Neuroprotective Agents With Reperfusion Therapies in Ischemic Stroke: Evidence From Recent Randomized Trials

This systematic review evaluates the effectiveness and safety of adjunctive neuroprotective therapies administered in combination with reperfusion treatments, either intravenous (IV) thrombolysis, mechanical thrombectomy, or both, in adult patients with acute ischemic stroke (AIS). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive search of four major databases was conducted with filters applied to include English-language randomized controlled trials (RCTs) published within the last five years. From an initial 622 records, 10 eligible RCTs were identified and analyzed. Interventions included nerinetide, edaravone (and its derivatives), nelonemdaz, cerebrolysin, minocycline, glyceryl trinitrate, and normobaric hyperoxia. Functional outcomes were primarily measured using the modified Rankin Scale (mRS), infarct volume, and safety endpoints such as symptomatic intracranial hemorrhage (sICH). Among the findings, normobaric hyperoxia showed the most consistent benefit in reducing infarct size and improving functional outcomes, while agents such as nerinetide and edaravone demonstrated mixed results. Quality assessment using the Cochrane Risk of Bias (RoB) 2.0 tool revealed low to moderate risk of bias across most studies. Although the evidence remains heterogeneous, this review highlights the potential role of neuroprotective agents as adjuncts to reperfusion therapy and identifies promising directions for future clinical trials.