Targeting the CRMP2-Ca2+ Channel Complex for Abortive Treatment of Migraine and Post-Traumatic Headache
Abstract
Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area Addressed: Chronic Migraine and Post-Traumatic Headache. Migraine is the most common neurological condition in the developed world, more prevalent than diabetes, epilepsy, and asthma combined. Soldiers have higher incidence of migraine than civilians. Post-traumatic headache (PTH) can occur following a traumatic brain injury (TBI). PTH often presents with a migraine phenotype and affects upwards of 97% of all Soldiers with TBI. Migraine is treated by acute (abortive) therapies and in some patients with frequent migraine, with prophylactic therapies. Abortive therapies include the triptans and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin, but these medicines are not sufficiently effective in many patients. Physicians have few choices for abortive treatment. The discovery of new therapies is urgently needed for migraineurs and for Soldiers who have a greater proclivity to suffer from migraines and/or PTH. Exciting new evidence points to a critical role of the neuropeptide calcitonin gene-related peptide (CGRP) in migraine. It is now known that release of CGRP from nerves that innervate the tissues that line the brain (i.e., the cranial meninges) promotes migraine pain. The pharmaceutical industry and academia have been focused on ways to inhibit CGRP signaling for over 20 years. Triptans likely prevent the release of CGRP from pain nerve endings resulting in relief of the migraine headache. Small molecule antagonists for the receptors to which CGRP binds have been developed. While these compounds are clinically effective for abortive treatment of migraine, their introduction to the market is uncertain due to unexpected liver toxicity. A second approach is to use antibodies to interfere with CGRP or to its receptor. These antibodies are currently being tested in safety/efficacy clinical trials (Phase II development) but are not yet available. Importantly, these antibodies are intended only for prophylactic and not for abortive therapy. Patients who will benefit from antibody therapy represent a subgroup of migraineurs including those with frequent episodic or chronic migraine. The release of CGRP, and other transmitters, from neurons depends on activation of calcium channels including a subtype of channel referred to as CaV2.2 (N-type); this channel is clinically validated in pain management by the effectiveness of Ziconotide (Prialt®), a product that is only administered spinally due to its toxicity. The CaV2.2 calcium channel is a multi-protein complex. We recently demonstrated that a protein called CRMP2 interacts with CaV2.2 to increase the release of CGRP from neurons. Modification of CRMP2 by an enzyme (i.e., a kinase that adds a phosphate group to proteins) further boosts the release of CGRP as the phosphorylated CRMP2 has increased association with CaV2.2. Our previous work has shown that a peptide that interferes with the CRMP2-CaV2.2 complex, but does not alter CRMP2 phosphorylation, inhibits CGRP release, and relieves acute and chronic pain. Unfortunately, this peptide does not have sufficient drug-like qualities that allow its use in the treatment of migraine and PTH. In order to rapidly translate this concept to clinical use, we searched for molecules interacting with CRMP2 that were amenable to a rapid development path for abortive treatment of migraine and PTH. This search led to the discovery of (S)-lacosamide ((S)-LCM), a small molecule related to clinically approved anti-epileptic drug Vimpat®. Notably, (S)-LCM blocked CRMP2 phosphorylation. These observations led us to hypothesize that (S)-LCM, by inhibiting CRMP2 phosphorylation, inhibits voltage-gated calcium channel CaV2.2 activity and consequently, CGRP release, potentially providing an effective, abortive treatment for migraines/PTH in Soldiers. While this molecule has not yet undergone clinical evaluation, it has pr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610533
Entities
People
- Rajesh Khanna
Organizations
- United States Army
- University of Arizona