Glutathione depletion in neurodegenerative disorders: Cell death mechanisms and neuroprotection, exacerbation of manganese neurotoxicity, and the role in glutathione regeneration pathway

Glutathione (GSH) (gamma-glutamyl cysteinyl glycine) is an antioxidant biosynthesisized in cells and is vital in maintaining the cellular redox environment. Depletion in GSH levels is reported in neurodegenerative disorders including Parkinson's disease. GSH depletion could lead to cellular oxidative stress and ultimately cell death. Regeneration of reduced GSH is an important aspect of GSH metabolism which needs reducing equivalent of NADPH and could control the availability of GSH to neutralize reactive oxygen species. GSH also helps in the cellular defense against xenobiotics such as toxic metals and thus depletion of GSH may enhance neurotoxicity of manganese. Molecular mechanisms of cell death induced by GSH depletion are not fully understood. Moreover, despite numerous research reports on GSH, the potential use of GSH in the pharmacotherapy of neurodegenerative disorders has not yet been achieved. Thus, we attempted to decipher the process of GSH depletion-induced cell death. Our results show that mitochondrial GSH plays a regulatory role in mitochondria-mediated apoptosis process induced by GSH depletion. We also confirmed the neuroprotective potential of astrocytes in a GSH depletion paradigm. Moreover, our research suggests that GSH depletion could be one of the mechanisms underlying Mn neurotoxicity. We also studied developmental changes and sexual dimorphism of activities of the enzymes of GSH regeneration pathway. Our research clearly contributes to an improved understanding of the role of GSH depletion in etiology of neurodegenerative disorders and could be helpful in developing potential pharmacotherapy for such diseases.