Validating Peripheral CCl2 and CCR2 as Novel Targets for Chronic Migraine Therapeutics
Abstract
This application responds to the Fiscal Year 2017 Peer Reviewed Medical Research Program (PRMRP) Topic Area Chronic Migraine and Post-Traumatic Headache. Our objective is to validate chemokine C-C motif ligand 2 (CCL2) and C-C chemokine receptor type 2 (CCR2) as molecular targets for novel, peripherally active therapeutics for chronic migraine. More than 140 million people experience chronic migraine, with at least 15 migraine days per months for at least 3 months. The prevalence of chronic migraine is even higher in military Service members and Veterans. Chronic migraine, especially the recurring throbbing headache, is highly debilitating and severely affects the return to active duty or a fully functional civilian life. Despite its high prevalence, chronic migraine remains poorly understood and inadequately treated. A large number of patients are not responsive to the current drugs or intolerant to their side effects. There is an urgent need for more effective medicine with fewer side effects. The recent success of antibodies against calcitonin gene-related peptide (CGRP) or its receptor in migraine prevention suggests that peripherally acting drugs can effectively reduce the number of episodes, thereby preventing or even reversing migraine chronification without the undesirable side effects of centrally active drugs. However, antagonizing the CGRP pathway only achieves less than 50% decrease of the headache frequency in less than 50% patients. For the majority of chronic migraine patients, blocking CGRP signaling is still not sufficient to reduce headache frequency, let alone reverse the disease process. This prompts us to search for novel peripheral targets to develop more efficacious migraine preventive drugs. With the support of a PRMRP Concept Award (W81XWH-11-1-0578), we have explored the interactions between the immune and nervous systems in a mouse model of chronic migraine. The level of chemokine C-C motif ligand 2 (CCL2) mRNA is significantly increased under chronic migraine-like state, consistent with elevated CCL2 level in chronic migraine patients. Importantly, blocking C-C chemokine receptor type 2 (CCR2), the receptor for CCL2, completely prevents the hyperactivation of the headache circuits. Blocking CCL2 function with an antibody that does not cross the blood-brain barrier abolishes headache-like behavior in mice. These results strongly suggest that antagonizing the peripheral CCL2-CCR2 pathway can prevent the onset of headache and reduce attack frequency, thereby preventing and/or reversing migraine chronification. In this application, we propose to conduct a preclinical study to thoroughly validate the peripheral CCL2 and CCR2 as molecular targets for novel chronic migraine therapeutics. Furthermore, we will investigate the interactions between the CCL2-CCR2 and CGRP pathways for potential combined therapy. To ensure that our results are clinically relevant, we will measure the chronic migraine-related facial skin sensitization and persistent aversive state in two mouse models of chronic migraine, along with anatomical endpoints. First, we will investigate whether eliminating CCL2 or CCR2 expression prevents the development of chronic migraine-like state in mice. Secondly, we will test whether antagonizing CCL2-CCR2 pathway reverses the established chronic migraine. Thirdly, we will investigate whether blocking antibodies against the peripheral CCL2-CCR2 signaling prevents and/or reverses migraine chronification. A positive outcome will suggest that targeting peripheral CCL2 and/or CCR2 warrant clinical trials for chronic migraine. Since drugs antagonizing the CCL2-CCR2 pathway are already in Phase II clinical trials for other diseases, this ensures the expedient translation of the results from current study to future clinical trials. We also propose to elucidate the mechanisms through which the CCL2-CCR2 signaling pathway contributes to migraine chronification. We w
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810627
Entities
People
- Yu-qing Cao
Organizations
- United States Army
- Washington University in St. Louis