Topiramate protects against neuroinflammation in response to traumatic brain injury via activating Sirt1 signaling.

Traumatic brain injury (TBI) elicits a sustained neuroinflammatory cascade that contributes to neuronal loss and poor functional recovery. Topiramate (TPM) is an FDA-approved antiepileptic drug with anti-excitotoxic and anti-inflammatory actions. Here, we tested whether TPM mitigates neuroinflammation and improves outcomes in experimental TBI models. Adult mice subjected to controlled cortical impact (CCI) received TPM (80 mg/kg, i.p.) 30 min post-injury and every 12 h for 48 h. Outcomes included neuronal survival, brain water content, neurological function, lipid peroxidation, inflammatory cytokines expression, astrocyte and microglia activation. The potential underlying mechanism was determined by measuring microglial polarization markers and neuronal Sirt1 expression. A traumatic neuronal injury (TNI) model in primary cortical neurons assessed dose (10–100 µM TPM) and therapeutic window (0–4 h post-injury). The Sirt1 inhibitor sirtinol was used in vivo and in vitro to probe mechanism. The results showed that TPM reduced neuronal loss, ipsilateral brain water content, and cleaved caspase-3, and improved mNSS and beam-walk performance on days 7 and 14. TPM decreased levels of MDA, 4-HNE, TNF-α, IL-1β, and IL-6 while increasing IL-10 expression, and suppressed GFAP⁺ astrocytosis and Iba-1⁺ microgliosis. Notably, TPM shifted microglial phenotype toward an M2-like state and enhanced nuclear Sirt1 expression in neurons. Sirtinol attenuated TPM-induced protection and partly reversed the TPM-induced changes in microglial polarization markers. In vitro, TPM (50–100 µM) reduced LDH release, preserved calcein signal, and inhibited lipid peroxidation, with efficacy observed when administered within 2 h post-injury, which were blunted by sirtinol. In summary, these data indicate that TPM confers neuroprotection after TBI, at least in part, by engaging Sirt1 and promoting a pro-resolving microglial phenotype, supporting its therapeutic potential for the treatment of TBI.