Abstract
Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis, and release in/from surrounding astrocytes. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a detoxifying master transcription factor, is expressed mainly in astrocytes and activates the gene expression of various phase II drug-metabolizing enzymes or antioxidants including GSH-related molecules and metallothionein by binding to the antioxidant response element (ARE) of these genes. Accumulating evidence has shown the involvement of dysfunction of antioxidative molecules including GSH and its related molecules in the pathogenesis of Parkinson’s disease (PD) or parkinsonian models. Furthermore, we found several agents targeting GSH synthesis in the astrocytes that protect nigrostriatal dopaminergic neuronal loss in PD models. In this article, the neuroprotective effects of supplementation and enhancement of GSH and its related molecules in PD pathology are reviewed, along with introducing new experimental findings, especially targeting of the xCT-GSH synthetic system and Nrf2–ARE pathway in astrocytes.
Highlights
Oxidative stress plays a pathogenic role in neurodegenerative disorders including Parkinson’s disease (PD)
We previously reported that L-DOPA treatment increases L-DOPA uptake into striatal astrocytes and astrocytic GSH release, exerting neuroprotective effects on DA neurons in the presence of astrocytes
Our previous studies demonstrated that cabergoline and ropinirole increased the expression of GSHrelated enzymes and GSH content to ameliorate the reduction in dopaminergic neurons in a parkinsonian model [97,98,99]
Summary
Oxidative stress plays a pathogenic role in neurodegenerative disorders including Parkinson’s disease (PD). Glutathione (GSH) is the most abundant antioxidative molecule in the central nervous system (CNS) and plays a critical role in protecting cells against oxidative stress such as reactive oxygen species (ROS). Accumulating evidence shows the involvement of dysfunction of antioxidative molecules including GSH and its related molecules in the pathogenesis of PD or parkinsonian models. A number of studies showed neuroprotective effects of supplementation and enhancement of GSH-related antioxidative molecules against neurodegeneration in PD or parkinsonian animals [6]. We found several agents targeting GSH synthesis in the striatal astrocytes that protect nigrostriatal dopaminergic neuronal loss in parkinsonian models [6]. This article contributes an overview of the involvement of GSH and its related molecules in PD pathogenesis, as well as of their disease-modifying properties in PD models
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