Comprehensive Insight of Neurodegenerative Diseases and The Role of Neurotoxin Agents — Glutamate

Abstract

The increased concentration of extracellular glutamate has been reported to play a key role in most of the neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease, even though its importance as an amino acid neurotransmitter in mammalian. Glutamate toxicity, which can be caused by excessive intake of monosodium glutamate (MSG), is the major contributor to pathological neuronal cell death. It causes neuronal dysfunction and degeneration in the central nervous system (CNS). Glutamate neurotoxicity can be categorized into two forms, which are receptor-mediated glutamate excitotoxicity and non-receptor mediated glutamate oxidative toxicity. The receptor-mediated glutamate excitotoxicity involved excessive stimulation of glutamate receptors (GluRs) which lead to excessive ion calcium (Ca2+) influx and activates a cell death cascade involving the accumulation of mitochondrially generated reactive oxygen species (ROS). Studies showed excessive extracellular glutamate leads to nerve cell death via the activation of N-methyl-Daspartate (NMDA) receptors in the cases of trauma or stroke. Whereas non-receptor mediated oxidative toxicity involved the breakdown of the cystine/glutamate antiporter (xc - ) mechanism, which leads to the depletion of glutathione (GSH) and causes oxidative stress and cell death. The cystine/glutamate antiporter couples the import of cystine to the export of glutamate. The increased concentration of extracellular glutamate could inhibit the uptake of cystine, which is required for the synthesis of the intracellular antioxidant GSH. GSH plays an important role in the disposal of peroxides by brain cells and in the protection against ROS. Depletion of GSH renders the cell to oxidative stress and ultimately leading to cell death. This article aims to provide a comprehensive review of neurodegenerative diseases and the role of neurotoxin agents, glutamate in these diseases.

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“…Glutamate is the most important excitatory neurotransmitter in the brain, but in excess it becomes neurotoxic. Excessive activation of glutamate receptors leads to excessive calcium influx and activates a cell death cascade due to mitochondrial reactive oxygen species (ROS) [97].…”

“…A mechanism that results in glial cells releasing nonvesicular glutamate into the extrasynaptic space is a key factor in pathological glutamate signaling [98]. The cystine-glutamate antiporter system, xc-is the major route by which cysteine is taken up into cells (in its oxidized form as cystine) [97]. Extracellular glutamate is a competitive inhibitor of xc-, preventing uptake of cystine by the cell.…”