Bimodal functions of calcitonin gene-related peptide in the brain

Abstract

Aims: Calcitonin gene-related peptide (CGRP) is a pluripotent neuropeptide crucial for maintaining vascular homeostasis, yet its full therapeutic potential remains incompletely exploited. Within the brain, CGRP demonstrates a distinct bimodal effect, contributing to neuroprotection in ischemic conditions while inducing neuronal sensitization and inflammation in non-ischemic settings. Despite extensive research on CGRP, the absence of a definitive determinant for this observed dichotomy has limited its potential for therapeutic applications in the brain. This review examines the effects of CGRP in both physiological and pathological conditions, aiming to identify a unifying factor that could enhance its therapeutic applicability.

Materials and methods: This comprehensive literature review analyzes the molecular pathways associated with CGRP and the specific cellular responses observed in these contexts. Additionally, the review investigates the psychological implications of CGRP in relation to cerebral perfusion levels, aiming to elucidate its underlying factors.

Key findings: Reviewing the literature reveals that, elevated levels of CGRP in non-ischemic conditions exert detrimental effects on brain function, while they confer protective effects in the context of ischemia. These encompass anti-oxidative, anti-inflammatory, anti-apoptotic, and angiogenic properties, along with behavioral normalization. Current findings indicate promising therapeutic avenues for CGRP beyond the acute phases of cerebral injury, extending to neurodegenerative and psychological disorders associated with cerebral hypoperfusion, as well as chronic recovery following acute cerebral injuries.

Significance: Improved understanding of CGRP's bimodal properties, alongside advancements in CGRP delivery methodologies and brain ischemia detection technologies, paves the way for realizing its untapped potential and broad therapeutic benefits in diverse pathological conditions.

Keywords: Calcitonin gene-related peptide; Cerebral ischemia; Migraine; Neuro-protection; Neuroinflammation; Neurovascular unit.