Nimodipine ameliorates subarachnoid hemorrhage-induced neuroinflammation and injury by protecting mitochondrial function and regulating autophagy.

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke, and the neuroprotective effects of nimodipine following SAH have been well-documented. Sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, plays a significant role in mitigating oxidative stress in various neurodegenerative conditions. However, the role of SIRT3 in the neuroprotective mechanisms of nimodipine after SAH remains unclear. In this study, the in vitro cytotoxicity of neurons exposed to 2% ethanol (to stimulate oxidative stress) was assessed. An in vivo experimental SAH model was established in adult mice through internal carotid perforation. A series of in vitro and in vivo experiments were conducted to investigate the function of SIRT3 and its potential mechanisms in nimodipine-treated SAH. Nimodipine, at a concentration of 10 μM within 48 h of incubation, exerted significant neuroprotective effects, enhancing SIRT3 protein expression under oxidative stress. Functional in vitro studies revealed that elevated SIRT3 expression improved mitochondrial function and promoted neuronal autophagy. Additional studies unveiled that SIRT3 knockdown or inhibition of autophagosome formation using inhibitor 3-methyladenine suppressed nimodipine-induced autophagy. The absence of autophagy increased neuronal cytotoxicity and mitochondrial dysfunction, decreased the release of anti-inflammatory cytokines, and increased the release of proinflammatory cytokines. Furthermore, blocking autophagy exacerbated neuronal apoptosis worsened neurological outcomes, and nullified the neuroprotective effects of nimodipine in the SAH mouse model. These findings highlight a mechanism where SIRT3 mediates nimodipine's neuroprotective effects by regulating mitochondrial function and autophagy. This suggests that SIRT3 serves as a promising therapeutic target for SAH.