Abstract
Antimony (Sb), a naturally occurring metal present in air and drinking water, has been found in the human brain, and there is evidence of its toxic effects on neurobehavioral perturbations, suggesting that Sb is a potential nerve poison. Here, we provide the first study on the molecular mechanism underlying Sb-associated neurotoxicity. Mice exposed to antimony potassium tartrate hydrate showed significantly increased neuronal apoptosis. In vitro, Sb triggered apoptosis in PC12 cells in a dose-dependent manner. Mechanically, Sb triggered autophagy as indicated by increased expression of microtubule-associated protein 1 light chain 3-II (LC3-II) and accumulation of green fluorescent protein-tagged LC3 dots. Moreover, Sb enhanced autophagic flux and sequestosome 1 (p62) degradation. Subsequent analyses showed that Sb treatment decreased phosphorylation of protein kinase B (Akt) as well as the mammalian target of rapamycin (mTOR), while an Akt activator protected PC12 cells from autophagy. Moreover, the antioxidant N-acetylcysteine attenuated Sb-induced Akt/mTOR inhibition and decreased autophagy and apoptosis, with autophagy inhibition also playing a cytoprotective role. In vivo, mice treated with Sb showed higher expression of LC3-II and p62 in the brain, consistent with the in vitro results. In summary, Sb induced autophagic cell death through reactive oxygen species-mediated inhibition of the Akt/mTOR pathway.