The neuropeptide in ischemic brain injury: insights, challenges, and horizon of targeted interventions

Abstract Background Cerebral ischemic stroke (CIS) is a highly lethal and disabling global disease with complex pathological mechanisms that pose significant challenges for effective treatment. In recent years, endogenous neuropeptides have emerged as critical signaling molecules, attracting increasing attention for their regulatory roles in the pathophysiology of CIS. Methods This systematic review examines the dynamic functions of various neuropeptides—including opioid peptides, oxytocin, orexin, pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP), cocaine- and amphetamine-regulated transcript (CART) peptide, substance P (SP), galanin, neuropeptide Y (NPY), and vasopressin—across the different pathological stages of CIS (hyperacute, acute, subacute, and chronic phases). It also evaluates therapeutic strategies targeting the neuropeptide system, including associated challenges and future directions. Results Neuropeptides exhibit stage-dependent regulatory roles in CIS, influencing processes such as neuroprotection, inflammation, excitotoxicity, and recovery. The review synthesizes evidence on how these molecules modulate stroke pathology, highlighting their potential as therapeutic targets. Conclusions Targeting the neuropeptide system offers a promising avenue for precision therapies in ischemic stroke, though challenges such as delivery methods and translational research must be addressed. Future directions include developing receptor subtype-specific drugs and novel drug delivery systems to enhance clinical efficacy. Graphical Abstract