Background Increasing evidence suggests that vasoactive neuropeptides such as pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide are involved in the pathophysiology of migraine in adults, but their role in pediatric migraineurs remains unclear. We prospectively investigated plasma levels of these vasoactive neuropeptides in pediatric migraine patients without aura and compared the results with those of age-matched healthy controls. Methods Thirty-eight children aged 6–18 years with migraine without aura and 20 age-matched control subjects were included in the study. Neuropeptides in plasma samples from the controls, and in either the ictal or interictal periods in pediatric migraine without aura, were measured using ELISA. Results PACAP-38 and vasoactive intestinal peptide levels in both ictal and interictal plasma were higher in the patients with pediatric migraine without aura than in the controls ( p < 0.001), although calcitonin gene-related peptide and substance P levels remained unchanged. Otherwise, no significant difference was determined between ictal and interictal periods in terms of all neuropeptide levels. Conclusions This study demonstrates increased plasma PACAP-38 and vasoactive intestinal peptide levels, but not calcitonin gene-related peptide and substance P levels, in pediatric patients with migraine during both attack and attack-free periods. The study findings suggest that PACAP-38 and vasoactive intestinal peptide may be implicated in the pathophysiology of migraine, particularly in pediatric migraineurs.

Growing evidence indicates that the parasympathetic system is implicated in migraine headache. However, the cholinergic mechanisms in the pathophysiology of migraine remain unclear. We investigated the effects and mechanisms of cholinergic modulation and a mast cell stabilizer cromolyn in the nitroglycerin‐induced in vivo migraine model and in vitro hemiskull preparations in rats. Effects of cholinergic agents (acetylcholinesterase inhibitor neostigmine, or acetylcholine, and muscarinic antagonist atropine) and mast cell stabilizer cromolyn or their combinations were tested in the in vivo and in vitro experiments. The mechanical hyperalgesia was assessed by von Frey hairs. Calcitonin gene‐related peptide (CGRP) and C‐fos levels were measured by enzyme‐linked immunosorbent assay. Degranulation and count of meningeal mast cells were determined by toluidine‐blue staining. Neostigmine augmented the nitroglycerin‐induced mechanical hyperalgesia, trigeminal ganglion CGRP levels, brainstem CGRP, and C‐fos levels, as well as degranulation of mast cells in vivo. Atropine inhibited neostigmine‐induced additional increases in CGRP levels in trigeminal ganglion and brainstem while it failed to do this in the mechanical hyperalgesia, C‐fos levels, and the mast cell degranulation. However, all systemic effects of neostigmine were abolished by cromolyn. The cholinergic agents or cromolyn did not alter basal release of CGRP, in vitro, but cromolyn alleviated the CGRP‐inducing effect of capsaicin while atropine failed to do it. These results ensure for a first time direct evidence that endogenous acetylcholine contributes to migraine pathology mainly by activating meningeal mast cells while muscarinic receptors are involved in CGRP release from trigeminal ganglion and brainstem, without excluding the possible role of nicotinic cholinergic receptors.

Background: Epilepsy has neuropsychiatric comorbidities such as depression, bipolar disorder, and anxiety. Drugs that target epilepsy may also be useful for its neuropsychiatric comorbidities. Objective: To investigate the effects of serotonergic modulation on pro-inflammatory cytokines and the seizures in pentylenetetrazole (PTZ)-induced seizure model in rats. Methods: Male Wistar rats were injected intraperitoneally with serotonin, selective serotonin reuptake inhibitor fluoxetine, 5-HT1B/D receptor agonist sumatriptan, or saline 30 min prior to PTZ treatment. Behavioral seizures were assessed by the Racine's scale. Concentrations of IL-1β, IL-6, and TNF-α in serum and brain tissue were determined by ELISA. Results: Serotonin and fluoxetine, but not sumatriptan, alleviated PTZ-induced seizures by prolonging onset times of myoclonic-jerk and generalized tonic-clonic seizures. The anti-seizure effect of fluoxetine was greater than that of serotonin. Likewise, serotonin and fluoxetine, but not sumatriptan, reduced PTZ-induced increases in the levels of IL-1β and IL-6 in both serum and brain tissue. None of the administered drugs including PTZ affected TNF-α concentrations. Conclusions: Our findings suggest that endogenous and exogenous serotonin exhibits anticonvulsant effects by suppressing the neuroinflammation. It seems that 5-HT1B/D receptors do not mediate anticonvulsant and anti-neuroinflammatory effects of serotonin.

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The excitotoxicity is a common pathological mechanism of perinatal brain injuries (PBI), however neuroinflammation resulting in PBI is both a cause and a consequence of excitotoxicity. TRESK background potassium channels are an important regulator of neuronal excitability. We therefore investigated effects of activation of TRESK channels by selective activator cloxyquin on excitotoxic-induced brain injury and neuroinflammation involving brain mast cells and inflammatory cytokines in neonatal rats. An excitotoxic model mimicking human perinatal brain lesions was established via intracerebral injection of the glutamatergic agonist ibotenate to into newborn rats. P5 rat pups were intraperitoneally pretreated with vehicle, three different doses of cloxyquin (0.2, 1 and 5 mg/kg), or NMDA receptor antagonist MK-801 (positive control) 30 minutes prior to intracerebral injection of 10 µg ibotenate. Rat pups were sacrificed one or five days after the injury. Coronal brain sections were stained with cresyl-violet for histopathological examinations, and with toluidine-blue for brain mast cells assessments. Concentrations of activin A, IL-1β, IL-6 and IL-10 in brain homogenates were measured using ELISA. Cloxyquin dose-dependently ameliorated ibotenate-induced impairments in the cortical and white matter, and suppressed ibotenate-induced activation and number of brain mast cells. Moreover, cloxyquin dose-dependently reduced concentrations of activin A, IL-1β and IL-6 in the brain tissue induced by ibotenate while it elevated IL-10 level. Our findings reveal for the first time that cloxyquin, a selective activator of TRESK channels, dose-dependently exerted protective effects against excitotoxic-induced neonatal brain injury and neuroinflammation. TRESK channels may be a promising new target for the treatment of PBIs.

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The dopaminergic system is implicated in the pathophysiology of migraine. However, the underlying mechanisms remain unclear. We explored the effects and mechanisms of dopaminergic system modulation in the in vivo and in vitro rat models of migraine. Dopaminergic agonist apomorphine, D2 receptor antagonists metoclopramide and haloperidol and 5‐HT3 receptor antagonist ondansetron alone and together were tested in nitroglycerin‐induced migraine model, in vivo. Likewise, the combinations of drugs were also tested on basal calcitonin gene‐related peptide (CGRP) release in vitro hemiskull preparations. Mechanical allodynia was tested by von Frey filaments. CGRP concentrations in trigeminovascular structures and in vitro superfusates and c‐Fos levels in the brainstem were determined by enzyme‐linked immunosorbent assay. Meningeal mast cells were evaluated with toluidine blue staining. Apomorphine further enhanced nitroglycerin‐induced mechanical allodynia, brainstem c‐fos expression, trigeminal ganglion and brainstem CGRP concentrations and meningeal mast cell degranulation, in vivo. Haloperidol completely antagonised all apomorphine‐induced effects and also alleviated changes induced by nitroglycerin without apomorphine. Metoclopramide and ondansetron partially attenuated apomorphine‐ or nitroglycerin‐induced effects. A combination of haloperidol and ondansetron decreased basal CGRP release, in vitro, whereas the other administrations were ineffective. Apomorphine‐mediated dopaminergic activation exacerbated nitroglycerin‐stimulated nociceptive reactions by further enhancing c‐fos expression, CGRP release and mast cell degranulation in strategical structures associated with migraine pain. Metoclopramide partially attenuated the effects of apomorphine, most likely because it is also a 5‐HT3 receptor antagonist. Haloperidol with pure D2 receptor antagonism feature appears to be more effective than metoclopramide in reducing migraine‐related parameters in dopaminergic activation‐ and/or NTG‐induced migraine‐like conditions.

Objective: Increased systemic inflammatory response during intrauterine period or period before the age of 3 is associated with cerebral palsy (CP) pathogenesis; however, effects of inflammatory processes involving mast cell activation in elder children with CP remain unclear. We aimed to investigate the role of mast cells and proinflammatory cytokines in children with CP at 3-18 years of age. Methods:In this cross-sectional study, venous blood samples were obtained from 30 volunteers with CP and 26 healthy volunteers at 3-18 years of age. Plasma levels of proinflammatory cytokines (IL-1β, IL-6 and IL-9) and mast cell biomarkers (histamine and tryptase beta-2) were determined using ELISA.Results: IL-1β, IL-6 and histamine levels were higher in individuals with CP compared to healthy controls. Likewise, IL-1β, IL-6, IL-9 and histamine levels were higher in the female patients with CP compared to the male patients, and in the female patients in adolescence compared to the female patients in pre-adolescence. Conclusion:Our findings indicate that the increased inflammatory response contributes to the pathogenesis of the disease in children with CP who are older than 2 years of age. Moreover the increased inflammatory response is more effective in female patients than in male patients, suggesting that there may be a gender difference in CP. Additionally mast cell activation contributes to the exacerbation of systemic inflammatory response in children with CP at 3-18 years of age.