Neuroprotective Effects of Angong Niuhuang Pill in Stroke: A Systematic Review of Preclinical and Clinical Evidence

BACKGROUND: Stroke is the second leading cause of death and the third leading cause of disability-adjusted life years lost. A narrow therapeutic window and the complex, dynamic nature of stroke pathophysiology limit current neuroprotective therapies. Angong Niuhuang Pill (ANP) is a traditional Chinese medicine emergency prescription used to treat acute conditions and is reported to have neuroprotective effects. The aim of this review was to evaluate the neuroprotection of ANP and to assess its efficacy and safety in the treatment of stroke. METHODS: This review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched four databases and selected studies that met the inclusion criteria (n = 16). The methodological quality was assessed using SYRCLE risk of bias tool (for animal studies), the Cochrane Risk of Bias tool (for Randomised Controlled Trials (RCTs)), and AMSTAR 2 (for systematic reviews/meta-analyses). Data were integrated using a narrative synthesis method. RESULTS: 12 preclinical studies suggested that ANP may provide neuroprotection in stroke via multiple pathways, half of them indicating anti-cell death properties. Two high-quality preclinical studies examine the mechanism of ANP in ischemic stroke (IS), namely via the PI3K/AKT axis and microcirculation. One RCT showed that ANP increased the proportion of patients achieving an mRS score of 0-2 at six months in patients with basal ganglia haemorrhage (26.2% vs. 2.6%) and the other one, which exhibits high methodological quality, showed for patients with moderate-to-severe acute IS, ANP showed no overall benefit in day-14 infarct or oedema volumes, although a significant reduction was observed in the large artery atherosclerosis subgroup (-12.3 mL, P = 0.03). Two meta-analyses indicated that ANP was associated with higher GCS (MD = 2.01, 95% CI [1.04, 2.98], P < 0.00001) and lower NIHSS scores, but both had low methodological quality. There was no statistically significant difference in the incidence of adverse events between the two groups. DISCUSSION: This review found that ANP has a relatively definite neuroprotective effect and can improve the clinical efficacy of stroke patients. However, due to the limited number of included studies and significant differences in study design, study population, and outcome definition, the existing evidence shows considerable heterogeneity, resulting in relatively low study quality and making reliable quantitative meta-analysis difficult. Future research should use relevant quality assessment tools in study design and implementation to enhance the credibility of evidence and thereby promote the generation of high-quality evidence. CONCLUSION: This review synthesizes evidence of neuroprotective effect and clinical effectiveness, suggesting potential neuroprotective benefit with an overall favorable safety profile.