The Glutathione System and its Regulation by Neurohormone Melatonin in the Central Nervous System

Jorge      H. Limon-Pacheco; Maria      E. Gonsebatt

doi:10.2174/187152410793429683

Abstract

The glutathione system includes reduced (GSH) and oxidized (GSSG) forms of glutathione; the enzymes required for its synthesis and recycling, such as gamma-glutamate cysteine ligase (γ-GCL), glutathione synthetase (GS), glutathione reductase (GSR) and gamma glutamyl transpeptidase (γ-GGT); and the enzymes required for its use in metabolism and in mechanisms of defense against free radical-induced oxidative damage, such as glutathione s-transferases (GSTs) and glutathione peroxidases (GPxs). Glutathione functions in the central nervous system (CNS) include maintenance of neurotransmitters, membrane protection, detoxification, metabolic regulation, and modulation of signal transduction. A common pathological hallmark in various neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimers and Parkinsons diseases, is the increase in oxidative stress and the failure of antioxidant systems, such as the decrease in the GSH content. The administration of exogenous neurohormone melatonin at pharmacological doses has been shown not only to be an effective scavenger of reactive oxygen and nitrogen species but also to enhance the levels of GSH and the expression and activities of the GSH-related enzymes including γ-GCL, GPxs, and GSR. The exact mechanisms by which melatonin regulates the glutathione system are not fully understood. The main purpose of this short review is to discuss evidence relating to the potential common modulation signals between the glutathione system and melatonin in the CNS. The potential regulatory mechanisms and interactions between neurons and non-neuronal cells are also discussed.

Keywords: Glutathione, γ-glutamate cysteine ligase, glutathione peroxidases, melatonin, brain, gamma-glutamate cysteine ligase (γ-GCL), glutathione synthetase (GS), glutathione reductase (GSR), gamma glutamyl transpeptidase (γ-GGT), glutathione s-transferases, glutathione peroxidases (GPxs), central nervous system, neurohormone melatonin, reactive oxidative species (ROS), lipid peroxidation (LPO), blood brain barrier (BBB), GSH monoethyl ester (GEE), N-acetyl cysteine, glutathione peroxidases (GPx), glutathione S-transferases (GSTs), glutathionylation, neurodegenerative diseases, Parkinson's diseases, traumatic brain injury, nuclear orphan receptor, nuclear factor κB (NF- κB), septum nuclei, selenium influences, neurohormone, cytochrome 1B1 (CYP1B1), environmental carcinogens, Cytosolic GPx, Astroglial cell line-derived neurotrophic factor, GSH monoethyl ester, Gastrointestinal GPx, Neurofibromin 1, p38 kinase, Sex-specific storage-protein 1, Sarcoma tyrosine kinases, Cysteine-permeable, Na+-dependent glutamate transporter