CGRP Mechanism Antagonists and Migraine Management

Abstract

Migraine is a complex disorder of the brain that is common and highly disabling. As understanding of the neural pathways has advanced, and it has become clear that the vascular hypothesis does not explain the disorder, new therapeutic avenues have arisen. One such target is calcitonin gene-related peptide (CGRP)-based mechanisms. CGRP is found within the trigeminovascular nociceptive system widely from the trigeminal ganglion to second-order and third-order neurons and in regulatory areas in the brainstem. Studies have shown CGRP is released during severe migraine attacks and the reversal of the attack with effective triptan treatment normalizes those levels. CGRP administration triggers migraine in patients, and CGRP receptor antagonists have been shown to abort migraine. Here, we review the current state of CGRP mechanism antagonist therapy as its research and development is increasing in migraine therapeutics. We discuss several recent trials, highlighting the evidence base behind these novel drugs, and their potential future contribution to migraine management.

Targeting Calcitonin Gene-Related Peptide and its Receptor by Monoclonal Antibody, New Developments in the Prevention of Migraine

“…4 Although glutamic acid is one of the main neurotransmitters in the sensory system, various neuropeptides have been implicated in pain but among them, Calcitonin Gene Related Peptide (CGRP) is the only one neuropeptide that was found elevated in the blood of migraine patients [5][6][7] and CGRP administration induces migraine-like attack in migraine patients. 8 Therefore, several studies in the last decade focused on drugs to block the CGRP receptor [9][10][11] or the effect of CGRP itself by antibodies against it [10][11][12] although, it is not clear if the site of action of these drugs is peripheral or central. 13 Nevertheless, triptan family drugs are currently some of the best and most potent compounds in the treatment of migraine, 4,14 but not all patients respond to them and search for other drugs that lack vasoconstrictive activity has continued.…”

“…[16][17][18][19][20][21] Unfortunately, these drugs were discontinued due to their side effects such as hepatotoxicity although they were able to treat migraine effectively. Nevertheless, some newer drugs in this category including MK-3207, 22,23 BMS-846372 24,25 and MK-1602 26 are still under investigation, see 10 for a brief review. Nevertheless, research in the treatment of migraine did not stop here and search for other drugs being able to block CGRP or its receptor continued.…”

“…10,27,28 In recent years, monoclonal Antibodies (mAbs) against CGRP or its receptor have been developed and are the newest anti-migraine drugs in clinical trials.…”

“…[10][11][12][29][30][31] Please see 31 and corresponding references for a brief review of the structure of CGRP and its receptor and related signalling molecules.…”

“…It is under clinical investigation and analysis but reduction in migraine days per month has been reported. 39 Please see [10][11][12]31 for brief review of the drugs against CGRP and its receptor and some of the biological activities of CGRP.…”