Role of AMPK/PGC-1α/ SIRT3-mediated mitochondrial dysfunction in the neurotoxicity of methanol

Methanol (MeOH) is a volatile, flammable liquid with systemic and ocular toxicity, commonly used in construction, automobiles, and medicinal industries. In the present study, the mitochondrial dysfunction of nerve cells caused by methanol was used as an entry point, and a total of 96 male SD rats were chosen and allocated into six groups: control, methanol low-, medium-, high-dose, ZLN005, and a combined group of medium-dose methanol plus ZLN005. The toxicity group was exposed to a static poison for 28 days, 2 h daily, and the ZLN005 group was injected with ZLN005 in the tail vein once a week. Experiments were carried out to elucidate the role of AMPK/PGC-1α/SIRT3-mediated mitochondrial dysfunction in methanol-induced neurotoxicity in rats through Morris water maze test, open field test, HE staining, electron microscopy, superoxide dismutase activity and malondialdehyde level measurements, real-time PCR, Western blot, and other methods. The results showed a decrease in body weight growth rate, an increase in avoidance latency, and a decrease in the number of uprights and horizontal movement frames in the open field test in the poisoned rats. Histological examination showed that cortical neurons were damaged, and oxidative stress indicators showed decreased superoxide dismutase activity and increased malondialdehyde content. In addition, methanol exposure induces oxidative damage and mitochondrial dysfunction by downregulating the expression level of AMPK/PGC-1α/SIRT3 pathway-related proteins, leading to neuronal and neurobehavioral impairments, which are significantly ameliorated by ZLN005 intervention. This study reveals that methanol-induced neurotoxicity is mediated by AMPK/PGC-1α/SIRT3-related mitochondrial dysfunction, and that ZLN005 intervention can mitigate this damage, highlighting a potential therapeutic target for environmental neurotoxicants.