Therapeutic potential of nerinetide in acute ischemic stroke: a comprehensive systematic review and meta-analysis.

Background and Objectives: Acute ischemic stroke (AIS) is a leading cause of disability and death worldwide. Nerinetide, a neuroprotective peptide, has shown potential in limiting neuronal damage when administered early after stroke onset. This study aimed to evaluate the efficacy and safety of nerinetide compared with placebo in patients with AIS. Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted in accordance with PRISMA and AMSTAR 2 guidelines. Electronic databases, including PubMed, MEDLINE, Cochrane Library, ScienceDirect, and ClinicalTrials.gov, were searched up to February 2025. The primary outcome assessed was mortality, while secondary outcomes included functional recovery (modified Rankin Scale, Barthel Index), infarct volume, and adverse events. Results: Three RCTs encompassing 2462 patients met the inclusion criteria. Nerinetide treatment demonstrated a modest yet statistically significant reduction in mortality risk (risk ratio = 0.86; P = 0.05). However, no significant improvement was observed in functional recovery or infarct size. The frequency of adverse events was comparable between the nerinetide and placebo groups, with minimal variability. Conclusion: Nerinetide may slightly reduce mortality in AIS, particularly among patients not treated with alteplase. Although functional outcomes did not significantly improve, its favorable safety profile and potential neuroprotective effect support further investigation in larger clinical trials.