A systematic review of silymarin and silibinin mechanisms for attenuating cerebral ischemia-reperfusion injuries

Objective: Cerebral ischemia-reperfusion injury (CI/RI) can lead to a range of impairments and even permanent disability.. This systematic review was designed to comprehensively investigate the biological effects of silymarin and silibinin in mitigating CI/RI.Materials and Methods: To find studies published before January ۰۲, ۲۰۲۴, a comprehensive electronic search was carried out across multiple databases, including Cochrane Library, PubMed, Embase, Web of Science, and Scopus. Data including study characteristics, methods, and biological mechanisms were extracted.Results: Silymarin and silibinin potentially improved endogenous antioxidants and reduced lipid peroxidation, nitric oxide (NO), and malondialdehyde (MDA) levels. They also enhances the nuclear factor erythroid ۲-related factor ۲ (Nrf۲) expression and upregulated HO-۱ and NAD(P)H: quinone oxidoreductase ۱ (NQO۱). They also protected the activity of Na+–K+ ATPase, activating mitochondrial membrane potential that suppresses mitochondrial permeability transition pores (mPTP). Moreover, they upregulated proliferator-activated receptor gamma coactivator ۱-alpha (PGC۱-α), uncoupling protein ۲ (UCP۲), nuclear respiratory factor ۱ (NRF۱), and reduced inducible-NO synthase (iNOS), cyclooxygenase-۲ (COX-۲), and myeloperoxidase (MPO) expression. They inhibited transcription factors, including nuclear factor-kappa B (NF-κB) and IκB-α degradation. They also attenuated tumor necrosis factor-α (TNF-α), interleukin-۱β (IL-۱β) and IL-۶. Anti-apoptotic properties were revealed by increasing protein Bcl-۲ and reducing p۵۳, Bax, caspase-۳, and ۹ expressions. silymarin improves pathological changes, behavioral tests, and decreases cerebral infarct size.Conclusion: Silymarin and silibinin indicated promising effects on CI/RI through various mechanisms. However, well-designed clinical trials are needed to validate these findings in human subjects.