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

Stelios Kokkoris,David J Webb,Peter Andrews

doi:10.3389/fendo.2012.00135

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.

Highlights

In the US, over 30,000 persons each year experience a subarachnoid hemorrhage (SAH)
Intracranial aneurysms account for approximately 85% of cases of non-traumatic SAH, whereas 10% have the pattern of non-aneurysmal perimesencephalic hemorrhage, a relatively harmless condition
We summarize the etiology and therapy of cerebral vasospasm, the biology of Calcitonin gene-related peptide (CGRP) and its receptors, and review the role of CGRP as a treatment in SAH-associated vasospasm in both animals and humans

Summary

INTRODUCTION

In the US, over 30,000 persons each year experience a subarachnoid hemorrhage (SAH). Whereas intracranial aneurysms are found in 2−5% of all autopsies, the incidence of rupture is only 2−20/100,000 individuals/year (Ingall et al, 2000). Calcitonin gene-related peptide receptor activation is known to involve several crucial elements, in common with other GPCRs, such as the presence of a proline “kink” in transmembrane helix (TM) (Conner et al, 2005), and a putative ‘DRY’ motif equivalent (Conner et al, 2007), similar to family A GPCRs. There is evidence suggesting stabilization of the CLR interaction with G “alpha” s (Gas) by another 17kDa intracellular membrane protein, called RCP (Evans et al, 2000). Activation of PLC is considered to occur through Gq/11α, rather than through Gαs, suggesting that the activated CGRP receptor is able to interact with both types of G protein If this mechanism is present in endothelial cells, it provides an alternative explanation for CGRP activation of eNOS (which is traditionally considered to be dependent on Ca2+/calmodulin for activation), independently of cAMP accumulation. The effect began to appear 5 min after the CGRP

Results

Study design

CONCLUSION