Migraine: New molecular mechanisms
ABSTRACT Migraine is an episodic headache disorder affecting more than 10% of the general population. Migraine arises from a primary brain dysfunction that leads to activation and sensitization of the trigeminovascular system. A major incompletely understood issue in the neurobiology of migraine concerns the molecular and cellular mechanisms that underlie the primary brain dysfunction and lead to activation and sensitization of the trigeminovascular system, thus generating and maintaining migraine pain. Here the author reviews recent discoveries that have advanced our understanding of these mechanisms toward a unifying pathophysiological hypothesis, in which cortical spreading depression (CSD), the phenomenon underlying migraine aura, assumes a key role. In particular, the author discusses the main recent findings in the genetics and neurobiology of familial hemiplegic migraine and the insights they provide into the molecular and cellular mechanisms that may lead to the increased susceptibility of CSD in migraineurs.
- SourceAvailable from: Shengyuan Yu
[Show abstract] [Hide abstract]
- "Migraines are the most common headache disorder and affect more than 10% of the general population [49,50]. Migraines are thought to arise from the activation and sensitization of the trigeminovascular system, followed by the release of inflammatory mediators from the trigeminal system, with a consequent vasodilation of innervate intracranial blood vessels and generation of neurogenic inflammation . Such inflammation causes hyperexcitability of TG neurons (peripheral sensitization) and the second-order sensory neurons (central sensitization) [52,53]. "
ABSTRACT: Amitriptyline (AMI) is tricyclic antidepressant that has been widely used to manage various chronic pains such as migraines. Its efficacy is attributed to its blockade of voltage-gated sodium channels (VGSCs). However, the effects of AMI on the tetrodotoxin-resistant (TTX-r) sodium channel Nav1.9 currents have been unclear to present. Using a whole-cell patch clamp technique, this study showed that AMI efficiently inhibited Nav1.9 currents in a concentration-dependent manner and had an IC50 of 15.16 μM in acute isolated trigeminal ganglion (TG) neurons of the rats. 10 μM AMI significantly shifted the steady-state inactivation of Nav1.9 channels in the hyperpolarizing direction without affecting voltage-dependent activation. Surprisingly, neither 10 nor 50 μM AMI caused a use-dependent blockade of Nav1.9 currents elicited by 60 pulses at 1 Hz. These data suggest that AMI is a state-selective blocker of Nav1.9 channels in rat nociceptive trigeminal neurons, which likely contributes to the efficacy of AMI in treating various pains, including migraines.Molecular Pain 06/2013; 9(1):31. DOI:10.1186/1744-8069-9-31 · 3.53 Impact Factor
[Show abstract] [Hide abstract]
- "The AMPA receptor proteins are products of separate genes that arrange to form ligand-gated ion channels in the plasma membrane permeable to Na+, K+ and Ca2+ (45). The four domains are arranged in a tetrameric structure to form a transmembrane aqueous pore (46). Two SNPs in GRIA1 (5q33.2, "
ABSTRACT: Migraine is a common genetically linked neurovascular disorder. Approximately ∼12% of the Caucasian population are affected including 18% of adult women and 6% of adult men (1, 2). A notable female bias is observed in migraine prevalence studies with females affected ∼3 times more than males and is credited to differences in hormone levels arising from reproductive achievements. Migraine is extremely debilitating with wide-ranging socioeconomic impact significantly affecting people's health and quality of life. A number of neurotransmitter systems have been implicated in migraine, the most studied include the serotonergic and dopaminergic systems. Extensive genetic research has been carried out to identify genetic variants that may alter the activity of a number of genes involved in synthesis and transport of neurotransmitters of these systems. The biology of the Glutamatergic system in migraine is the least studied however there is mounting evidence that its constituents could contribute to migraine. The discovery of antagonists that selectively block glutamate receptors has enabled studies on the physiologic role of glutamate, on one hand, and opened new perspectives pertaining to the potential therapeutic applications of glutamate receptor antagonists in diverse neurologic diseases. In this brief review, we discuss the biology of the Glutamatergic system in migraine outlining recent findings that support a role for altered Glutamatergic neurotransmission from biochemical and genetic studies in the manifestation of migraine and the implications of this on migraine treatment.03/2013; 9(1):1-8.
[Show abstract] [Hide abstract]
- "The exact mechanism of topiramate is unknown. It is proposed that epilepsy and migraine share some of the same pathophysiological mechanisms, including abnormal function of voltage-gated sodium and calcium channels, reduced gamma-aminobutyric acid (GABA) -mediated inhibition, and increased glutamate-mediated excitation. "
ABSTRACT: Migraine is a common neurological disorder in childhood and adolescence. Topiramate is a new anticonvulsant drug, recently being used in migraine prophylaxis in adults, although it is not approved by the Food and Drug Administration for prevention of pediatric migraine. The present study was planned and performed to evaluate the efficacy of low-dose topiramate in pediatric migraine prophylaxis. A prospective study, including 60 patients with migraine headaches was performed for a period of two months. The patients were randomly divided into two treatment groups - treated by topiramate < 2 mg/kg/day and > 2 mg/kg/day. All the patients were evaluated at 0, 4, and 8 weeks of the study for the clinical response. The patients receiving topiramate < 2 mg/kg/day (mean dose of 1.2 ± 0.7 mg/kg/day) showed a reduction in the mean (±SD) of migraine frequency from 6.2 (±2.4) to 3.0 (±1.8) episodes per month, headache intensity from 7.2 (±1.95) to 3.7 (±1.8) based on the Visual Analog Scale, and headache duration from 5.4 (±2.1) to 2.2 (±1.3) h. In the patients treated with topiramate > 2 mg/kg/day (mean dose of 2.4 ± 0.5 mg/kg/day), the mean (±SD) of monthly headache frequency reduced from 6.9 (±2.1) to 3.24 (±1.2) per month, intensity from 7.11 (±1.4) to 3.14 (±2.41), and headache duration from 5.2 (±2.4) to 1.8 (±1.2) h, at the end of follow-up (P > 0.05). The most common side effects of topiramate were paresthesias (five patients), anorexia (four patients), drowsiness (four patients). The results of this study demonstrated that low-dose of topiramate (<2 mg/kg/day) is effective, well-tolerated, safe, and suggested as an alternative prophylactic treatment for pediatric migraine.Journal of Pediatric Neurosciences 09/2012; 7(3):171-4. DOI:10.4103/1817-1745.106470