Neuroprotective effects of berberine in preclinical models of ischemic stroke: a systematic review.

Background/objective: Berberine, a naturally occurring alkaloid, has shown promise as a neuroprotective agent in preclinical models of ischemic stroke. This systematic review aims to comprehensively evaluate the neuroprotective effects of berberine in animal models of cerebral ischemia and elucidate its potential mechanisms of action.

Methods: A systematic search was conducted across nine databases, including PubMed, Embase, Cochrane CENTRAL, Web of Science, Scopus, ScienceDirect, Europe PMC, DOAJ, and Google Scholar, from inception to June 30, 2024. Controlled in vivo studies investigating the neuroprotective effects of berberine in animal models of focal cerebral ischemia were included. Two independent reviewers screened studies, extracted data, and assessed the risk of bias using the SYRCLE tool.

Results: Eighteen studies met the inclusion criteria, encompassing various animal models of ischemic stroke. Berberine treatment consistently resulted in significant reductions in infarct volume and improvements in neurological function compared to control groups. Specifically, berberine doses ranging from 10 mg/kg to 300 mg/kg significantly decreased infarct sizes (p < 0.05). Berberine also exhibited anti-inflammatory effects by reducing pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and downregulating the TLR4/NF-κB signaling pathway (p < 0.05). Antioxidant effects were evidenced by decreased malondialdehyde levels and increased antioxidant enzymes like superoxide dismutase and glutathione (p < 0.05). Additional findings from studies with smaller sample sizes indicated that berberine reduced apoptotic cell death by decreasing TUNEL-positive cells and modulating apoptosis-related proteins, including increasing Bcl-2 and decreasing cleaved caspase-3 levels (p < 0.05). Berberine also promoted neurogenesis and synaptic plasticity by increasing the expression of BDNF, TrkB, and synaptic proteins SYP and PSD95 (p < 0.05), and enhanced autophagic flux by modulating key autophagy markers (p < 0.05). The risk of bias varied among studies, with some lacking detailed reporting on randomization and blinding procedures.

Conclusion: Berberine demonstrates significant neuroprotective effects in preclinical models of ischemic stroke through multiple mechanisms, including anti-inflammatory, antioxidant, anti-apoptotic, and neuroregenerative actions. These findings support the potential of berberine as a multifaceted therapeutic agent for ischemic stroke. Further well-designed clinical trials are warranted to confirm its efficacy and safety in human patients.