Ginkgolide B alleviates traumatic brain injury in mice via inhibiting the HIF-1α/AKT/mTOR signaling pathway and modulating microglial polarization.

Traumatic brain injury (TBI) is commonly accompanied by aberrant microglial activation, uncontrolled neuroinflammation and subsequent neurological dysfunction. Ginkgolide B (GB) exerts prominent neuroprotective and anti-inflammatory activities; however, the precise molecular mechanism underlying its therapeutic efficacy against TBI remains poorly defined. The present study aimed to explore whether GB relieves TBI by modulating the HIF-1α/AKT/mTOR cascade and redirecting microglial polarization. A controlled cortical impact (CCI) model was established in mice followed by intraperitoneal GB administration. Network pharmacology, molecular docking and GEO database mining were performed to screen core therapeutic targets. An in vitro inflammatory model was constructed using LPS-stimulated BV2 microglia, CETSA and DARTS assays provided supportive evidence for a potential physical association between GB and HIF 1α, with subsequent rescue experiments implemented for mechanistic verification. In vivo behavioral assessments revealed that GB significantly mitigated acute neurological deficits, improved subacute motor coordination, and rescued chronic cognitive impairment and anxiety-like behaviors in TBI mice. Mechanistically, GB suppresses the HIF 1α/AKT/mTOR signaling cascade in a HIF 1α dependent manner. M1-type microglial polarization, reduced pro-inflammatory cytokine secretion and elevated the levels of anti-inflammatory cytokines. Notably, HIF-1α overexpression abolished the neuroprotective effects of GB, whereas HIF-1α knockdown recapitulated GB-mediated beneficial phenotypes. Collectively, GB acts through the candidate functional target HIF 1α to block the HIF 1α/AKT/mTOR pathway, ameliorates neuroinflammation through regulating microglial phenotypic transition, and ultimately alleviates neurological damage post-TBI. This work provides experimental evidence for the preclinical application of GB in TBI intervention.