ABSTRACT
Methamphetamine (METH) has been established to selectively target and impair dopaminergic neurons through multiple pathways. Ferroptosis is a unique form of non-apoptotic cell death driven by cellular iron accumulation-induced lipid peroxidation. Nonetheless, it remains unclear whether METH can induce ferroptosis. In the present study, we sought to assess alterations in iron levels after chronic METH exposure and reveal the modulatory role of iron on METH-induced pathologies. Importantly, we demonstrated that METH increased iron deposition in the nigrostriatal system, including the substantia nigra (SN) and caudate putamen (CPu). Moreover, decreases in GPx4 levels, increases in lipid peroxidation products, and pathological alterations were observed in the nigrostriatal system as a consequence of chronic METH exposure. The iron chelator deferiprone not only alleviated nigrostriatal iron deposition, dopaminergic cell death, and lipid peroxidation, but alsoattenuated the decreases in GPx4 induced by METH. These findings suggest an alleviation of ferroptosis in dopaminergic neurons. In addition, we found that the ferroptosis inhibitor liproxstatin-1 attenuated METH-induced dopaminergic degeneration in the nigrostriatal system. Our findings corroborated that METH might induce dopaminergic neurodegeneration through iron-dependent ferroptosis. Interestingly, reducing iron levels or inhibiting ferroptosis may alleviate METH-induced dopaminergic neurodegeneration.
