Neuroprotective effects and mechanistic insights of sinomenine in ischemic stroke: a systematic review and meta-analysis of preclinical animal studies

Abstract

Ischemic stroke is a leading cause of long-term disability and mortality worldwide. Despite substantial advances in reperfusion therapy, effective neuroprotective strategies remain limited. Sinomenine, a bioactive alkaloid derived from plants of the Menispermaceae family, has shown neuroprotective effects in preclinical models of ischemic stroke. However, the available preclinical evidence has not been systematically quantified, and the relationship between sinomenine dosage and therapeutic efficacy remains unclear. Eight electronic databases were searched from inception to 30 March 2026. The risk of bias, reporting quality, and translational readiness were assessed using the SYRCLE risk-of-bias tool, the ARRIVE 2.0 guidelines, and the Stroke Therapy Academic Industry Roundtable criteria, respectively. Data synthesis and quantitative analyses were performed with RevMan 5.3 and Stata 17.0. Subgroup and sensitivity analyses were conducted for outcomes with high heterogeneity. Additionally, dose-response curves were fitted using restricted cubic spline models. This meta-analysis included 15 studies. In animal models of ischemic stroke, sinomenine significantly reduced cerebral infarct volume, improved neurological function score (NFS), and preserved blood-brain barrier (BBB) integrity. Sinomenine also downregulated neuroinflammation-related biomarkers, enhanced superoxide dismutase (SOD) activity, and modulated apoptosis-related marker levels. RCS analysis suggested nonlinear dose-response relationships between sinomenine dosage and cerebral infarct volume, NFS, and brain water content. Subgroup analyses revealed that animal strain, comorbidity status, experimental blinding, drug dosage, and timing of administration may influence effect sizes. Trim-and-fill analysis showed that the pooled standardized mean difference (SMD) for cerebral infarct volume attenuated from −3.02 (95% CI [-3.96, −2.08]) to −1.97 (95% CI [-2.93, −1.01]) after adjustment, whereas that for NFS attenuated from −1.57 (95% CI [-2.18, −0.97]) to −1.06 (95% CI [-1.72, −0.40]). In animal models, sinomenine may mitigate ischemic stroke injury through multiple pathways, with the efficacy following nonlinear dose-response relationships, suggesting its potential as an adjunctive neuroprotective intervention warranting further investigation. However, given the methodological limitations of the included studies, these findings should be interpreted cautiously. To facilitate clinical translation, future studies should incorporate more rigorous and standardized experimental designs to strengthen the evidence base and validate its therapeutic potential. https://www.crd.york.ac.uk/PROSPERO/view/CRD420261359581 , identifier CRD420261359581.