Abstract
Alpha-calcitonin gene-related peptide (α-CGRP) is a vasodilator neuropeptide of the calcitonin gene family. Pharmacological and gene knock-out studies have established a significant role of α-CGRP in normal and pathophysiological states, particularly in cardiovascular disease and migraines. α-CGRP knock-out mice with transverse aortic constriction (TAC)-induced pressure-overload heart failure have higher mortality rates and exhibit higher levels of cardiac fibrosis, inflammation, oxidative stress, and cell death compared to the wild-type TAC-mice. However, administration of α-CGRP, either in its native- or modified-form, improves cardiac function at the pathophysiological level, and significantly protects the heart from the adverse effects of heart failure and hypertension. Similar cardioprotective effects of the peptide were demonstrated in pressure-overload heart failure mice when α-CGRP was delivered using an alginate microcapsules-based drug delivery system. In contrast to cardiovascular disease, an elevated level of α-CGRP causes migraine-related headaches, thus the use of α-CGRP antagonists that block the interaction of the peptide to its receptor are beneficial in reducing chronic and episodic migraine headaches. Currently, several α-CGRP antagonists are being used as migraine treatments or in clinical trials for migraine pain management. Overall, agonists and antagonists of α-CGRP are clinically relevant to treat and prevent cardiovascular disease and migraine pain, respectively. This review focuses on the pharmacological and therapeutic significance of α-CGRP-agonists and -antagonists in various diseases, particularly in cardiac diseases and migraine pain.
Highlights
Alpha-calcitonin gene-related peptide (α-CGRP) is a regulatory neuropeptide, a potent vasodilator, and belongs to calcitonin gene family (Brain et al, 1985; Russell et al, 2014)
Pharmacological, and genetic studies carried out in a variety of animal models have established the role of α-CGRP in normal and disease states, in cardiovascular disease and migraine pain
The ongoing efforts to enhance the bioactivity of CGRP in circulation via CGRP-analogs and delivery systems are promising therapeutic agents to treat patients suffering from cardiovascular diseases
Summary
Alpha-calcitonin gene-related peptide (α-CGRP) is a regulatory neuropeptide, a potent vasodilator, and belongs to calcitonin gene family (Brain et al, 1985; Russell et al, 2014). One study carried out using left-to-right shunt-induced pulmonary hypertensive rats demonstrated that intravenous injection of endothelial progenitor cells modified to secrete α-CGRP reduced the severity of the disease and prevented adverse vascular remodeling (Zhao et al, 2007) These studies demonstrated that α-CGRP is a potent vasopressor and is a potential therapeutic peptide to treat patients suffering from high blood pressure. Levels of circulating α-CGRP increase in humans following an acute myocardial infarction and isolated hearts of guinea pigs and rats release more α-CGRP after experiencing myocardial ischemia (Franco-Cereceda, 1988; Mair et al, 1990; Lechleitner et al, 1992) During these pathological events, stimuli such as bradykinin, prostaglandins, and low pH activate TRPV1 receptors to induce α-CGRP release. Administration of α-CGRP attenuated TAC-induced increased activation of sirt and AMPK, and inhibited oxidative stress and apoptotic cell death in TAC mice who received α-CGRP Together, these events inhibited cardiac hypertrophy and protected hearts at the pathophysiological levels. Approved by the FDA and developed by Teva Pharmaceuticals, fremanezumab
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