Targeting the CRMP2- Ca2+ Channel Complex for Abortive Treatment of Migraine and Post Traumatic Headache

Abstract

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 growth/specification 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 found that oral or intraperitoneal (S)-LCM blocked capsaicin-evoked CGRP release from dural nerve terminals in the rat ex vivo cranial cup preparation and inhibited cephalic and extracephalic cutaneous allodynia (CA) induced in rats by activation of dural nociceptors with a cocktail of inflammatory mediators (IM). We also found that (S)-LCM inhibited nitric oxide (NO)-donor-induced allodynia in a rat model with triptan-induced latent sensitization, demonstrating its potential in mitigating migraine. These data are now in preparation for publication.

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Document Details

Document Type
Technical Report
Publication Date
Dec 01, 2020
Accession Number
AD1132076

Entities

People

  • Frank Porreca
  • Yeon S. Lee

Organizations

  • University of Arizona

Tags

DTIC Thesaurus Topics

  • Anticonvulsants
  • Biomedical Research
  • Blood
  • Brain
  • Brain Injuries
  • Catheters
  • Chemistry
  • Cyanides
  • Dura Mater
  • Electronic Mail
  • Headache Disorders
  • Inflammation
  • Inhibition
  • Jugular Vein
  • Medical Personnel
  • Neurology
  • Pharmacology
  • Small Molecules
  • Targeting
  • Therapy
  • United States
  • Veins

Fields of Study

  • Biology
  • Medicine

Readers

  • Cellular and Molecular Pathways of Apoptosis.
  • Neurotrauma and Rehabilitation Medicine.