sioutas C, Finch CE
Glutamatergic neurons in rodent models respond to nanoscale particulate urban air pollutants in vivo and in vitro.
Environ Health Perspect. 2011 Jul;119(7):1003-9.
[PubMed Citation] [Order full text from Infotrieve]

4) Biasi E
Effects of postnatal dietary choline manipulation against MK-801 neurotoxicity in pre- and postadolescent rats.
Brain Res. 2010 Nov 29;1362:117-32.
Prenatal supplementation of rat dams with dietary choline has been shown to provide their offspring with neuroprotection against N-methyl-d-aspartate (NMDA) antagonist-mediated neurotoxicity. This study investigated whether postnatal dietary choline supplementation exposure for 30 and 60 days of rats starting in a pre-puberty age would also induce neuroprotection (without prenatal exposure). Male and female Sprague-Dawley rats (postnatal day 30 of age) were reared for 30 or 60 concurrent days on one of the four dietary levels of choline: 1) fully deficient choline, 2) 1/3 the normal level, 3) the normal level, or 4) seven times the normal level. After diet treatment, the rats received one injection of MK-801 (dizocilpine 3mg/kg) or saline control. Seventy-two hours later, the rats were anesthetized and transcardially perfused. Their brains were then postfixed for histology with Fluorojade-C (FJ-C) staining. Serial coronal sections were prepared from a rostrocaudal direction from 1.80 to 4.2mm posterior to the bregma to examine cell degeneration in the retrosplenial and piriform regions. MK-801, but not control saline, produced significant numbers of FJ-C positive neurons, indicating considerable neuronal degeneration. Dietary choline supplementation or deprivation in young animals reared for 30-60days did not alter NMDA antagonist-induced neurodegeneration in the retrosplenial region. An interesting finding is the absence of the piriform cortex involvement in young male rats and the complete absence of neurotoxicity in both hippocampus regions and DG. However, neurotoxicity in the piriform cortex of immature females treated for 60days appeared to be suppressed by low levels of dietary choline. [PubMed Citation] [Order full text from Infotrieve]

5) Paquette MA, Anderson AM, Lewis JR, Meshul CK, Johnson SW, Paul Berger S
MK-801 inhibits L-DOPA-induced abnormal involuntary movements only at doses that worsen parkinsonism.
Neuropharmacology. 2010 Jun;58(7):1002-8.
Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia in Parkinson's disease patients and abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA) rat model. These medications have been hypothesized to exert their therapeutic effects by a noncompetitive N-methyl-D-aspartate (NMDA) antagonist mechanism, but they also have known serotonin (5-HT) indirect agonist effects that could suppress AIMs. This raised the possibility that NMDA antagonists lacking 5-HTergic effects would not have the anti-dyskinetic action predicted by previous investigators. To test this hypothesis, we investigated MK-801, the most widely-studied NMDA antagonist. We found that chronic low-dose MK-801 (0.1 mg/kg) had no effect on development of AIMs or contraversive rotation. In addition, in L-DOPA-primed rats, low-dose MK-801 (0.1 mg/kg) had no effect on expression of AIMs, contraversive rotation, or sensorimotor function. Conversely, higher doses of MK-801 (0.2-0.3 mg/kg) suppressed expression of AIMs. However, as we show for the first time, anti-dyskinetic doses of MK-801 also suppressed L-DOPA-induced contralateral rotation and impaired sensorimotor function, likely due to non-specific interference of MK-801 with L-DOPA-induced behavior. We conclude that noncompetitive NMDA antagonists are unlikely to suppress dyskinesia clinically without worsening parkinsonism. [PubMed Citation] [Order full text from Infotrieve]

6) Morissette M, Samadi P, Hadj Tahar A, Bélanger N, Di Paolo T
Striatal Akt/GSK3 signaling pathway in the development of L-Dopa-induced dyskinesias in MPTP monkeys.
Prog Neuropsychopharmacol Biol Psychiatry. 2010 Apr 16;34(3):446-54.
L-Dopa treatment, the gold standard therapy for Parkinson's disease, is hampered by motor complications such as dyskinesias. Recently, impairment of striatal Akt/GSK3 signaling was proposed to play a role in the mechanisms implicated in development of L-Dopa-induced dyskinesias in a rodent model of Parkinson's disease. The present experiment investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys, the effects on Akt/GSK3 of chronic L-Dopa treatment inducing dyskinesias compared to L-Dopa with CI-1041 (NMDA receptor antagonist) or a low dose of cabergoline (dopamine D2 receptor agonist) preventing dyskinesias. The extensive dopamine denervation induced by MPTP was associated with a decrease by about half of phosphorylated Akt(Ser473) levels in posterior caudate nucleus, anterior and posterior putamen; smaller changes were observed for phosphorylated Akt(Thr308) levels that did not reach statistical significance. Dopamine depletion reduced phosphorylated GSK3beta(Ser9) levels, mainly in posterior putamen whereas pGSK3beta(Tyr216) and pGSK3alpha(Ser21) were unchanged. In posterior caudate nucleus, anterior and posterior putamen of dyskinetic L-Dopa-treated MPTP monkeys, pAkt(Ser473) and pGSK3beta(Ser9) were elevated whereas L-Dopa+cabergoline treated MPTP monkeys without dyskinesias had lower values in posterior striatum as vehicle-treated MPTP monkeys. In non-dyskinetic MPTP monkeys treated with L-Dopa+CI-1041, putamen pAkt(Ser473) and pGSK3beta(Ser9) levels remained elevated as in dyskinetic monkeys while in posterior caudate nucleus, these levels were low as vehicle-treated and lower than L-Dopa treated MPTP monkeys. Extent of phosphorylation of Akt and GSK3beta in putamen correlated positively with dyskinesias scores of MPTP monkeys; these correlations were higher with dopaminergic drugs (L-Dopa, cabergoline) suggesting implication of additional mechanisms and/or signaling molecules in the NMDA antagonist antidyskinetic effect. In conclusion, our results showed that in MPTP monkeys, loss of striatal dopamine decreased Akt/GSK3 signaling and that increased phosphorylation of Akt and GSK3beta was associated with L-Dopa-induced dyskinesias. [PubMed Citation] [Order full text from Infotrieve]

7) Varanese S, Howard J, Di Rocco A
NMDA antagonist memantine improves levodopa-induced dyskinesias and "on-off" phenomena in Parkinson's disease.
Mov Disord. 2010 Mar 15;25(4):508-10.
[PubMed Citation] [Order full text from Infotrieve]

8) Zhu X, Yao H, Peng F, Callen S, Buch S
PDGF-mediated protection of SH-SY5Y cells against Tat toxin involves regulation of extracellular glutamate and intracellular calcium.
Toxicol Appl Pharmacol. 2009 Oct 15;240(2):286-91.
The human immunodeficiency virus (HIV-1) protein Tat has been implicated in mediating neuronal apoptosis, one of the hallmark features of HIV-associated dementia (HAD). Mitigation of the toxic effects of Tat could thus be a potential mechanism for reducing HIV toxicity in the brain. In this study we demonstrated that Tat-induced neurotoxicity was abolished by NMDA antagonist-MK801, suggesting the role of glutamate in this process. Furthermore, we also found that pretreatment of SH-SY5Y cells with PDGF exerted protection against Tat toxicity by decreasing extracellular glutamate levels. We also demonstrated that extracellular calcium chelator EGTA was able to abolish PDGF-mediated neuroprotection, thereby underscoring the role of calcium signaling in PDGF-mediated neuroprotection. We also showed that Erk signaling pathway was critical for PDGF-mediated protection of cells. Additionally, blocking calcium entry with EGTA resulted in suppression of PDGF-induced Erk activation. These findings thus underscore the role of PDGF-mediated calcium signaling and Erk phosphorylation in the protection of cells against HIV Tat toxicity. [PubMed Citation] [Order full text from Infotrieve]

9) Coleman LG, Jarskog LF, Moy SS, Crews FT
Deficits in adult prefrontal cortex neurons and behavior following early post-natal NMDA antagonist treatment.
Pharmacol Biochem Behav. 2009 Sep;93(3):322-30.
The prefrontal cortex (PFC) is associated with higher cognitive functions including attention and working memory and has been implicated in the regulation of impulsivity as well as the pathology of complex mental illnesses. N-methyl D-aspartate (NMDA) antagonist treatment with dizocilpine induces cell death which is greatest in the frontal cortex on post-natal day seven (P7), however the long-term structural and behavioral effects of this treatment are unknown. This study investigates both the acute neurotoxicity of P7 dizocilpine and the persistent effects of this treatment on pyramidal cells and parvalbumin interneurons in the adult PFC, a brain region involved in the regulation of impulsivity. Dizocilpine treatment on P7 increased cleaved caspase-3 immunoreactivity (IR) in the PFC on P8. In adult mice (P82), P7 dizocilpine treatment resulted in 50% fewer parvalbumin-positive interneurons (p<0.01) and 42% fewer layer V pyramidal neurons (p<0.01) in the PFC. Double immunohistochemistry revealed cleaved caspase-3 IR in both GAD67 IR interneurons and GAD67 (-) neurons. Following dizocilpine treatment at P7, adults showed reduced time in the center of the open field suggesting increased anxiety-like behavior. These findings indicate that early brain insults affecting glutamatergic neurotransmission lead to persistent brain pathology that could contribute to impulsivity and cognitive dysfunction. [PubMed Citation] [Order full text from Infotrieve]

10) Ouattara B, Belkhir S, Morissette M, Dridi M, Samadi P, Grégoire L, Meltzer LT, Di Paolo T
Implication of NMDA receptors in the antidyskinetic activity of cabergoline, CI-1041, and Ro 61-8048 in MPTP monkeys with levodopa-induced dyskinesias.
J Mol Neurosci. 2009 Jun;38(2):128-42.
This study assessed striatal N-methyl-D-aspartate (NMDA) glutamate receptors of 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys with levodopa (L-DOPA)-induced dyskinesias (LID). In a first experiment, four MPTP monkeys receiving L-DOPA/Benserazide alone developed dyskinesias. Four MPTP monkeys received L-DOPA/Benserazide plus CI-1041 an NMDA antagonist selective for NR1/NR2B and four were treated with L-DOPA/Benserazide plus a small dose of cabergoline; one monkey of each group developed mild dyskinesias at the end of treatment. In a second experiment, a kynurenine 3-hydroxylase inhibitor Ro 61-8048, combined with L-DOPA/Benserazide, reduced dyskinesias in MPTP monkeys. Drug-treated MPTP monkeys were compared to intact monkeys and saline-treated MPTP monkeys. Glutamate receptors were investigated by autoradiography using [(3)H]CGP-39653 (NR1/NR2A antagonist) and [(3)H]Ro25-6981 (NR1/NR2B antagonist). In general, striatal [(3)H]CGP-39653 specific binding was unaltered in all experimental groups. MPTP lesion decreased striatal [(3)H]Ro25-6981 specific binding; these levels were enhanced in the L-DOPA-alone-treated MPTP monkeys and decreased in antidyskinetic drugs treated monkeys. Maximal dyskinesias scores of the MPTP monkeys correlated significantly with [(3)H]Ro25-6981 specific binding in the rostral and caudal striatum. Hence, MPTP lesion, L-DOPA treatment and prevention of LID with CI-1041 and cabergoline, or reduction with Ro 61-8048 were associated with modulation of NR2B/NMDA glutamate receptors. [PubMed Citation] [Order full text from Infotrieve]

11) Klimaviciusa L, Safiulina D, Kaasik A, Klusa V, Zharkovsky A
The effects of glutamate receptor antagonists on cerebellar granule cell survival and development.
Neurotoxicology. 2008 Jan;29(1):101-8.
N-Methyl-d-aspartate (NMDA) receptor stimulation promotes neuronal survival and differentiation under both in vitro and in vivo conditions. We studied the effects of various NMDA receptor antagonists acting at different NMDA receptor binding sites and non-NMDA receptor antagonists on the development and survival of cerebellar granule cell (CGC) culture. Only three of the drugs tested induced neurotoxicity-MK-801 (non-competitive NMDA channel blocking antagonist), ifenprodil (an antagonist of the NR2B site and polyamine site of the NMDA receptor) and L-701.324 (full antagonist at glycine site), while CGP-37849 (a competitive NMDA antagonist), (+)-HA-966 (a partial agonist of the glycine site of the NMDA receptor), and NBQX (a competitively acting AMPA receptor antagonist) were not toxic at any concentration (1-100 microM) used. Among these drugs, only MK-801 was toxic for the immature CGC on second day in vitro (2DIV), and toxicity was diminished parallel to the neuronal maturation. In more mature neurons (7DIV), MK-801 demonstrated some neuroprotection, which diminished spontaneously occurring neuronal death in culture. Neither NMDA nor glutamate were able to prevent the neurotoxic effect of MK-801 at 2DIV. MK-801, ifenprodil and L-701.324 induced DNA fragmentation on 2DIV in CGC culture measured by the TUNEL method. The BOC-D-FMK, the universal caspase inhibitor, completely reversed MK-801-induced DNA fragmentation, suggesting an apoptotic pathway of MK-801-induced cell death. Neurite outgrowth as a characteristic feature of the development of CGC was diminished after treatment with MK-801, ifenprodil and L-701.324. In conclusion, the results of the present study demonstrate that only nonselective channel blocker MK-801 decreases cell viability, induces apoptosis and inhibits neurite outgrowth of CGC in a development-dependent manner. [PubMed Citation] [Order full text from Infotrieve]

12) Winter JC
Antagonism of phencyclidine-induced stimulus control in the rat by other psychoactive drugs.
Pharmacol Biochem Behav. 2008 Jan;88(3):189-95.
It has been observed that agents with agonist activity at 5-HT2A receptors prevent neurotoxicity induced by the non-competitive NMDA antagonist, dizocilpine (MK-801). Subsequent behavioral studies reported complete antagonism by LSD and DOM of the stimulus effects of the related NMDA antagonist, phencyclidine [PCP]. The present study sought to extend those observations to include other psychoactive drugs. Male F-344 rats were trained in a 2-lever, fixed-ratio 10, food-reinforced task with PCP (3.0 mg/kg; IP; 30 min pretreatment) as a discriminative stimulus. Tests of generalization were then conducted using the training dose of PCP in combination with a range of doses of DOM, LSD, d-amphetamine, MDMA, psilocybin, buspirone, and GHB. All of the drugs tested in combination with PCP produced a statistically significant diminution of PCP-appropriate responding but for none was antagonism complete. These data, obtained using a stimulus control model of the hallucinogenic effects of PCP, fail to support the hypothesis that LSD and DOM completely antagonize stimulus control by PCP. Instead, the data suggest complex interactions between PCP-induced stimulus control and a variety of psychoactive drugs including GHB, an agent with no known affinity for serotonergic receptors. [PubMed Citation] [Order full text from Infotrieve]

13) Werner CG, Scartabelli T, Pancani T, Landucci E, Moroni F, Pellegrini-Giampietro DE
Differential role of mGlu1 and mGlu5 receptors in rat hippocampal slice models of ischemic tolerance.
Eur J Neurosci. 2007 Jun;25(12):3597-604.
Activation of glutamate receptors has been proposed as a key factor in the induction of ischemic tolerance. We used organotypic rat hippocampal slices exposed to 30 min oxygen-glucose deprivation (OGD) to evaluate postischemic pyramidal cell death in the CA1 subregion. In this model, 10 min exposure to OGD 24 h before the exposure to toxic OGD was not lethal and reduced the subsequent OGD neurotoxicity by approximately 53% (ischemic preconditioning). Similarly, a 30 min exposure to the group I mGlu receptor agonist DHPG (10 microM) significantly reduced OGD neurotoxicity 24 h later (pharmacological preconditioning). Ischemic tolerance did not develop when either the selective mGlu1 antagonists LY367385 and 3-MATIDA or the AMPA/KA antagonist CNQX were present in the incubation medium during exposure to sublethal OGD. Neither the NMDA antagonist MK801 nor the mGlu5 antagonist MPEP affected the preconditioning process. On the other hand, pharmacological preconditioning was prevented not only by LY367385 or CNQX, but also by MPEP. In preconditioned slices, the toxic responses to AMPA or NMDA were reduced. The neurotoxicty of 100 microM DHPG in slices simultaneously exposed to a mild (20 min) OGD was differentially altered in the two preconditioning paradigms. After ischemic preconditioning, DHPG neurotoxicity was reduced in a manner that was sensitive to LY367385 but not to MPEP, whereas after pharmacological preconditioning it was enhanced in a manner that was sensitive to MPEP but not to LY367385. Our results show that mGlu1 and mGlu5 receptors are differentially involved in the induction and expression of ischemic tolerance following two diverse preconditioning stimuli. [PubMed Citation] [Order full text from Infotrieve]

14) Crome O, Doeppner TR, Schwarting S, Müller B, Bähr M, Weise J
Enhanced poly(ADP-ribose) polymerase-1 activation contributes to recombinant tissue plasminogen activator-induced aggravation of ischemic brain injury in vivo.
J Neurosci Res. 2007 Jun;85(8):1734-43.
Recombinant tissue plasminogen activator (rt-PA) treatment improves functional outcome after acute ischemic stroke, inducing reperfusion by its thrombolytic activity. Conversely, there is evidence that rt-PA can mediate neuronal damage after ischemic brain injury in vivo. In addition to other mechanisms, enhancement of N-methyl-D-aspartate (NMDA) receptor signalling has been proposed to underlie rt-PA-mediated neurotoxicity. However, the role of poly(ADP-ribose) polymerase-1 (PARP-1) activation, which mediates postischemic excitotoxic cell death, in rt-PA-mediated aggravation of ischemic brain injury has not been established and was therefore addressed in this study. After permanent focal cerebral ischemia, intravenous rt-PA application significantly increased early postischemic PARP-1 activation within ischemic hemispheres and infarct volumes compared with control mice without affecting cerebral blood flow. Rt-PA induced increase in PARP-1 activation, and infarct volumes could be blocked by the PARP inhibitor 3-aminobenzamide. Moreover, the rt-PA-induced increase in PARP-1 activation was also prevented by the NMDA antagonist MK-801. In summary, we demonstrate that rt-PA treatment enhances postischemic PARP-1 activation, which contributes to rt-PA induced aggravation of ischemic brain injury in vivo. Furthermore, we provide evidence that NMDA receptor activation is required for rt-PA-mediated effects on postischemic PARP-1 activation. [PubMed Citation] [Order full text from Infotrieve]

15) Gilbert ME, Lasley SM
Developmental lead (Pb) exposure reduces the ability of the NMDA antagonist MK-801 to suppress long-term potentiation (LTP) in the rat dentate gyrus, in vivo.
Neurotoxicol Teratol. 2007 May-Jun;29(3):385-93.
Chronic developmental lead (Pb) exposure increases the threshold and enhances decay of long-term potentiation (LTP) in the dentate gyrus of the hippocampal formation. MK-801 and other antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype impair induction of LTP. In addition, Pb exposure reduces presynaptic glutamate release and is associated with alterations in NMDA receptor expression. This study examined LTP in Pb-exposed animals challenged with a low dose of MK-801 to assess the sensitivity of this receptor to inhibition. Pregnant rats received 0.2% Pb acetate in the drinking water beginning on gestational day 16, and this regimen was continued through lactation. Adult male offspring maintained on this solution from weaning were prepared with indwelling electrodes in the perforant path and dentate gyrus. Several weeks later, input/output (I/O) functions were collected in awake animals before and after saline or MK-801 administration (0.05 mg/kg, s.c.). LTP was induced using suprathreshold train stimuli 60 min post-drug. Post-train I/O functions were reassessed 1 and 24 h after train delivery. Upon full decay of any induced LTP, drug conditions were reversed such that each animal was tested under saline and MK-801. I/O functions measured 1 and 24 h after train induction as well as immediate post-train responses revealed significant LTP of comparable magnitude that was induced in both control and Pb-exposed animals tested under saline conditions. In contrast, MK-801 reduced LTP in control but not in Pb-exposed animals. The broadening of the excitatory postsynaptic potential evident in responses evoked by train stimuli is NMDA-dependent. Pb exposure attenuated the MK-801-induced reduction in area of this NMDA component by approximately 50%. These findings are consistent with other neurochemical and behavioural observations and suggest that up-regulation of postsynaptic NMDA receptors produces subsensitivity to the inhibitory effects of MK-801 on hippocampal LTP following chronic developmental Pb exposure. [PubMed Citation] [Order full text from Infotrieve]

16) Marino S, Marani L, Nazzaro C, Beani L, Siniscalchi A
Mechanisms of sodium azide-induced changes in intracellular calcium concentration in rat primary cortical neurons.
Neurotoxicology. 2007 May;28(3):622-9.
An intracellular calcium ([Ca(2+)](i)) increase is involved in sodium azide (NaN(3))-induced neurotoxicity, an in vitro model of brain ischemia. In this study the questions of possible additional sources of calcium influx, besides glutamate receptor activation, and of the time-course of NaN(3) effects have been addressed by measuring [Ca(2+)](i) in rat primary cortical cultures with the FURA-2 method. Basal [Ca(2+)](i) of neuronal populations was concentration-dependently increased 30 min, but not 24h, after a 10-min NaN(3) (3-30 mM) treatment; conversely, the net increase induced by electrical stimulation (10Hz, 10s) was consistently reduced. All the above effects depended on glutamate release and consequent NMDA receptor activation, since the NMDA antagonist MK-801 (1 microM) prevented them, and the spontaneous efflux of [(3)H]-d-aspartate from superfused neurons was concentration-dependently increased by NaN(3). In single neuronal cells, NaN(3) application progressively and concentration-dependently increased [Ca(2+)](i) (to 177+/-5% and 249+/-7% of the controls, 4 and 12 min after a 10mM-treatment, respectively). EGTA (5mM) pretreatment reduced the effect of 10mM NaN(3) (to 118+/-5% at 4 min, and to 148+/-10% at 12 min, respectively), while 1 microM cyclosporin A did not. Both MK-801 and CNQX (a non-NMDA glutamate antagonist, 10 microM) prevented NaN(3) effect at 4 min (to 147+/-8% and 153+/-5%, respectively), but not at 12 min after NaN(3) treatment. Conversely, 10 microM verapamil and 0.1 microM omega-conotoxin (L- and N-type calcium channel blockers, respectively) significantly attenuated NaN(3) effects at 12 min (to 198+/-8% and 164+/-5%, respectively), but not at 4 min; the P/Q-type calcium channel blocker, agatoxin, 0.3 microM, was ineffective. These findings show that the predominant source of calcium increase induced by NaN(3) is extracellular, involving glutamate receptor activation in a first step and calcium channel (mainly of the N-type) opening in a second step. [PubMed Citation] [Order full text from Infotrieve]

17) Feng HJ, Yang L, Faingold CL
Role of the amygdala in ethanol withdrawal seizures.
Brain Res. 2007 Apr 13;1141:65-73.
Ethanol withdrawal (ETX) after induction of ethanol dependence results in a syndrome that includes enhanced seizure susceptibility. During ETX in rodents, generalized audiogenic seizures (AGS) can be triggered by intense acoustic stimulation. Previous studies have implicated specific brainstem nuclei in the neuronal network that initiates and propagates AGS during ETX. Although ethanol and ETX are known to affect amygdala neurons, involvement of the amygdala in the network subserving AGS is unclear. Since ethanol and ETX affect N-methyl-d-aspartate (NMDA) receptors in the amygdala, the present study evaluated the effect of focally microinjecting a NMDA antagonist into the amygdala of rats treated with a binge protocol (intragastric administration of ethanol 3 times daily for 4 days). Separate experiments examined extracellular neuronal firing in the amygdala. Cannulae or microwire electrodes were chronically implanted into the amygdala, and changes in seizure behaviors and/or extracellular action potentials were evaluated. Bilateral focal microinjection of a NMDA antagonist, 2-amino-7-phosphonoheptanoate (AP7), into either central nucleus or lateral nucleus of the amygdala (LAMG) significantly reduced AGS. The doses of AP7 and time course of effect were similar in each site, suggesting that both amygdala nuclei participate in the AGS network. Acoustic responses of LAMG neurons were significantly decreased 1 h after the first ethanol dose and also during ETX, as compared to pre-binge controls. However, LAMG neurons consistently exhibited rapid tonic firing during the generalized tonic convulsions of AGS. These findings suggest a critical role of the amygdala in the ETX seizure network in generating tonic convulsions during AGS. [PubMed Citation] [Order full text from Infotrieve]

18) Slikker W, Paule MG, Wright LK, Patterson TA, Wang C
Systems biology approaches for toxicology.
J Appl Toxicol. 2007 May-Jun;27(3):201-17.
Systems biology/toxicology involves the iterative and integrative study of perturbations by chemicals and other stressors of gene and protein expression that are linked firmly to toxicological outcome. In this review, the value of systems biology to enhance the understanding of complex biological processes such as neurodegeneration in the developing brain is explored. Exposure of the developing mammal to NMDA (N-methyl-D-aspartate) receptor antagonists perturbs the endogenous NMDA receptor system and results in enhanced neuronal cell death. It is proposed that continuous blockade of NMDA receptors in the developing brain by NMDA antagonists such as ketamine (a dissociative anesthetic) causes a compensatory up-regulation of NMDA receptors, which makes the neurons bearing these receptors subsequently more vulnerable (e.g. after ketamine washout), to the excitotoxic effects of endogenous glutamate: the up-regulation of NMDA receptors allows for the accumulation of toxic levels of intracellular Ca(2+) under normal physiological conditions. Systems biology, as applied to toxicology, provides a framework in which information can be arranged in the form of a biological model. In our ketamine model, for example, blockade of NMDA receptor up-regulation by the co-administration of antisense oligonucleotides that specifically target NMDA receptor NR1 subunit mRNA, dramatically diminishes ketamine-induced cell death. Preliminary gene expression data support the role of apoptosis as a mode of action of ketamine-induced neurotoxicity. In addition, ketamine-induced cell death is also prevented by the inhibition of NF-kappaB translocation into the nucleus. This process is known to respond to changes in the redox state of the cytoplasm and has been shown to respond to NMDA-induced cellular stress. Although comprehensive gene expression/proteomic studies and mathematical modeling remain to be carried out, biological models have been established in an iterative manner to allow for the confirmation of biological pathways underlying NMDA antagonist-induced cell death in the developing nonhuman primate and rodent. Published in 2007 John Wiley & Sons, Ltd. [PubMed Citation] [Order full text from Infotrieve]

19) Chase LA, Peterson NL, Koerner JF
The lathyrus toxin, beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (ODAP), and homocysteic acid sensitize CA1 pyramidal neurons to cystine and L-2-amino-6-phosphonohexanoic acid.
Toxicol Appl Pharmacol. 2007 Feb 15;219(1):1-9.
A brief exposure of hippocampal slices to L-quisqualic acid (QUIS) sensitizes CA1 pyramidal neurons 30- to 250-fold to depolarization by certain excitatory amino acids analogues, e.g., L-2-amino-6-phosphonohexanoic acid (L-AP6), and by the endogenous compound, L-cystine. This phenomenon has been termed QUIS sensitization. A mechanism similar to that previously described for QUIS neurotoxicity has been proposed to describe QUIS sensitization. Specifically, QUIS has been shown to be sequestered into GABAergic interneurons by the System x(c)(-) and subsequently released by heteroexchange with cystine or L-AP6, resulting in activation of non-NMDA receptors. We now report two additional neurotoxins, the Lathyrus excitotoxin, beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (ODAP), and the endogenous compound, L-homocysteic acid (HCA), sensitize CA1 hippocampal neurons >50-fold to L-AP6 and >10-fold to cystine in a manner similar to QUIS. While the cystine- or L-AP6-mediated depolarization can be inhibited by the non-NMDA receptor antagonist CNQX in ODAP- or QUIS-sensitized slices, the NMDA antagonist D-AP5 inhibits depolarization by cystine or L-AP6 in HCA-sensitized slices. Thus, HCA is the first identified NMDA agonist that induces phosphonate or cystine sensitization. Like QUIS sensitization, the sensitization evoked by either ODAP or HCA can be reversed by a subsequent exposure to 2 mM alpha-aminoadipic acid. Finally, we have demonstrated that there is a correlation between the potency of inducers for triggering phosphonate or cystine sensitivity and their affinities for System x(c)(-) and either the non-NMDA or NMDA receptor. Thus, the results of this study support our previous model of QUIS sensitization and have important implications for the mechanisms of neurotoxicity, neurolathyrism and hyperhomocystinemia. [PubMed Citation] [Order full text from Infotrieve]

20) Creeley CE, Wozniak DF, Nardi A, Farber NB, Olney JW
Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain.
Neurobiol Aging. 2008 Feb;29(2):153-67.
The NMDA antagonist, memantine (Namenda), and the cholinesterase inhibitor, donepezil (Aricept), are currently being used widely, either individually or in combination, for treatment of Alzheimer's disease (AD). NMDA antagonists have both neuroprotective and neurotoxic properties; the latter is augmented by drugs, such as pilocarpine, that increase cholinergic activity. Whether donepezil, by increasing cholinergic activity, might augment memantine's neurotoxic potential has not been investigated. In the present study, we determined that a dose of memantine (20mg/kg, i.p.), considered to be in the therapeutic (neuroprotective) range for rats, causes a mild neurotoxic reaction in the adult rat brain. Co-administration of memantine (20 or 30 mg/kg) with donepezil (2.5-10mg/kg) markedly potentiated this neurotoxic reaction, causing neuronal injury at lower doses of memantine, and causing the toxic reaction to become disseminated and lethal to neurons throughout many brain regions. These findings raise questions about using this drug combination in AD, especially in the absence of evidence that the combination is beneficial, or that either drug arrests or reverses the disease process. [PubMed Citation] [Order full text from Infotrieve]