Regulation of Neuronal Glutathione Synthesis

Abstract

Abstract. The brain is among the major organs generating large amounts of reactive oxygen species and is especially susceptible to oxidative stress. Glutathione (GSH) plays critical roles as an antioxidant, enzyme cofactor, cysteine storage form, the major redox buffer, and a neuromodulator in the central nervous system. GSH deficiency has been implicated in neurodegenerative diseases. GSH is a tripeptide comprised of glutamate, cysteine, and glycine. Cysteine is the rate-limiting substrate for GSH synthesis within neurons. Most neuronal cysteine uptake is mediated by sodium-dependent excitatory amino acid transporter (EAAT) systems, known as excitatory amino acid carrier 1 (EAAC1). Previous studies demonstrated EAAT is vulnerable to oxidative stress, leading to impaired function. A recent study found EAAC1-deficient mice to have decreased brain GSH levels and increased susceptibility to oxidative stress. The function of EAAC1 is also regulated by glutamate transporter associated protein 3-18. This review focuses on the mechanisms underlying GSH synthesis, especially those related to neuronal cysteine transport via EAAC1, as well as on the importance of GSH functions against oxidative stress.

Enhanced Phosphatidylinositol 3-kinase (PI3K)/Akt Signaling Has Pleiotropic Targets in Hippocampal Neurons Exposed to Iron-induced Oxidative Stress

“…In consequence, the most appropriate candidate for clearing hydroxyl radicals becomes GSH (56). Moreover, the increase in superoxide can also be overcome non-enzymatically by the consumption of GSH (57). In line with this, we demonstrate that ␥-GCSc expression increases in the presence of iron, which may be responsible for the maintenance in the levels of GSH under oxidative stress conditions, and that this preferential defeating pathway is dependent on PI3K/Akt activation because its inhibition strongly diminished not only GSH but also ␥-GCSc expression levels.…”

Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells

“…In this study we selected concentrations that could be generated locally at a site of oxidative stress and mediate acute stress to neurons in regions subject to neurodegeneration, stroke or seizure. The presence of HNE has been suggested to lead to depletion of cellular glutathione (GSH) levels in both Alzheimer and Parkinson disease brains, 18,19 which leads to increased overall oxidative stress and mitochondrial dysfunction. Importantly, mitochondria are major targets of HNE, which has been shown to form adducts with respiratory chain subunits, increase reactive species production, and decrease mitochondrial reserve capacity, all of which contribute to bioenergetic dysfunction.…”

Cerebrospinal fluid concentrations of N-acetylcysteine after oral administration in Parkinson's disease

“…GSH itself cannot be taken up by neurons, but N-acetylcysteine (NAC) can restore neuronal GSH levels by functioning as a cellpermeable source of cysteine, the rate-limiting substrate for GSH synthesis [6,8]. In addition, NAC may also have a direct role in neuroprotection as a scavenger of oxygen radicals, and as a modulator of the immune system and mitochondrial processes [9].…”