Age-Dependent Anti-migraine Effects of Valproic Acid and Topiramate in Rats

Abstract

Background: Valproic acid (VPA) and topiramate (TPM), initially developed as antiepileptics, are approved for migraine prophylaxis in adults but not children. The differences in their antimigraine mechanism(s) by age remain unclear.Methods: A migraine model induced by intra-cisternal (i.c.) capsaicin instillation in pediatric (4–5 weeks) and adult (8–9 weeks) rats was pretreated with VPA (30, 100 mg/kg) or TPM (10, 30, 100 mg/kg). Noxious meningeal stimulation by the irritant capsaicin triggered trigeminovascular system (TGVS) activation mimicking migraine condition, which were assessed peripherally by the depletion of calcitonin gene-related peptide (CGRP) in sensory nerve fibers of the dura mater, the increased CGRP immunoreactivity at trigeminal ganglia (TG) and centrally by the number of c-Fos-immunoreactive (c-Fos-ir) neurons in the trigeminocervical complex (TCC). Peripherally, CGRP released from dural sensory nerve terminals of TG triggered pain signal transmission in the primary afferent of trigeminal nerve, which in turn caused central sensitization of the TGVS due to TCC activation and hence contributed to migraine.Results: In the VPA-treated group, the central responsiveness expressed by reducing the number of c-Fos-ir neurons, which had been increased by i.c. capsaicin, was significant in pediatric, but not adult, rats. Inversely, VPA was effective in peripheral inhibition of elevated CGRP immunoreactivity in the TG and CGRP depletion in the dura mater of adult, but not pediatric, rats. In TPM group, the central responsiveness was significant in both adult and pediatric groups. Peripherally, TPM significantly inhibited capsaicin-induced CGRP expression of TG in adult, but not pediatric, rats. Interestingly, the capsaicin-induced depletion of CGRP in dura was significantly rescued by TPM at high doses in adults, but at low dose in pediatric group.Conclusion: These results suggest VPA exerted peripheral inhibition in adult, but central suppression in pediatric migraine-rats. In contrast, TPM involves both central and peripheral inhibition of migraine with an optimal therapeutic window in both ages. These findings may clarify the age-dependent anti-migraine mechanism of VPA and TPM, which may guide the development of new pediatric anti-migraine drugs in the future.

Plasma Calcitonin Gene-Related Peptide: A Potential Biomarker for Diagnosis and Therapeutic Responses in Pediatric Migraine

“…Pre-clinical studies in migraine animal models have shown that topiramate inhibited neurogenic dural vasodilation by inhibiting CGRP release from pre-junctional trigeminal neurons induced by noxious inoculation (17, 51). We also found that topiramate inhibited CGRP immunoreactivity in the trigeminal ganglia and dura (23, 24) of rats in a capsaicin-stimulated migraine model (22). Topiramate has been also reported to enhance GABA currents of GABA A receptors, including the α6 subunit-containing GABA A receptors (α6GABA A Rs) (52).…”

“…Thus, CGRP is believed to be a potential biomarker of migraine (11–21). Pre-clinical studies have shown that trigeminal activation can induce CGRP release from peri-vascular nerve endings (22–24), resulting in pia vessel dilatation, leading to migraine (17). Moreover, CGRP antagonists can reduce cortical spreading depression, which is believed to be an important pathogenic manifestation of migraine with aura (18, 20, 21), in animal models of migraine.…”

Use of capsaicin as a model in the study of migraine: a literature review

“…Szolcsanyi 23 analyzed the depletion of sensory neurons by capsaicin and the relation of neuropeptides released in the analysis of the diameter of the cranial arteries, to verify whether there was dilation. Huang et al 27 observe that chemical stimulation with capsaicin also influences the release of CGRP assessed immunohistochemically through the polyclonal antibody of rabbits.…”

TRP Channels and Migraine: Recent Developments and New Therapeutic Opportunities

“…Although conclusive evidence is still needed, one may hypothesize that the abovementioned mechanisms related to TRP channels contribute to the decreased release of CGRP associated to BoNTA; initial evidence of the role of this circuitry has also been emerging for other drugs. Both valproic acid and topiramate have been shown to inhibit the capsaicin-induced elevation of CGRP immunoreactivity in the trigeminal ganglia and CGRP depletion in the dura mater of rats, even if with some differences among adult and pediatric rats [136]. Finally, the pretreatment with valproic acid has been shown to attenuate the enhanced blood flow responses observed after inhalation of the TRPA1 agonist acrolein in a rodent model of chronic migraine [111].…”