cyclic-gmp and Migraine-Disorders

Migraine remains a challenging condition to treat, thus highlighting the need for a better understanding of its molecular mechanisms. This review intends to unravel a new emerging target in migraine pathophysiology, the adenosine 5'-triphosphate-sensitive K. K

Topics: Animals; Bronchodilator Agents; Cromakalim; Cyclic AMP; Cyclic GMP; Drug Delivery Systems; Humans; KATP Channels; Migraine Disorders; Potassium Channel Blockers

Ample evidence that nitric oxide (NO) is a causative molecule in migraine has encouraged research to develop drugs that target the NO-cGMP cascade for migraine treatment. NO synthase (NOS) inhibition is an innovative therapeutic principle.. This paper reviews the rationale underlying NOS inhibition in migraine treatment. It also provides a review on the efficacy and safety data for NOS inhibitors (nonselective NOS inhibitor L-N(G)-methyl-arginine hydrochloride [L-NMMA], selective inducible NOS [iNOS] inhibitors GW273629 and GW274150, combined neuronal NOS [nNOS] inhibitor and 5-HT1B/1D receptor agonist NXN-188) in acute or preventive migraine treatment.. The data highlighted herein, from four placebo-controlled trials and 1 open-labeled clinical trial using 4 different NOS inhibitors on a total of 705 patients, provide convincing efficacy data only for the nonselective NOS inhibitor L-NMMA. Unfortunately, this NOS inhibitor raises cardiovascular safety concerns and has an unfavorable pharmacokinetic profile. As experimental studies predicted, iNOS inhibitors are ineffective in migraine. Still, upcoming selective nNOS inhibitors are a hope for migraine treatment, with the nNOS isoform being most clearly involved in trigeminovascular transmission and central sensitization. Future studies should help to clarify whether NOS inhibition is equally fruitful in acute and preventive treatment. It should also clarify if nNOS inhibition holds promise as a therapeutic tool for the treatment of chronic migraine and other forms of headache.

Topics: Animals; Cyclic GMP; Drug Design; Enzyme Inhibitors; Humans; Migraine Disorders; Molecular Targeted Therapy; Nitric Oxide; Nitric Oxide Synthase

The most important primary headaches (i.e. independent disorders that are not caused by another disease) are migraine, tension-type headache and cluster headache. All primary headaches are in need of better treatments. Migraine has a prevalence of 10% in the general population and its societal costs are high. Although the precise mechanisms underlying the pathophysiology of migraine are still elusive, the last decades have witnessed some progress (e.g. involvement of serotonin, calcitonin gene-related peptide, nitric oxide, etc). Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-NMMA effectively treats attacks of migraine without aura. Similar results have been obtained for chronic tension-type headache and cluster headache. Inhibition of the breakdown of cGMP also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine. Several relationships exist between NO, calcitonin gene-related peptide and other molecules important in migraine. Also ion channels, particularly the K(ATP) channels, are important for the action of NO. In conclusion, inhibition of NO production or blockade of steps in the NO-cGMP pathway or scavenging of NO may be targets for new drugs for treating migraine and other headaches. Indeed, selective n-NOS and i-NOS inhibitors are already in early clinical development.

Topics: Animals; Calcitonin Gene-Related Peptide; Cluster Headache; Cyclic GMP; Drug Delivery Systems; Humans; Ion Channels; Migraine Disorders; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Tension-Type Headache

To assess whether migraine patients display a chronic nitric oxide synthase (NOS) hyperactivity by comparing the nitric oxide (NO) production before and following a loading dose of L-arginine between migraine patients (interictally) and matched healthy control subjects. In addition, we evaluated whether a loading dose of L-arginine triggers an acute migraine headache in migraineurs.. Twenty healthy subjects and 20 migraine patients participated in a 2-period, randomised, double-blind, placebo-controlled study. Each subject received a 30-min infusion, by peripheral vein, of 30 g L-arginine hydrochloride or placebo (i.e. an equal volume of 0.9% saline solution). Meanwhile, biomarkers associated with the L-arginine-NO pathway (i.e. exhaled NO/nasal NO), plasma citrulline and urinary excretion of nitrite/nitrate and cGMP were assessed before and for 6 h following the start of the infusion.. At baseline, exhaled NO and nasal NO were higher in migraineurs compared to healthy subjects (mean±95% confidence interval): 15.9 (8.8, 23.0) parts per billion (ppb) versus 10.8 (7.0, 14.5) ppb for exhaled NO (P=0.04) and 76.3 (61.2, 91.4) versus 61.6 (51.2, 72.0) ppb for nasal NO (P=0.03), respectively. The AUC0-6 in ppb for exhaled NO and nasal NO following L-arginine or saline infusion did not differ between both groups. The increase in L-citrulline, following L-arginine infusion, was smaller in migraine patients (15 (13, 18) µmol/l) compared to healthy volunteers (19 (16, 23) µmol/l; P=0.046). In healthy subjects, both nitrate and cGMP excretion were higher following L-arginine compared to placebo infusion: 132.63 (100.24, 165.02) versus 92.07 (66.33, 117.82) µmol/mmol creatinine for nitrate (P=0.014) and 50.53 (42.19, 58.87) versus 39.64 (33.94, 45.34) nmol/mmol creatinine for cGMP (P=0.0003), respectively. In migraineurs, excretion of these biomarkers was comparable following L-arginine or saline infusion.. The results of the present study do not support the idea of a generalised increase in NO synthase activity in migraine patients outside of a migraine attack. The smaller increase in plasma L-citrulline, urinary nitrate and cGMP excretion following L-arginine infusion in migraine patients might indicate dysfunction of endothelial NO synthase.

Topics: Area Under Curve; Arginine; Biomarkers; Citrulline; Cyclic GMP; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrites

Over the past three decades, calcitonin gene-related peptide (CGRP) has emerged as a key molecule. Provocation experiments have demonstrated that intravenous CGRP infusion induces migraine-like attacks in migraine with and without aura patients. In addition, these studies have revealed a heterogeneous CGRP response, i.e., some migraine patients develop migraine-like attacks after CGRP infusion, while others do not. The role of CGRP in human migraine models has pointed to three potential sites of CGRP-induced migraine: (1) vasodilation via cyclic adenosine monophosphate (cAMP) and possibly cyclic guanosine monophosphate (cGMP); (2) activation of trigeminal sensory afferents, and (3) modulation of deep brain structures. In the future, refined human experimental studies will continue to unveil the role of CGRP in migraine pathogenesis.

Topics: Calcitonin; Calcitonin Gene-Related Peptide; Cyclic AMP; Cyclic GMP; Humans; Migraine Disorders

The group of catecholamines, which include dopamine, adrenaline, and noradrenaline, are neurotransmitters which have been considered to play a role in the pathogenesis of migraine. However, the impact of catecholamines, especially dopamine on migraine as well as the exact mechanisms is not clear to date as previous studies have yielded in part conflicting results.. This study aimed to produce a comprehensive examination of dopamine in migraineurs.. Catecholamines and various parameters of the homocysteine, folate, and iron metabolism as well as cyclic guanosine monophosphate (cGMP) and inflammatory markers were determined in 135 subjects.. We found increased dopamine levels in the headache free period in female migraineurs but not in male patients. Increased dopamine is associated with a 3.30-fold higher risk for migraine in women. We found no significant effects of aura symptoms or menstrual cycle phases on dopamine levels. Dopamine is strongly correlated with cGMP and the homocysteine-folate pathway.. We show here that female migraineurs exhibit increased dopamine levels in the headache free period which are associated with a higher risk for migraine.

Topics: Adult; Biomarkers; Brain; Cyclic GMP; Dopamine; Female; Homocysteine; Humans; Inflammation Mediators; Interleukins; Iron; Male; Middle Aged; Migraine Disorders; Predictive Value of Tests; Sex Characteristics; Up-Regulation

Migraine is associated with increased risk of cardiovascular disease, but the mechanisms are unclear.. To investigate the activity of endothelial and vascular smooth muscle cells (VSMCs) in patients with migraine.. Case-control study of 12 patients with migraine without aura and 12 matched healthy control subjects. Endothelial and VSMC components of vascular reactivity were explored by plethysmography measurement of forearm blood flow (FBF) during infusions of vasoactive agents into the brachial artery. Forearm production of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) was also quantified.. In patients with migraine, the vasodilating effect of acetylcholine (ACh), an endothelium-dependent vasodilator, was markedly reduced (p < 0.001 by analysis of variance). In response to the highest dose of ACh, FBF rose to 8.6 +/- 2.2 in patients with migraine and to 22.7 +/- 3.0 mL x dL(-1) x min(-1) in controls (p = 0.001). The dose-response curve to nitroprusside, a vasodilator directly acting on VSMCs, was depressed in patients with migraine (p < 0.001 by analysis of variance). The maximal response of FBF to nitroprusside was 12.1 +/- 2.0 in patients with migraine and 24.1 +/- 1.8 mL x dl(-1) x min(-1) in controls (p < 0.001). During ACh infusion, NO release from the endothelium was similar in patients and controls. In contrast, there was a marked release of cGMP from VSMCs in controls, but not in patients with migraine (-1.9 +/- 2.2 in patients with migraine and -19.1 +/- 5.4 nmol x dL(-1) x min(-1) in controls; p = 0.03).. Patients with migraine are characterized by a distinct vascular smooth muscle cell dysfunction, revealed by impaired cyclic guanosine monophosphate and hemodynamic response to nitric oxide.

Topics: Acetylcholine; Adult; Blood Pressure; Brachial Artery; Cardiovascular Diseases; Case-Control Studies; Comorbidity; Cyclic GMP; Endothelial Cells; Female; Hemodynamics; Humans; Male; Migraine Disorders; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Regional Blood Flow; Vasoconstriction; Vasodilation; Vasodilator Agents

Although the involvement of nitric oxide (NO) in mediating pain and neurovascular coupling is well established, the precise mechanisms sustaining these effects are still unclear. Cyclic GMP (cGMP) probably represents the main effector of the biological effects of NO at the vascular and neuronal levels. Nitroglycerin is a NO donor, which easily crosses the blood brain barrier. Several reports have suggested that the study of nitroglycerin effects upon neuronal and cerebrovascular elements is a useful animal model for investigating the pathophysiological mechanisms underlying migraine. In this study, the anatomic distribution of cGMP in the rat brain was evaluated at serial time-points after systemic administration of nitroglycerin or vehicle. The results show an increase in cGMP immunoreactivity in the nucleus trigeminalis caudalis and in the superficial cortical arterioles 2, 3 and 4h after the drug administration. The data obtained sustains the idea that cGMP is an important mediator of nitroglycerin effect in vascular and neuronal structures that are critical elements for the transmission of cephalic pain.

Topics: Animals; Arterioles; Brain; Cerebrovascular Circulation; Cyclic GMP; Disease Models, Animal; Immunohistochemistry; Male; Migraine Disorders; Neurons; Nitroglycerin; Rats; Rats, Sprague-Dawley; Time Factors; Vasodilator Agents

1. The pharmaceutical compound, dihydroergotamine (DHE) is dispensed to prevent and reduce the occurrence of migraine attacks. Although still controversial, the prophylactic effect of this drug is believed to be caused through blockade and/or activation of numerous receptors including serotonin (5-HT) receptors of the 5-HT2 subtype. 2. To elucidate if 5-HT2 receptors (5-HT2Rs) may be involved in DHE prophylactic effect, we performed investigations aimed to determine the respective pharmacological profile of DHE and of its major metabolite 8'-hydroxy-DHE (8'-OH-DHE) at the 5-HT2B and 5-HT2CRs by binding, inositol triphosphate (IP3) or cyclic GMP (cGMP) coupling studies in transfected fibroblasts. 3. DHE and 8'-OH-DHE are competitive compounds at 5-HT2B and 5-HT2CRs. 8'-OH-DHE interaction at (5-HT2BRs) was best fitted by a biphasic competition curve and displayed the highest affinity with a Ki of 5 nm. These two compounds acted as agonists for both receptors in respect to cGMP production with pEC50 of 8.32+/-0.09 for 8'-OH-DHE at 5-HT2B and 7.83+/-0.06 at 5-HT2CRs. 4. Knowing that the antimigraine prophylactic effect of DHE is only observed after long-term treatment, we chronically exposed the recombinant cells to DHE and 8'-OH-DHE. The number of 5-HT2BR-binding sites was always more affected than 5-HT2CRs. At 5-HT2BRs, 8'-OH-DHE was more effective than DHE, with an uncoupling that persisted for more than 40 h for IP3 or cGMP. By contrast, the 5-HT2CR coupling was reversible after either treatment. 5. Chronic exposure to 8'-OH-DHE caused a persistent agonist-mediated desensitisation of 5-HT2B, but not 5-HT2CRs. This may be of relevance to therapeutic actions of the compound.

Topics: Amphetamines; Animals; Binding, Competitive; Cell Line; Cyclic GMP; Dihydroergotamine; Humans; Inositol Phosphates; Iodine Radioisotopes; Kinetics; Migraine Disorders; Radioligand Assay; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists; Time Factors; Treatment Outcome

Migraine headache is proposed to be mediated by nitric oxide (NO). Suitable mechanisms for eliciting increases in brain NO concentration in migraineurs have not yet been identified, although, animal models highlight cortical spreading depression (CSD) as a potential candidate. These studies have focused on CSD-associated NO release at highly acute time points (min-hours) and have not employed markers of NO metabolism with direct clinical application e.g. cGMP. The current study evaluated changes in plasma cGMP concentrations 3 h, 24 h and 3 days post-CSD and compared these to cortical and brainstem cGMP concentrations at 3 days. Moreover, this study also examined the effect of sumatriptan, a clinically effective antimigraine agent, and tonabersat (SB-220453) a potential novel antimigraine agent, on any observed changes in cGMP. Following pre-treatment with vehicle (n=3), sumatriptan (300 microg kg(-1) i.v, n=3) or tonabersat (SB-220453 10 mg kg(-1) i.p., n=3), CSD was evoked in anaesthetised rats by a 6-min KCl application to the parietal cortex. In the vehicle-treated group a median of eight depolarisations, were observed. Sumatriptan had no effect on the number of depolarisations, whereas tonabersat significantly reduced the number of events (median=2). No depolarisation events were observed throughout the recording period in the sham group. Following KCl application plasma cGMP concentrations were reduced up to 24 h post-CSD, but not significantly different from sham animals at 3 days. CSD in vehicle-treated animals produced a highly significant elevation in cGMP concentration in the brain stem 3 days after application of KCl. cGMP concentration increased 2.3-fold from 68+/-8 fmol/mg in sham animals (n=3) to 158+/-28 fmol/mg in the vehicle group. This increase in brain stem cGMP was abolished by tonabersat pre-treatment but not by sumatriptan.

Topics: Analgesics; Animals; Benzamides; Benzopyrans; Brain Stem; Cerebral Cortex; Cortical Spreading Depression; Cyclic GMP; Male; Migraine Disorders; Nitric Oxide; Nitric Oxide Synthase; Potassium Chloride; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sumatriptan; Vasoconstrictor Agents

Nitric oxide (NO) is a candidate as a causative molecule in migraine. We determined nitrite, total nitrate/nitrite, and cyclic guanosine 3',5'-monophosphate (cGMP) concentrations in platelets from 30 migraine without aura (MwoA) patients and 17 migraine with aura (MwA) patients. All migraine patients were studied during their migraine attacks. The control group consisted of 28 healthy volunteers. Concentrations of platelet nitrite and total nitrate/nitrite were determined using simple and sensitive nitrate/nitrite fluorometric assay techniques. High concentrations of platelet nitrite and total nitrate/nitrite were found in patients with MwoA and MwA when compared with healthy controls. High concentrations of platelet cGMP were also found in patients with MwoA and MwA. The levels of platelet total nitrate/nitrite significantly decreased in headache-free periods after treatment with oral propranolol. These findings suggest that NO is produced in platelets during migraine attacks. It may also be related to the migrainous pain and the changes in cerebral blood flow experienced during migraine attacks. These data may provide new strategies for the treatment of migraine.

Topics: Adult; Blood Platelets; Case-Control Studies; Cyclic GMP; Female; Humans; Male; Migraine Disorders; Nitrates; Nitric Oxide; Nitrites

It is believed that nitric oxide (NO) plays a significant role in migraine attacks. This molecule is formed due to the conversion of L-arginine into L-citrulline. The target receptor for NO is ferrum in the heme group of cytoplasmic guanyl cyclase, the enzyme catalyzing cyclic guanosine monophosphate (cGMP) formation. To confirm this hypothesis, cGMP and nitrite level in the blood serum were measured in patients with migraine. The group under study included 37 subjects suffering from migraine with and without aura and 40 normal control subjects. The cGMP was measured during a migraine attack and 60 min following the administration of sumatriptan 6 mg subcutaneously. A statistically significant increase in cGMP level was observed in patients during a migraine attack compared to the controls. This level decreased after the administration of sumatriptan, but it was still higher than in the controls. No correlation was found between the increased cGMP level and pain intensification with clinical symptoms of migraine. The results suggest the participation of biochemical changes in migraine pathogenesis in the L-arginine-NO-cGMP pathway.

Topics: Adult; Cyclic GMP; Female; Humans; Male; Middle Aged; Migraine Disorders; Nitric Oxide; Serotonin Receptor Agonists; Sumatriptan

Decreased serum and intracellular levels of magnesium have been reported in patients with migraine. It has been suggested that magnesium may play an important role in the attacks and pathogenesis of headaches. We measured ionized magnesium, cyclic AMP (adenosine monophosphate), and cyclic GMP (guanosine monophosphate) in platelets of patients with migraine, in patients with tension-type headache, and in healthy controls. The platelet level of ionized magnesium from patients with tension-type headache was significantly lower than the levels from the other two groups. The platelet level of cyclic AMP from patients with migraine was higher than those from the other groups. We found no significant differences in the platelet cyclic GMP levels among the three groups. It is suggested that reduced platelet ionized magnesium in patients with tension-type headache is related to abnormal platelet function, and that increased platelet cyclic AMP in patients with migraine is related to alteration of neurotransmitters in the platelet.

Topics: Adolescent; Adult; Blood Platelets; Cyclic AMP; Cyclic GMP; Female; Humans; Ions; Magnesium; Male; Middle Aged; Migraine Disorders; Tension-Type Headache

Nitric oxide (NO) in platelets has been proposed as a promising tool for studying NO variations in migraine. In the present research the platelet response to collagen and the basal and collagen-induced production of NO and cGMP in platelet cytosol were assessed in migraine patients (25 with aura and 35 without aura) both interictally and ictally, and compared with the same parameters in 30 age-matched control subjects. A reduced responsiveness to collagen was found in migraine patients, particularly those with aura, and this was more marked during attacks (ANOVA interictal periods: p < 0.01, attacks: p < 0.02) The basal and collagen-stimulated production of NO and cGMP in the platelet cytosol was significantly higher in migraine patients with aura assessed in interictal periods than in control subjects, and this production was further increased during attacks (interictal period: NO ANOVA: p < 0.001, ictal period: p < 0.01; cGMP: interictal period p < 0.01, ictal period: p < 0.02). The increase in platelet NO and cGMP production was also evident, though to a lesser extent, in migraine patients without aura. The present research supports the hypothesis of an activation of the L-arginine/NO pathway in migraine patients, especially those with aura, and confirms the findings of a previous study of increased levels of L-arginine in platelets of migraine patients studied in headache free-periods, and decreased collagen aggregation in whole blood.

Topics: Adult; Arginine; Blood Platelets; Cyclic GMP; Cytosol; Female; Humans; Male; Migraine Disorders; Nitric Oxide; Platelet Aggregation; Serotonin

Previous studies have reported the existence of an arginine/nitric oxide (NO) pathway and the involvement of a Ca2+, NADPH-dependent nitric oxide synthase enzyme (NOS) in the generation of NO in human platelets. In the present research, we determined the rate of production of NO and cGMP in the cytosol of platelets stimulated by collagen in 20 females with menstrual migraine (MM), (age range 24-40 years), assessed in the follicular and luteal phases, interictally and ictally in the latter period. The same patients were also assessed at mid-cycle. At the same time, the variations in the collagen response of platelets were evaluated. Moreover, these parameters were determined in the same periods in 20 age-matched control females and in 20 females affected by non-menstrually related migraine (nMM). The collagen-stimulated production of NO in the cytosol of the platelet cytosol was significantly higher in migraine patients with MM than in the control subjects. In MM patients, the increase was greater in the luteal phase of the cycle than during the follicular phase (p < 0.005). A rise in NO production in platelets was also present, although to a lesser extent, in females affected by nMM compared to the healthy females, but this rise was most evident at ovulation (p < 0.001). A slight but significant increase was also observed at mid-cycle in control women, but this increase did not reach the values determined in the migraine groups (p < 0.02). NO production in platelets stimulated by collagen was significantly increased during attacks with respect to the interictal period in both patient groups. Similar variations were observed in the production of cGMP in MM and nMM patients. The increase in NO production was accompanied by a decrease in platelet aggregation in the migraine groups compared with the control group; this decrease was most evident at mid-cycle in nMM patients and in the luteal phase in MM patients. These data suggest an activation of the L-arginine/ NO pathway in MM and nMM patients which could explain the modifications in the platelet response to collagen evidenced in migraine-free periods and during attacks. The activation of this pathway is more accentuated in the luteal phase in MM patients, and this could be the cause of the increased susceptibility to migraine attacks in perimenstrual and menstrual periods in these patients.

Topics: Adult; Analysis of Variance; Arginine; Blood Platelets; Collagen; Cyclic GMP; Female; Humans; Menstrual Cycle; Migraine Disorders; Nitric Oxide; Platelet Aggregation

The molecular mechanisms of migraine pain remain to be determined. Our studies of glyceryl trinitrate (GTN)-induced and histamine-induced headaches have led us to propose that nitric oxide (NO) may be the causative molecule in migraine pain. We also propose that substances capable of inducing experimental vascular headache do so with NO as the common mediator. Finally, we suggest that drugs with antimigraine activity inhibit NO and the cascade of intracellular reactions triggered by NO. We believe these observations provide new insight into the mechanisms of vascular headache. The importance of NO as a potential initiator of the migraine attack indicates new directions for the pharmacological treatment of migraine and other vascular headaches.

Topics: Cyclic GMP; Histamine; Humans; Migraine Disorders; Nitric Oxide; Nitroglycerin; Vascular Headaches

Topics: Adult; Cyclic AMP; Cyclic GMP; Epinephrine; Female; Humans; Male; Methacholine Chloride; Methacholine Compounds; Migraine Disorders