Wenjing Tang

Interictal plasma pituitary adenylate cyclase-activating polypeptide levels are decreased in migraineurs but remain unchanged in patients with tension-type headache.

BACKGROUND Pituitary adenylate cyclase-activating polypeptide (PACAP) is associated with migraine phase; however, whether PACAP levels could be used to distinguish between migraine and tension-type headache (TTH) remains unknown. We compared interictal plasma PACAP levels among healthy controls, migraineurs, and patients with TTH. METHODS Interictal plasma levels of PACAP were measured in 133 migraineurs, 106 patients with TTH, and 50 controls using enzyme-linked immunoassays. We further evaluated the relationships between interictal PACAP plasma concentrations and clinical parameters, such as headache severity, attack frequency, and duration. RESULTS We found that migraineurs had significantly lower interictal plasma PACAP levels than patients with TTH and healthy controls. However, there were no significant differences between patients with TTH and healthy controls. Plasma PACAP levels were significantly lower in patients with episodic migraine (EM) than in patients with episodic tension-type headache (ETTH) and in patients with chronic migraine (CM) than in patients with chronic tension-type headache (CTTH). Interictal PACAP levels were negatively correlated with duration in the CM group. CONCLUSIONS The results of this study demonstrated differences in interictal PACAP levels in migraine and TTH, suggesting that PACAP is involved in the pathogenesis of migraine rather than TTH.

Chronic changes in pituitary adenylate cyclase-activating polypeptide and related receptors in response to repeated chemical dural stimulation in rats.

Background Preclinical experimental studies revealed an acute alteration of pituitary adenylate cyclase-activating polypeptide in response to a single activation of the trigeminovascular system, which suggests a potential role of pituitary adenylate cyclase-activating polypeptide in the pathogenesis of migraine. However, changes in pituitary adenylate cyclase-activating polypeptide after repeated migraine-like attacks in chronic migraine are not clear. Therefore, the present study investigated chronic changes in pituitary adenylate cyclase-activating polypeptide and related receptors in response to repeated chemical dural stimulations in the rat. Methods A rat model of chronic migraine was established by repeated chemical dural stimulations using an inflammatory soup for a different numbers of days. The pituitary adenylate cyclase-activating polypeptide levels were quantified in plasma, the trigeminal ganglia, and the trigeminal nucleus caudalis using radioimmunoassay and Western blotting in trigeminal ganglia and trigeminal nucleus caudalis tissues. Western blot analysis and real-time polymerase chain reaction were used to measure the protein and mRNA expression of pituitary adenylate cyclase-activating polypeptide-related receptors (PAC1, VPAC1, and VPAC2) in the trigeminal ganglia and trigeminal nucleus caudalis to identify changes associated with repetitive applications of chemical dural stimulations. Results All rats exhibited significantly decreased periorbital nociceptive thresholds to repeated inflammatory soup stimulations. Radioimmunoassay and Western blot analysis demonstrated significantly decreased pituitary adenylate cyclase-activating polypeptide levels in plasma and trigeminal ganglia after repetitive chronic inflammatory soup stimulation. Protein and mRNA analyses of pituitary adenylate cyclase-activating polypeptide-related receptors demonstrated significantly increased PAC1 receptor protein and mRNA expression in the trigeminal ganglia, but not in the trigeminal nucleus caudalis, and no significant differences were found in the expression of the VPAC1 and VPAC2 receptors. Conclusions This study demonstrated the chronic alteration of pituitary adenylate cyclase-activating polypeptide and related receptors in response to repeated chemical dural stimulation in the rat, which suggests the crucial involvement of pituitary adenylate cyclase-activating polypeptide in the development of migraine. The selective increase in pituitary adenylate cyclase-activating polypeptide-related receptors suggests that the PAC1 receptor pathway is a novel target for the treatment of migraine.

Inhibition of toll-like receptor 4 alleviates hyperalgesia induced by acute dural inflammation in experimental migraine

Objective Although nociceptive sensitisation is an important pathophysiological process in migraine and migraine chronification, its underlying mechanisms remain unclear. Toll-like receptor 4 (TLR4), a pattern-recognition molecule, has a critical role in both neuropathic pain and morphine tolerance. The present study examined whether elements of the TLR4 pathway contribute to hyperalgesia induced by dural inflammation in rats. Methods A rat model of migraine was established by infusing a dural inflammatory soup. A group pretreated with TAK-242 was used to inhibit the activation of TLR4. The protein levels of TLR4 and its downstream molecules in the trigeminal pathway were examined by Western blot and immunofluorescence. The expression of activated microglia and astrocytes was also analysed. Levels of interleukin-1 beta, tumour necrosis factor-alpha, and brain-derived neurotrophic factor were measured by enzyme-linked immunosorbent assay. Results Acute inflammatory soup infusion induced time-dependent facial mechanical hyperalgesia, which was blocked by TAK-242 pretreatment. The inflammatory soup stimulus increased the production of TLR4 downstream molecules and interleukin-1 beta. Higher levels of microglia activation and brain-derived neurotrophic factor release were observed following the administration of the inflammatory soup but were alleviated by TAK-242. Conclusions These data suggest that the TLR4 signalling pathway promotes hyperalgesia induced by acute inflammatory soup delivery by stimulating the production of proinflammatory cytokines and activating microglia.

Higher prevalence of migraine in essential tremor: A case–control study

Background The existence of an association between migraine and essential tremor has long been controversial. The prevalence of migraine in essential tremor patients was surveyed to explore the association between the two diseases. Methods A case–control clinical study was conducted to investigate the prevalence of migraine in 150 consecutive essential tremor patients and in 150 matched controls without tremor. Detailed information about essential tremor and migraine was obtained using a structured questionnaire at a face-to-face interview. Moreover, a functional variant of the dopamine receptor D3 gene (Ser9Gly, rs6280) was studied in 46 essential tremor patients with and without migraine using direct sequencing analysis. Results The prevalence of lifetime migraine in essential tremor patients was significantly higher than that in controls (22.0% vs. 12.7%; p = 0.035; odds ratio = 1.95; 95% confidence interval = 1.05–3.60). No significant difference was found in the migraine features between the essential tremor and control groups and most tremor characteristics were no different in essential tremor patients with and without migraine. A higher male prevalence of essential tremor patients without migraine was observed. Moreover, 44 of 46 (95.7%) essential tremor patients had the dopamine receptor D3 Ser9Gly variant, but no significant difference was found in the frequencies of the variant between essential tremor patients with and without migraine (87.5% vs. 100.0%; p = 0.22). Conclusion Our data suggest that essential tremor patients have a higher risk of lifetime migraine than do controls and the dopamine receptor D3 Ser9Gly variant may be lower in essential tremor with migraine than the general essential tremor patients.

Pituitary adenylate cyclase-activating polypeptide expression in peripheral blood mononuclear cells of migraineurs

BackgroundPituitary adenylate cyclase-activating polypeptide (PACAP) plays several important roles in vasodilation, neurotransmission, neuromodulation and neurotrophy, as well as activation of the trigeminovascular system. The aim of the present study was to explore the relationship between altered PACAP levels in peripheral blood and different types of headache.MethodsThe present study enrolled 101 outpatients with headache and 35 healthy control volunteers. Blood samples were collected from the cubital vein and peripheral blood mononuclear cells (PBMCs) were separated. Total mRNA in the PBMCs was extracted and the expression of PACAP mRNA was analyzed by quantitative-polymerase chain reaction (Q-PCR).ResultsThere was a significant decrease in PACAP mRNA expression in the PBMCs of the migraine (M) group relative to the healthy control group. However, there were no significant differences in PACAP mRNA expression between the control group and tension-type headache (TTH), cluster headache (CH), or medication overuse headache (MOH) groups.ConclusionThe PBMC levels of patients with migraine, but not other commonly seen headache types, exhibited a significant reduction in PACAP mRNA expression compared with healthy control subjects.

Association between angiotensin-converting enzyme insertion/deletion polymorphism and migraine: a meta-analysis

Background: Many studies investigated the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and migraine, with controversial results. Thus, we performed a meta-analysis to better evaluate the correlation of this polymorphism and migraine. Methods: We retrieved studies published up to September 2014 about the ACE gene polymorphism and migraine from electronic database. Pooled odds ratios (ORs) with 95% confidence interval (CI) were calculated to examine the strength of association between the ACE I/D polymorphism and migraine, using random-effects models. Results: We identified 14 separate studies, in which 7334 migraineurs and 22 990 healthy controls were eligible for the meta-analysis. The results showed no relationship between the ACE I/D polymorphism and any migraine. Stratification revealed a protective effect in the Turkish population against migraine with aura for the II genotype model (II vs. DD: pooled OR = 0.366, 95% CI = 0.137–0.980; II vs. DI + DD: pooled OR = 0.370, 95% CI = 0.145–0.945). Similar results were obtained for Turkish people with migraine without aura (II vs. DD: pooled OR = 0.386; 95% CI = 0.166–0.900; II vs. DI + DD: pooled OR = 0.347; 95% CI = 0.156–0.773). Conclusions: The data suggest that the ACE II genotype could exert a protective effect against migraine with aura and without aura at least in the Turkish population.

Tumor Necrosis Factor (TNF) –308G>A, Nitric Oxide Synthase 3 (NOS3) +894G>T Polymorphisms and Migraine Risk: A Meta-Analysis

Background and Objective Conflicting data have been reported on the association between tumor necrosis factor (TNF) –308G>A and nitric oxide synthase 3 (NOS3) +894G>T polymorphisms and migraine. We performed a meta-analysis of case-control studies to evaluate whether the TNF –308G>A and NOS3 +894G>T polymorphisms confer genetic susceptibility to migraine. Method We performed an updated meta-analysis for TNF –308G>A and a meta-analysis for NOS3 +894G>T based on studies published up to July 2014. We calculated study specific odds ratios (OR) and 95% confidence intervals (95% CI) assuming allele contrast, dominant model, recessive model, and co-dominant model as pooled effect estimates. Results Eleven studies in 6682 migraineurs and 22591 controls for TNF –308G>A and six studies in 1055 migraineurs and 877 controls for NOS3 +894G>T were included in the analysis. Neither indicated overall associations between gene polymorphisms and migraine risk. Subgroup analyses suggested that the “A” allele of the TNF –308G>A variant increases the risk of migraine among non-Caucasians (dominant model: pooled OR = 1.82; 95% CI 1.15 – 2.87). The risk of migraine with aura (MA) was increased among both Caucasians and non-Caucasians. Subgroup analyses suggested that the “T” allele of the NOS3 +894G>T variant increases the risk of migraine among non-Caucasians (co-dominant model: pooled OR = 2.10; 95% CI 1.14 – 3.88). Conclusions Our findings appear to support the hypothesis that the TNF –308G>A polymorphism may act as a genetic susceptibility factor for migraine among non-Caucasians and that the NOS3 +894G>T polymorphism may modulate the risk of migraine among non-Caucasians.

[EXPRESS] Volumetric abnormalities of the brain in a rat model of recurrent headache

Voxel-based morphometry is used to detect structural brain changes in patients with migraine. However, the relevance of migraine and structural changes is not clear. This study investigated structural brain abnormalities based on voxel-based morphometry using a rat model of recurrent headache. The rat model was established by infusing an inflammatory soup through supradural catheters in conscious male rats. Rats were subgrouped according to the frequency and duration of the inflammatory soup infusion. Tactile sensory testing was conducted prior to infusion of the inflammatory soup or saline. The periorbital tactile thresholds in the high-frequency inflammatory soup stimulation group declined persistently from day 5. Increased white matter volume was observed in the rats three weeks after inflammatory soup stimulation, brainstem in the in the low-frequency inflammatory soup-infusion group and cortex in the high-frequency inflammatory soup-infusion group. After six weeks’ stimulation, rats showed gray matter volume changes. The brain structural abnormalities recovered after the stimulation was stopped in the low-frequency inflammatory soup-infused rats and persisted even after the high-frequency inflammatory soup stimulus stopped. The changes of voxel-based morphometry in migraineurs may be the result of recurrent headache. Cognition, memory, and learning may play an important role in the chronification of migraines. Reducing migraine attacks has the promise of preventing chronicity of migraine.