We have used primary cultures of trigeminal neurons under conditions simulating migraine pathology and therapy to study the mechanisms controlling the CGRP promoter.
If data from real-world settings can confirm the initial clinical trial findings, it is hoped that antibodies antagonizing the calcitonin gene-related peptide pathway will be able to improve quality of life for patients with episodic and chronic migraine, and help relieve the huge patient and societal burden of migraine.
Neurogenic inflammation is presumed to be an important factor in migraine pathophysiology, mediated by the activation of primary neurons, leading to the release of various pro-inflammatory neuropeptides and neurotransmitters such as Calcitonin Gene-Related Peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP).
In testing of the antimigraine drugs the capsaicin-induced skin redness with activated TRPV1 receptors in sensory neurons associated with the release of the migraine mediator CGRP has already been widely used.
Familial hemiplegic migraine (FHM) patients do not show hypersensitivity of the calcitonin gene-related peptide (CGRP)-cyclic adenosine 3',5'-monophosphate pathway, as characteristically seen in migraine patients without aura.
Amgen and Novartis are developing erenumab (AIMOVIG™, erenumab-aooe)-a fully human monoclonal antibody calcitonin gene-related peptide (CGRP) receptor antagonist-for the prevention of migraine.
However, a peripheral site of action is indicated by the ability of intravenous CGRP to trigger migraine in humans and the efficacy of CGRP receptor antagonists that evidently do no penetrate the CNS in effective amounts.
These results demonstrate that RAMP1 is functionally rate limiting for CGRP receptor activity in the trigeminal ganglion, which raises the possibility that elevated RAMP1 might sensitize some individuals to CGRP actions in migraine.
Conclusion We found no statistical association between familial aggregation of migraine and hypersensitivity to calcitonin gene-related peptide infusion in migraine without aura patients.
We will further discuss the potential role of CGRP in the brainstem and its modulation for migraine therapy, given the emergence of targeted CGRP small molecule and monoclonal antibody therapies.
Calcitonin gene-related peptide (CGRP) is a major player in migraine pathophysiology, and CGRP monoclonal antibodies including fremanezumab may be a safe effective preventive therapy.
Thus, erenumab, a monoclonal antibody antagonist of the CGRP receptor, administered as a once monthly dose of 70 or 140 mg has been approved for the preventive treatment of migraine in adults.
Galcanezumab is a humanized immunoglobulin G (IgG) monoclonal antibody (mAb) indicated for the prevention of migraine that binds to calcitonin gene-related peptide.
The recent identification of the CGRP-responsive calcitonin receptor/RAMP1 complex (AMY<sub>1</sub> receptor - amylin subtype 1 receptor) in the trigeminovascular system warrants a deeper consideration of the molecular identity of CGRP receptor(s) involved in the pathophysiology, and thus potential treatment of migraine.
Anti-CGRP peptide and anti-CGRP receptor antibodies are the first effective treatments, which were specifically developed for the prevention of migraine.
In the last 15 years relevant efforts have been made to demonstrate that calcitonin gene-related peptide (CGRP) antagonism is a valuable and druggable mechanism for treatment or prevention of migraine.
CLR/RAMP1, or CGRP receptor, antagonists have been developed for the treatment of migraine headache and osteoarthritis pain; whereas CLR/RAMP2, or ADM receptor, antagonists are being developed for the treatment of tumor growth/metastasis.
Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT<sub>1B/1D</sub> receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT<sub>1F</sub> receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu<sub>5</sub> modulators; with the promise of more to come.