Simvastatin-induced neuroprotective effect after brain injury is mediated by mitochondrial protection through modulation of the 18 kDa translocator protein

Traumatic brain injury (TBI) remains a leading cause of mortality and chronic disability. Among therapeutic agents investigated, simvastatin has emerged as a potential therapeutic opportunity for management of TBI although its mechanism of action has not been yet elucidated. Recent advance in 3D molecular docking simulations has suggested a possible interaction between simvastatin and the 18 ​kDa translocator protein (TSPO). Accumulating evidence suggest that The TSPO may play a pivotal role following TBI with TSPO ligands enhancing mitochondrial function and survival. Here, we examined the neuroprotective effects of simvastatin on cognitive and locomotor functions, histopathological outcome, and mitochondrial respiration following TBI in rats. In addition, molecular docking/interactions of simvastatin with TSPO were simulated. The current result show that simvastatin treatment significantly improved cognitive recovery in Morris water maze, motor performance in rotarod test, and neuronal density in the lesion area and hippocampus compared with untreated TBI groups. Importantly, these effects were attenuated by PK11195 pretreatment. Moreover, molecular docking simulations revealed that simvastatin exhibits a high binding affinity to TSPO, suggesting that its beneficial role could be the result of TSPO modulation. Furthermore, simvastatin treatment restored mitochondrial respiration by enhancing oxygen consumption rates across various respiratory states. In contrast, comparative analyses revealed that PK11195 attenuated simvastatin-induced respiratory enhancement, providing strong evidence for a TSPO-mediated mechanism of action of simvastatin. In conclusion, the current result highlights simvastatin's therapeutic potential in mitigating mitochondrial dysfunction and promoting neuroprotection effects following TBI. Our findings underscore mitochondrial protection as an important therapeutic target in TBI.