Sarchielli P, Alberti A, Codini M, Floridi A, Gallai V
oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal
jugular vein blood during spontaneous migraine attacks.
Despite evidence emerging from the experimental model
of nitroglycerin-induced headache, the endogenous increase in nitric oxide (NO)
production during migraine attacks is only speculative. It has been hypothesized
that there is a close relationship between activation of the L-arginine/NO pathway
and production of certain vasoactive and algogenic prostaglandins during spontaneous
migraine attacks, but this suggestion also needs to be confirmed. In the present
study the levels of nitrites, the stable metabolites of NO, were determined with
high performance liquid chromatography (HPLC) in the internal jugular venous blood
of five patients affected by migraine without aura examined ictally. These samples
were taken within 30 min, 1, 2, and 4 h from the onset of the attack and at the
end of the ictal period. At the same time, the plasma levels of calcitonin gene-related
peptide (CGRP), neurokinin A (NKA), prostaglandin E2 (PGE2) and 6 keto PGF1alpha,
the stable product of PGI2, were assessed with radioimmunoassay (RIA) kits in
the same samples. The levels of the intracellular messengers, cGMP and cAMP, were
also measured with the RIA method. Nitrite, cGMP, CGRP and NKA levels reached
their highest values at the first hour, then they tended to decrease progressively
and returned, after the end of attacks, to values similar or below those detected
at the time of catheter insertion (ANOVA, statistical significance: P<0.001;
P<<0.002; P<0.002; P<0.003, respectively). PGE2 and 6 keto PGF1alpha,
as well as cAMP levels also significantly increased at the first hour but reached
a peak at the 2nd hour and remained in the same range until the 4th and 6th hours.
Then their values tended to decrease after the end of attacks, becoming lower
than those measured immediately after catheter positioning for internal jugular
venous blood drawing (ANOVA: P<0.002, P<0.004, P<0.001, respectively).
Our results support early activation of the L-arginine/NO pathway which accompanies
the release of vasoactive peptides from trigeminal endings and a late rise in
the synthesis of prostanoids with algogenic and vasoactive properties which may
intervene in maintaining the headache phase. [Abstract]
DW, Feniuk W, Humphrey PP
Characterization of the
prostanoid receptor types involved in mediating calcitonin gene-related peptide
release from cultured rat trigeminal neurones.
J Pharmacol. 2001 Nov;134(6):1296-302.
1. Prostaglandins and the vasodilator
neuropeptide, calcitonin-gene related peptide (CGRP), have both been implicated
in the pathogenesis of migraine headache. We have used primary cultures of adult
rat trigeminal neurones to examine the effects of prostanoids on CGRP release
in vitro. 2. CGRP release was stimulated by prostaglandin E2 (PGE2) and the IP
receptor agonist, carbaprostacyclin (cPGI2). These responses were extracellular
calcium-dependent, and the PGE2-induced CGRP release was unaltered by inhibition
of nitric oxide synthase (NOS), ATP receptor blockade, or the addition of adenosine
deaminase. 3. Increases in CGRP levels were also observed in response to prostaglandin
D2 (PGD2), and the EP2 receptor selective agonist, butaprost. No increases in
CGRP release were observed in response to prostaglandin F2alpha (PGF2alpha) or
the TP receptor selective agonist, U46619, or the EP3 receptor selective agonist,
GR63799X. 4. The selective DP receptor antagonist, BWA868C, antagonized the PGD2-,
but not PGE2- or cPGI2-induced release. Furthermore, the EP1 selective antagonist,
ZM325802, failed to antagonize the PGE2-induced CGRP release from these cells.
5. These data indicate that activation of DP, EP and IP receptors can each cause
CGRP release from trigeminal neurones, and suggest that the predominant EP receptor
subtype involved may be the EP2 receptor. Together with evidence that the cyclo-oxygenase
inhibitor, aspirin, particularly when administered intravenously is effective
in treating acute migraine, these findings further suggest a role for prostaglandins
in migraine pathophysiology. [Abstract]
D, Vettori A, Carraro G, Marchioni E, Vazza G, Bellini S, Tupler R, Savoldi F,
A locus for migraine without aura
maps on chromosome 14q21.2-q22.3.
Am J Hum Genet.
Migraine is a common and disabling neurological disease
of unknown origin characterized by a remarkable clinical variability. It shows
strong familial aggregation, suggesting that genetic factors are involved in its
pathogenesis. Different approaches have been used to elucidate this hereditary
component, but a unique transmission model and causative gene(s) have not yet
been identified. We report clinical and molecular data from a large Italian pedigree
in which migraine without aura (MO) segregates as an autosomal dominant trait.
After exclusion of any association between MO and the known familial hemiplegic
migraine and migraine with aura loci, we performed a genomewide linkage analysis
using 482 polymorphic microsatellite markers. We obtained significant evidence
of linkage between the MO phenotype and the marker D14S978 on 14q22.1 (maximum
two-point LOD score of 3.70, at a recombination fraction of 0.01). Multipoint
parametric analysis (maximum LOD score of 5.25 between markers D14S976 and D14S978)
and haplotype construction showed strong evidence of linkage in a region of 10
cM flanked by markers D14S1027 and D14S980 on chromosome 14q21.2-q22.3. These
results indicate the first evidence of a genetic locus associated with MO on chromosome
- Online Mendelian Inheritance in Man: Prostaglandin
E Receptor 2 (EP2)
[The PTGER2 gene has been located at 14q22]
- Online Mendelian Inheritance in Man: Prostaglandin
[The PGDS gene has been located at 14q21-q22]
DW, Langmead CJ, Parsons AA, Strijbos PJ
of calcitonin gene-related peptide release from rat trigeminal nucleus caudalis
slices in vitro.
Neurosci Lett. 2004 Aug 19;366(3):241-4.
gene-related peptide (CGRP) released from trigeminal primary afferents has been
implicated in the pathophysiology of migraine. Here, we have used an in vitro
slice preparation to investigate its release from nerve terminals in the rat trigeminal
nucleus caudalis. Extracellular-calcium dependent CGRP release was stimulated
by both capsaicin and neuronal depolarization with KCl. The capsaicin (1microM)-evoked
CGRP release was blocked by capsazepine and was also attenuated in the presence
of the cyclooxygenase inhibitor, indomethacin, an effect that was reversed when
slices were stimulated with capsaicin in the presence of the cyclooxygenase metabolite,
prostaglandin E(2). Taken together, these data further highlight the importance
of prostaglandins as enhancers of neuropeptide release and suggest that CGRP released
from the central terminals of trigeminal neurones has the potential to be involved
in the transmission of nociceptive information of relevance to migraine headache.
A, Averbeck B, Messlinger K, Reeh PW
Release of substance
P, calcitonin gene-related peptide and prostaglandin E2 from rat dura mater encephali
following electrical and chemical stimulation in vitro.
Neurogenic inflammation of the dura, expressed in plasma
extravasation and vasodilatation, putatively contributes to different types of
headache. A novel in vitro preparation of the fluid-filled skull cavities was
developed to measure mediator release from dura mater encephali upon antidromic
electrical stimulation of the trigeminal ganglion and after application of a mixture
of inflammatory mediators (serotonin, histamine and bradykinin, 10(-5) M each,
pH 6.1) to the arachnoid side of rat dura. The release of calcitonin gene-related
peptide, substance P and prostaglandin E2 from dura mater was measured in 5-min
samples of superfusates using enzyme immunoassays. Orthodromic chemical and antidromic
electrical stimulation of dural afferents caused significant release of calcitonin
gene-related peptide (2.8- and 4.5-fold of baseline). The neuropeptide was found
to be increased during the 5-min stimulation period and returned to baseline (20.9
+/- 12 pg/ml) in the sampling period after stimulation. In contrast, release of
substance P remained at baseline levels (19.3 +/- 11 pg/ml) throughout the experiment.
Prostaglandin E2 release was elevated during chemical and significantly also after
antidromic electrical stimulation (6- and 4.2-fold of baseline, which was 305
+/- 250 pg/ml). Prostaglandin E2 release outlasted the stimulation period for
at least another 5 min. The data support the hypothesis of neurogenic inflammation
being involved in headaches and provide new evidence for prostaglandin E2 possibly
facilitating meningeal nociceptor excitation and, hence, pain. [Abstract]
RJ, Murdoch CE, Ali M, Purbrick S, Ravid R, Baxter GS, Tilford N, Sheldrick RL,
Clark KL, Coleman RA
EP4 prostanoid receptor-mediated
vasodilatation of human middle cerebral arteries.
J Pharmacol. 2004 Feb;141(4):580-5.
1. Dilatation of the cerebral vasculature
is recognised to be involved in the pathophysiology of migraine. Furthermore,
elevated levels of prostaglandin E(2) (PGE(2)) occur in the blood, plasma and
saliva of migraineurs during an attack, suggestive of a contributory role. In
the present study, we have characterised the prostanoid receptors involved in
the relaxation and contraction of human middle cerebral arteries in vitro. 2.
In the presence of indomethacin (3 microm) and the TP receptor antagonist GR32191
(1 microM), PGE(2) was found to relax phenylephrine precontracted cerebral arterial
rings in a concentration-dependent manner (mean pEC(50) 8.0+/-0.1, n=5). 3. Establishment
of a rank order of potency using the EP(4)>EP(2) agonist 11-deoxy PGE(1), and
the EP(2)>EP(4) agonist PGE(1)-OH (mean pEC(50) of 7.6+/-0.1 (n=6) and 6.4+/-0.1
(n=4), respectively), suggested the presence of functional EP(4) receptors. Furthermore,
the selective EP(2) receptor agonist butaprost at concentrations <1 microM
failed to relax the tissues. 4. Blockade of EP(4) receptors with the EP(4) receptor
antagonists AH23848 and EP(4)A caused significant rightward displacements in PGE(2)
concentration-response curves, exhibiting pA(2) and pK(B) values of 5.7+/-0.1,
n=3, and 8.4, n=3, respectively. 5. The IP receptor agonists iloprost and cicaprost
relaxed phenylephrine precontracted cerebral arterial rings (mean pEC(50) values
8.3+/-0.1 (n=4) and 8.1+/-0.1 (n=9), respectively). In contrast, the DP and FP
receptor agonists PGD(2) and PGF(2 alpha) failed to cause appreciable relaxation
or contraction at concentrations of up to 30 microm. In the absence of phenylephrine
contraction and GR32191, the TP receptor agonist U46619 caused concentration-dependent
contraction of cerebral artery (mean pEC(50) 7.4+/-0.3, n=3). 6. These data demonstrate
the presence of prostanoid EP(4) receptors mediating PGE(2) vasodilatation of
human middle cerebral artery. IP receptors mediating relaxation and TP receptors
mediating contraction were also functionally demonstrated. [Abstract]
K, Reeh PW, Averbeck B
ATP can enhance the proton-induced
CGRP release through P2Y receptors and secondary PGE(2) release in isolated rat
Pain. 2002 Jun;97(3):259-65.
afferent neurons express ionotropic P2X receptors for extracellular ATP which
are known to be sensitive to low interstitial pH. Both conditions - ATP release
and tissue acidosis - may occur in the dura following the ischemia phase of migraine
attacks. Aim of this study was to investigate whether and how ATP and protons
may cooperate in exciting meningeal afferents. After removal of the cerebral hemispheres
hemisected scull cavities of adult Wistar rats were used as organ bath of their
own lining, the dura mater. The dura was chemically stimulated and the amounts
of immunoreactive calcitonin gene-related peptide (iCGRP) and prostaglandin E(2)
(PGE(2)) released into incubation fluid were measured using enzyme immunoassays.
Stimulation with ATP (10(-4) and 10(-3)M) augmented iPGE(2) release dose-dependently
whereas iCGRP secretion was minimally enhanced only if the dura had previously
been depleted of extracellular ATP using hexokinase. Acid buffer solutions (pH
5.9 and 5.4) resulted in pH-dependent increase of iCGRP release but reduced iPGE(2)
release. Purines (ATP 10(-3)>UTP 10(-4)M>ATP 10(-4)M) and PGE(2) (10(-5)M)
were found to facilitate the proton-induced increase in iCGRP release. The proton-reduction
of PGE(2) release was overcome by adding ATP (10(-3)M). S(+)-flurbiprofen (10(-6)M)
suppressed both the basal and stimulated iPGE(2) release and prevented the ATP(10(-4)M)-induced
facilitation of the proton response. The facilitating effect of ATP was also blocked
under suramin, a non-selective P2 antagonist, and under reactive blue, an non-selective
P2Y-antagonist, but not under pyridoxalphosphate-6-azophenyl-2',4'-disulphonic
acid, a P2X-antagonist. The present results provide evidence that ATP has poor,
if at all, direct excitatory effects on CGRP-containing trigeminal nerve endings
in the isolated dura and its facilitatory action seems to depend on G-protein
coupled P2Y receptors and secondary PGE(2) release. The UTP effect and the antagonist
profile is indicative for the P2Y(2) receptor subtype. [Abstract]
NSAIDs: behind the mechanisms of action.
Neurol. 2000;15 Suppl 3202-7.
Non-steroidal anti-inflammatory drugs (NSAIDs)
are a heterogeneous group of compounds. These heterogeneous agents have a similar
therapeutic action for the treatment of pain, fever and inflammation. The major
mechanism of action of NSAIDs is the inhibition of cyclooxygenase (COX), the enzyme
catalysing the synthesis of prostaglandins (PGs). Appropriate and effective treatment
for migraine depends upon an accurate diagnosis. The goals of treatment are amelioration
of the symptoms of an acute attack and prevention of further attacks. [Abstract]
W, Goa KL
Diclofenac-potassium in migraine: a review.
The NSAID diclofenac is a potent inhibitor of prostaglandin
synthesis and an established antipyretic and analgesic agent. Diclofenac-potassium
was developed as an immediate-release tablet with the aim of providing rapid onset
of action after oral administration. This formulation has been investigated in
the acute treatment of migraine. Data from available placebo-controlled clinical
trials indicate that diclofenac-potassium 50 or 100mg as an immediate-release
tablet is more effective than placebo and as effective as oral sumatriptan 100mg
and ergotamine plus caffeine at reducing pain intensity in patients with migraine
2 hours after initial administration. Duration of pain relief is similar for the
3 drugs but onset appears to be faster with diclofenac-potassium than with oral
sumatriptan or ergotamine plus caffeine. Diclofenac-potassium appears to have
favourable effects on some accompanying symptoms such as nausea and vomiting.
The frequency of these symptoms was significantly lower with diclofenac-potassium
than with sumatriptan in 1 study, although only a few patients had vomiting at
baseline. Effects on phonophobia or photophobia did not differ between diclofenac-potassium,
sumatriptan and ergotamine plus caffeine. The need for rescue medication is consistently
less with diclofenac-potassium than with placebo. Data are inconsistent or scarce
regarding the effects of diclofenac-potassium versus placebo on other measures
such as headache recurrence and working ability. Diclofenac-potassium was generally
well tolerated in clinical trials in patients with migraine. Adverse events reported
most frequently (abdominal pain, tiredness and fatigue and nausea) were typically
mild to moderate. CONCLUSION: Diclofenac-potassium provides rapid pain relief
(within 60 to 90 minutes), is well tolerated and reduces the frequency of some
of the accompanying symptoms in patients with migraine. Available trials indicate
that diclofenac-potassium provides similar pain relief to sumatriptan and is at
least as effective as ergotamine plus caffeine, but appears to have a greater
effect on nausea and vomiting than sumatriptan and a faster onset of action than
both drugs. Comparisons with other NSAIDs are lacking. Diclofenac-potassium is
likely to find a role as a useful first-line option in the acute treatment of
AE, Micieli G, Bellantonio P, Buzzi MG, Marcheselli S, Pompeo F, Rossi F, Nappi
Indomethacin increases the effect of isosorbide
dinitrate on cerebral hemodynamic in migraine patients: pathogenetic and therapeutic
Cephalalgia. 1998 Nov;18(9):622-30.
vascular reactivity induced by the nitric oxide (NO) donor isosorbide dinitrate
(IDN, 5 mg sublingually) is more major and longer-lasting in migraine patients
who develop delayed headache in response to the drug. The headache is purportedly
due to neuronally-mediated vascular mechanisms. Indomethacin inhibits prostaglandin
synthesis, which is involved in NO generation. Indomethacin also decreases cerebral
blood flow by constricting precapillary resistance vessels. In the present study,
the hemodynamic effects of indomethacin were evaluated in migraine patients and
healthy controls by means of transcranial Doppler monitoring. Indomethacin caused
a significant decrease in mean flow velocity in the middle cerebral artery. This
was an additional effect to the mean velocity decrease induced by IDN. The interactions
between the two drugs suggest that their effects on cerebral hemodynamics (and
pain) may be of relevance both in understanding the role of NO in migraine pathogenesis
and in evaluating symptomatic treatments for migraine attacks. [Abstract]
Management of menstrual migraine.
1999;53(4 Suppl 1):S14-8.
Migraines may occur at any time during the menstrual
cycle but are commonly associated with the menses. Migraine-specific medications,
such as the triptans, may be effective for acute management of menstrual migraine.
However, it is important to recognize the relationship between migraines and the
menstrual cycle because these headaches may not respond to the usual antimigraine
medications. In that case, management may involve perimenstrual migraine prophylaxis,
with migraine-specific medications used in addition for severe breakthrough migraines.
Prostaglandin inhibitors started just before the time of headache vulnerability
may prevent menstrual migraine attacks or reduce the severity of the headaches.
Estrogen withdrawal has been shown to precipitate migraine headaches, and a sustained
elevated level of estrogen will postpone the migraine. Transdermal estrogen started
just before menstruation can provide a sustained low level of estrogen, decreasing
the degree of estrogen decline, and thus may prevent induction of migraines. Ergotamine
tartrate is usually taken only for acute migraine, but may also be effective for
prevention of menstrual migraine when used regularly once or twice per day during
the time of risk. By understanding the underlying pathophysiology of the relationship
between migraines and the menstrual cycle, the physician can successfully treat
migraines associated with menses. [Abstract]
Parantainen J, Vapaatalo H, Hokkanen E
of prostaglandins in migraine.
May;5 Suppl 293-7.
Prostaglandins (PG), particularly PGE, may be linked to
the pathophysiology of migraine in several important ways. PGE1 may "simulate"
a migraine attack in healthy volunteers. PGE may be elevated in patients with
migraine. In animal experiments and in human infusions, PGEs cause vasodilation
and hyperalgesia, both typical reactions of inflammation. The view that vascular
headache is an "inflammatory reaction" allows the best concept concerning
the local role of PGs and the effectiveness of PG-inhibitors in the treatment
of migraine. The local role of PGs may provide a common denominator in several
hormonal, neural and other influences on vessels. The common triggers of a migraine
attack like menstruation, alcohol and stress influence the PG-system and even
the dietary reactions, hormonal influences, sleep and reserpine have some connections
with the PG-system. A local role for PGs does not diminish the importance of other
pathophysiological mechanisms operating during an attack. On the contrary, PGs
may fill in gaps in our understanding of how the overt pain of attacks is produced.
G, Allais G, De Lorenzo C, Benedetto C, Zonca M, Melzi E, Massobrio M
of prostaglandins in true menstrual migraine.
Eighteen patients suffering from true menstrual migraine
and 12 control subjects were studied. We evaluated in different phases of the
menstrual cycle and during the migraine crisis the peripheral plasma concentrations
of 6-keto-PGF1 alpha (the stable metabolite of PGI2), thromboxane B2 (the stable
metabolite of thromboxane A2), PGF2 alpha and PGE2. The mean values of 6-keto-PGF1
alpha in menstrual migraine sufferers are lower than in normal women throughout
the whole cycle. The difference between the trends observed in the two groups
is statistically significant (p less than 0.05). The plasma levels of TXB2 and
of PGF2 alpha are similar in the two groups investigated, both in basal conditions
and during the attack. The plasma concentrations of PGE2 are slightly lower in
migraineurs in basal conditions than in normals. However, during the crisis they
increase significantly (p less than 0.05). In conclusion, among all the parameters
considered, PGE2 seems to play the most important role during the pain phase of
the attack. The results of the present study suggest that a deficit of PGI2, one
of the most important protecting agents against ischemia, might be a typical feature
of menstrual migraine and might cause in these patients a vascular hypersensitivity
to different ischemic stimuli. [Abstract]
G, Zicari A, Favilla M, Lipari M, Martelletti P
activation of nitric oxide synthase and cyclooxygenase in peripheral monocytes
of asymptomatic migraine without aura patients.
Many reports indicate that nitric oxide (NO) could be
involved in migraine without aura (MWA), an extremely diffuse clinical event.
Since monocyte may be a relevant source of NO, we analysed monocyte activation
in MWA patients, in a period in which they were free of symptoms. NO basal production
by MWA peripheral monocytes was significantly higher than in healthy subjects
(91.25+/-8.6 microM/10(6) cells vs. 22.6+/-3.2 microM/106 cells). Interestingly,
even the release of prostaglandin E2 (PGE2), was higher in MWA patients than in
healthy subjects (3137+/-320 pg/10(6) cells vs. 1531+/-220 pg/10(6) cells). The
incubation of monocytes from healthy subjects and MWA patients with N-nitro-L-arginine
methyl ester caused a marked decrease of both NO and PGE2 release. We hypothesise
that NOS and cyclooxygenase pathways in monocytes are linked and are, in MWA patients,
up-regulated, even in a symptoms-free period. NO and PGE2 hyperproduction could
therefore be involved in the neurovascular modifications leading to migraine attacks.
V, Sarchielli P, Trequattrini A, Paciaroni M
chemotactic and phagocytic responses in migraine and tension-type headache patients.
J Neurol Sci. 1993 Mar;14(2):153-64.
Monocyte chemotactic and phagocytic responses
were assessed in two groups of migraine patients (with and without aura) and in
two groups of tension-type headache patients (episodic and chronic). The chemotactic
but not the phagocytic response, assessed interictally, is significantly lower
in migraine patients (p < 0.006) and in episodic tension-type headache patients,
though not so significantly in the latter (p < 0.05), than in the control
individuals. The chemotactic response tends to increase significantly during attack
in migraine patients both with and without aura (p < 0.008 and p < 0.007
respectively). The same was evident for the phagocytic response in both migraine
patient groups (p < 0.007 and 0.0004). No modifications of monocyte functions
were found during attacks neither in episodic nor chronic tension-type headache
patients. These findings suggest that one or more mediators of neurogenic inflammation
having phagocytic and chemotactic enhancing properties (substance P, prostaglandin
E and thromboxane A2 etc.) are implicated in the modification of monocyte function.
The demonstration of a defect in monocyte function during the interictal period
in migraine patients confirms the results of recent research which evidenced reduced
capacity of monocyte to phagocyte and kill microorganisms in the course of migraine.
P, Hummel T, Arora C, Carpenter T
of inflammatory mediators in migraineurs during headache-free periods.
OBJECTIVES: The present study investigated the peripheral
inflammatory changes of the trigeminovascular system by measuring the inflammatory
mediators leukotriene B4 (LTB(4)), prostaglandin E2 (PGE(2)), and thromboxane
B2 (TXB(2)) in the nasal fluid, as well as saliva, of patients with migraine.
BACKGROUND: Migraine has been hypothesized to be as a result of changes in the
peripheral or central nervous system or both. It is still unclear whether peripheral
changes in the trigeminovascular system are involved in the pathogenesis of migraine.
METHODS: Participants were 18 subjects, 9 patients with migraine and 9 controls,
matched for age and sex. Each subject took part in one experimental session during
which nasal lavage fluid and saliva samples were collected. These samples were
analyzed by competitive enzyme immunoassay using goat anti-rabbit polyclonal antibody.
RESULTS: With the exception of TXB(2), correlational analyses indicated good correlations
between results obtained using nasal lavage or saliva (LTB(4), r(18) = 0.91; PGE(2),
r(18) = 0.95). When comparing inflammatory mediators measured in controls and
migraineurs, the LTB(4) level was significantly lower in migraineurs, while no
differences were found for PGE(2) and TXB(2). CONCLUSIONS: The study demonstrated
that nasal lavage, a noninvasive method, can be easily used for investigations
of pathophysiological mechanisms of migraine. In addition, the results may indicate
that there is no peripheral trigeminal sensitization in the headache-free period
of migraineurs compared with controls when PGE(2), LTB(4), and TXB(2) in saliva
and nasal lavage samples are measured. [Abstract]
Z, Blix GG, Hopp HP, Leslie FM, Schell MJ
of a low-fat diet on incidence and severity of migraine headaches.
Womens Health Gend Based Med. 1999 Jun;8(5):623-30.
Migraine headaches are
a common, debilitating syndrome causing untold suffering and loss of productivity.
A review of the literature indicates that high levels of blood lipids and high
levels of free fatty acids are among the important factors involved in triggering
migraine headaches. Under these conditions, platelet aggregability, which is associated
with decreased serotonin and heightened prostaglandin levels, is increased. This
leads to vasodilation, the immediate precursor of migraine headache. A high-fat
diet is one factor that may directly affect this process. This study, undertaken
to evaluate the impact of dietary fat intake on incidence and severity of migraine
headache, was conducted over a 12-week period on 54 previously diagnosed migraine
headache patients. During the first 28 days, the study subjects recorded all food
consumption in a diet diary and maintained a headache diary. At the conclusion
of this 28-day baseline period, subjects were individually counseled to limit
fat intake to no more than 20 g/day. A 28-day run-in period was allowed for adaptation
to the low-fat diet. Results are reported on the final 28-day postintervention
period. Subjects significantly decreased the ingestion of dietary fat in grams
between baseline (mean 65.9 g/day, p < 0.0001) and the postintervention period
(mean 27.8 g/day). The decreased dietary fat intervention was associated with
statistically significant decreases in headache frequency, intensity, duration,
and medication intake (all p < 0.0001). There was a significant positive correlation
between baseline dietary fat intake and headache frequency (r = .44, p = 0.02).
This study indicates that a low-fat diet can reduce headache frequency, intensity,
and duration and medication intake. [Abstract]
Mechanisms in adverse reactions to food. The brain.
Specific chemical mediator release such as histamine
and the prostaglandins (PG2a or PGD2) associated with headaches has been found
in a few patients who were repeatedly challenged with specific foods, using DBPCFC
F, de Luyk S, Radillo O, Simeone R, Mangiarotti M
possible role of platelet insensitivity to prostaglandin E1 (PGE1).
Neurol. 1993 Nov-Dec;8(6):403-8.
Platelet aggregation inhibition, induced by
prostaglandin E1 (PGE1), was evaluated in 38 patients affected by migraine. Our
data indicate a complete insensitivity to PGE1 in these subjects. The insensitivity
to PGE1 leads to decreased cyclic-AMP (cAMP) levels, determining an imbalance
in the inhibitory mechanism. From this observation we can suppose that the decreased
affinity of PGE1-receptors, causing decreased cAMP levels, may be involved in
pathogenesis of migraine. [Abstract]
Z, Kis B, Gecse A, Tajti J, Boda B, Telegdy G, Vécsei L
arachidonate cascade of migraineurs in the interictal phase.
Morphological and functional alterations of platelets
in migraineurs may be linked to the development of migraine. We examined the eicosanoid
synthesis of platelets of untreated female migraineurs in a headache-free period
and compared it to that of age- and blood group-matched healthy female volunteers.
In the platelets of headache-free migraineurs significantly less amounts of anti-aggregatory
prostaglandin D2 and prostacyclin, as well as of 12-L-hydroxy-5,8,10-heptadecatrienoic
acid (a potent endogenous inducer of endothelial prostacyclin production) were
produced, while the synthesis of platelet aggregatory thromboxane did not differ
when compared to that of healthy women. These results suggest that the platelet
eicosanoids of migraineurs in the headache-free period might promote the development
of cellular, vascular and neurological events inducing headache. [Abstract]
J, Mattsson P, Basu S
Prostaglandin F(2alpha) metabolite
and F(2)-isoprostane excretion rates in migraine.
Sci (Lond). 2002 Jan;102(1):39-43.
The pathophysiology theory of migraine postulates
a local, neurogenic inflammation and the possible involvement of oxidative stress.
We analysed the levels of 15-oxo-dihydro-prostaglandin F(2alpha) (a metabolite
of prostaglandin F(2alpha)) and 8-iso-prostaglandin F(2alpha) (a major isoprostane),
which are biomarkers for inflammation and oxidative stress respectively, in urine
from 21 patients with migraine, with and without aura. Urine samples from migraine
patients were collected during a migraine attack, and control samples were collected
from the same subjects on a migraine-free morning. The mean basal levels of 15-oxo-dihydro-prostaglandin
F(2alpha) and 8-iso-prostaglandin F(2alpha) in the morning control urine samples
were 0.54+/-0.11 and 0.31+/-0.13 nmol/mmol of creatinine respectively. The mean
levels of 15-oxo-dihydro-prostaglandin F(2alpha) and 8-iso-prostaglandin F(2alpha)
in the urine samples collected during the migraine attack in the 21 patients were
0.53+/-0.13 and 0.32+/-0.11 nmol/mmol of creatinine respectively. Thus there were
no differences in the 15-oxo-dihydro-prostaglandin F(2alpha) and 8-iso-prostaglandin
F(2alpha) excretion rates during the migraine attack compared with on the migraine-free
day. However, the basal 8-iso-prostaglandin F(2alpha) excretion levels on the
migraine-free day were significantly lower in pre-menopausal women (0.24+/-0.08
nmol/mmol of creatinine, n=11) compared with post-menopausal women (0.39+/-0.14
nmol/mmol of creatinine; n=7; P=0.009). In conclusion, in this study we found
no support for the involvement of inflammation and oxidative stress in migraine
pathophysiology. Our results indicate, however, a lower level of oxidative stress
in pre-menopausal compared with post-menopausal women. [Abstract]
M, Sakai K
Increased main urinary metabolite of prostaglandin
F2 alpha excretion in childhood migraine.
Child. 1988 Mar;63(3):342. [Abstract]
JK, Breder CD, Sherin JE, Scammell TE, Hickey WF, Dewitt D, Saper CB
lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain
perivascular microglia and meningeal macrophages.
Comp Neurol. 1997 May 5;381(2):119-29.
Production of prostaglandins is a critical
step in transducing immune stimuli into central nervous system (CNS) responses,
but the cellular source of prostaglandins responsible for CNS signalling is unknown.
Cyclooxygenase catalyzes the rate-limiting step in the synthesis of prostaglandins
and exists in two isoforms. Regulation of the inducible isoform, cyclooxygenase
2, is thought to play a key role in the brain's response to acute inflammatory
stimuli. In this paper, we report that intravenous lipopolysaccharide (LPS or
endotoxin) induces cyclooxygenase 2-like immunoreactivity in cells closely associated
with brain blood vessels and in cells in the meninges. Neuronal staining was not
noticeably altered or induced in any brain region by endotoxin challenge. Furthermore,
many of the cells also were stained with a perivascular microglial/macrophage-specific
antibody, indicating that intravenous LPS induces cyclooxygenase in perivascular
microglia along blood vessels and in meningeal macrophages at the edge of the
brain. These findings suggest that perivascular microglia and meningeal macrophages
throughout the brain may be the cellular source of prostaglandins following systemic
immune challenge. We hypothesize that distinct components of the CNS response
to immune system activation may be mediated by prostaglandins produced at specific
intracranial sites such as the preoptic area (altered sleep and thermoregulation),
medulla (adrenal corticosteroid response), and cerebral cortex (headache and encephalopathy).
K, Ebersberger A, Pawlak M, Oppmann M, Messlinger K
of trigeminal brain stem neurons by chemical stimulation of the dura mater encephali--preparation
for studying meningeal nociception in the rat]
1997 Oct 24;11(5):322-7.
INTRODUCTION: Headache is thought to be generated
by nociceptive processes within the meninges, followed by activation of trigeminal
neurons within the brainstem. The noxious stimuli initially involved in these
nociceptive processes are unknown. A preparation was developed in the barbiturate-anesthetized
rat, in which the activation of trigeminal brain stem neurons by selective local
stimulation of the dura mater could be observed. METHODS: The dura mater encephali
was exposed by trepanizing the parietal bone up to the sagittal superior sinus.
The surface of the dura was stimulated with electrical pulses using bipolar electrodes.
Extracellular recordings were made from neurons in the subnucleus interpolaris
and caudalis of the spinal trigeminal nucleus. Neurons driven by meningeal afferents
were identified by electrical stimulation and by probing their receptive fields
on the dura mater. For chemical stimulation a combination of several inflammatory
mediators (bradykinin, serotonin, histamine and prostaglandin E(2), each 10(-4)M,
6.1) was topically applied to the dura mater or injected through a catheter into
the sagittal sinus. RESULTS: Most of the trigeminal brain stem neurons with input
from the parietal dura mater had convergent input from the facial skin with preponderance
of the periorbital region. A high proportion of neurons (69%) could be activated
by the combination of inflammatory mediators administered to the dura mater. CONCLUSION:
We conclude that chemical stimuli activating the meningeal nociceptive system
may play a decisive role in the generation of headache. This is particularly relevant
for the nociceptive processes during neurogenic inflammation, which is believed
to be an important step in the pathophysiology and development of migraine pain.
The preparation presented here may be a valuable model for further studying the
neurophysiological changes that are involved in the generation of headache. [Abstract]
YE, Levy MJ, O'Shaughnessy CT, Goadsby PJ
E2 injected into the posterior hypothalamus has no effect on trigeminal nociception
in the rat.
Neurosci Lett. 2003 Oct 23;350(2):85-8.
prostaglandin E2 (PGE2) release is elevated in the headache phase of migraine
and in experimental models of headache. PGE2 synthesised in the brain may be involved
in modulating trigeminal nociception. We examined whether PGE2 injected into the
posterior hypothalamus could modulate trigeminovascular nociception. In seven
rats, electrophysiological recordings were made from trigeminal nucleus caudalis
neurons responsive to noxious middle meningeal artery stimulation and inhibited
by bicuculline activation of the posterior hypothalamus. Microinjection into the
posterior hypothalamus of a non-pyrogenic dose of PGE2 (2.5 microg/ml) produced
no effect on nociceptive trigeminal nucleus caudalis neurons compared with saline
injection (P=0.29). The mean response to PGE2 injection was 97% of baseline. We
conclude that PGE2 in the posterior hypothalamus is unlikely to play a significant
role in modulating trigeminal nociception. [Abstract]