Targeting the CRMP2-Ca2+ Channel Complex for Abortive Treatment of Migraine and Post-Traumatic Headache
Technical Report,01 Sep 2017,31 Aug 2018
University of Arizona, Tucson Tucson United States
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Migraine is one of the worlds most common neurological disorders. Current acute migraine treatments have sub-optimal efficacy and new therapeutic options are needed. Approaches targeting calcitonin gene related peptide CGRP signaling are clinically effective but small molecule antagonists have not been advanced due to toxicity. In this study, we explored the axonal growthspecification collapsin response mediator protein 2 CRMP2 as a novel druggable target for inhibiting CGRP release and for potential relevance for treatment of migraine pain and post-traumatic headache. CRMP2 has been demonstrated to regulate N-type voltage gated Ca2 channel CaV2.2 activity and Ca2-dependent CGRP release in sensory neurons. The co-expression of CRMP2 with CaV2.2 and CGRP in trigeminal ganglia TG sensory neurons suggested the possibility of a novel approach to regulate CGRP release in the trigeminal system. Screening protocols surprisingly revealed that S-Lacosamide S-LCM, an inactive analog of the clinically-approved small molecule anti-epileptic drug R-Lacosamide Vimpat, inhibited CRMP2 phosphorylation by cyclin dependent kinase 5 Cdk5 in rat TG slices and decreased depolarization-evoked Ca2 influx in TG cells in culture. We foundthatS-LCM significantly blocked capsaicin-evoked CGRP release from dural nerve terminals in the rat ex vivo cranial cup preparation. Additionally, cephalic and extracephalic cutaneous allodynia CA induced in rats by activation of dural nociceptors with a cocktail of inflammatory mediators IM, was prevented and reversed by oral and intraperitoneal administrations demonstrating its high potential in mitigating migraine.
- Medicine and Medical Research