Role of calcitonin gene-related peptide in cerebral vasospasm, and as a therapeutic approach to subarachnoid hemorrhage

Abstract

Calcitonin gene-related peptide (CGRP) is one of the most potent microvascular vasodilators identified to date. Vascular relaxation and vasodilation is mediated via activation of the CGRP receptor. This atypical receptor is made up of a G protein-coupled receptor called calcitonin receptor-like receptor (CLR), a single transmembrane protein called receptor activity-modifying protein (RAMP), and an additional protein that is required for Gas coupling, known as receptor component protein (RCP). Several mechanisms involved in CGRP-mediated relaxation have been identified. These include nitric oxide (NO)-dependent endothelium-dependent mechanisms or cAMP-mediated endothelium-independent pathways; the latter being more common. Subarachnoid hemorrhage (SAH) is associated with cerebral vasoconstriction that occurs several days after the hemorrhage and is often fatal. The vasospasm occurs in 30–40% of patients and is the major cause of death from this condition. The vasoconstriction is associated with a decrease in CGRP levels in nerves and an increase in CGRP levels in draining blood, suggesting that CGRP is released from nerves to oppose the vasoconstriction. This evidence has led to the concept that exogenous CGRP may be beneficial in a condition that has proven hard to treat. The present article reviews: (a) the pathophysiology of delayed ischemic neurologic deficit after SAH (b) the basics of the CGRP receptor structure, signal transduction, and vasodilatation mechanisms and (c) the studies that have been conducted so far using CGRP in both animals and humans with SAH.

Calcitonin Gene-Related Peptide in Serum After Spontaneous Subarachnoid Hemorrhage

“…CGRP is one of the most potent endogenous vasodilators in humans (Hokfelt et al, 1992;Kokkoris et al, 2012). Intrinsic production in the trigeminal ganglion of Gasseri, neuronal transport, presynaptic release and consecutive re-uptake have been evaluated in detail and the major role of CGRP in migraine has been repeatedly confirmed (Guldiken et al, 2013).…”

“…Because the patients showed severe arterial hypotension, the study was prematurely terminated, so that no statistical analysis was conducted. Nevertheless, in the elaborated review of the literature concerning the role of CGRP in SAH, Kokkoris et al (2012) emphasized the need for more research into the contribution of CGRP in SAH.…”

“…Described the functional antagonism of NPY and the vasodilator Calcitonin Gene-Related Peptide (CGRP) in mesenteric resistance arteries (De Mey et al, 2008). This antagonism had also been proposed to be present in the central nervous system and some research groups have evaluated the possible role of CGRP in SAH (Kokkoris et al, 2012;Juul et al, 1990;1995;Schebesch et al, 2013b).…”

“…The role of CGRP in the pathophysiology of vasospasmrelated CI due to SAH and its potential in preventing SAH-related stroke have been advocated before (Kokkoris et al, 2012;Johnston et al, 1992;. However, to the best of our knowledge, no data are yet available on the influence of the anatomical localization of the ruptured aneurysm and the effect of endovascular or surgical occlusion on the intrinsic release and dynamics of CGRP in serum.…”

“…Although the peptidergic regulation of the cerebral vasculature under normal conditions is well established (Edvinsson et al, 1994;McCulloch et al, 1986;Hokfelt et al, 1992), its role in pathophysiology after spontaneous Subarachnoid Hemorrhage (SAH), arterial vasospasm and Cerebral Ischemia (CI) remains unclear (Kokkoris et al, 2012). Recently, Jung et al (2013) have emphasized the importance of endogenous molecular and peptidergic biomarkers that potentially predict cerebral vasospasm, subsequent CI and functional outcome after SAH and traumatic brain injury.…”