Researching glutamate – induced cytotoxicity in different cell lines: a comparative/collective analysis/study

Abstract

Although glutamate is one of the most important excitatory neurotransmitters of the central nervous system, its excessive extracellular concentration leads to uncontrolled continuous depolarization of neurons, a toxic process called, excitotoxicity. In excitotoxicity glutamate triggers the rise of intracellular Ca2+ levels, followed by up regulation of nNOS, dysfunction of mitochondria, ROS production, ER stress, and release of lysosomal enzymes. Excessive calcium concentration is the key mediator of glutamate toxicity through over activation of ionotropic and metabotropic receptors. In addition, glutamate accumulation can also inhibit cystine (CySS) uptake by reversing the action of the CySS/glutamate antiporter. Reversal of the antiporter action reinforces the aforementioned events by depleting neurons of cysteine and eventually glutathione’s reducing potential. Various cell lines have been employed in the pursuit to understand the mechanism(s) by which excitotoxicity affects the cells leading them ultimately to their demise. In some cell lines glutamate toxicity is exerted mainly through over activation of NMDA, AMPA, or kainate receptors whereas in other cell lines lacking such receptors, the toxicity is due to glutamate induced oxidative stress. However, in the greatest majority of the cell lines ionotropic glutamate receptors are present, co-existing to CySS/glutamate antiporters and metabotropic glutamate receptors, supporting the assumption that excitotoxicity effect in these cells is accumulative. Different cell lines differ in their responses when exposed to glutamate. In this review article the responses of PC12, SH-SY5Y, HT-22, NT-2, OLCs, C6, primary rat cortical neurons, RGC-5, and SCN2.2 cell systems are systematically collected and analyzed.

Concentration-Dependent Dual Role of Thrombin in Protection of Cultured Rat Cortical Neurons

“…Future experiments using these proteolytic inhibitors in combination with accurate measures of thrombin concentration in PAR-1 knockout animals could aid in the investigation of mechanisms of thrombin's neurotoxic effects independent of the receptor. Another mechanism to explore is calcium regulation in the cellular microenvironment, because both activation of PAR-1 (37) and glutamate (38)are known to increase intracellular calcium.…”

Low Dose Administration of Glutamate Triggers a Non-Apoptotic, Autophagic Response in PC12 Cells

“…Alternatively, prolonged or and/or enhanced stimulation of the cells with glutamate could lead progressively to cell death either through apoptosis or another death mechanism [20]. Conclusively, the final outcome of glutamate activity is highly depended on its concentration as well as the duration of its action and this observation follows a global pattern of glutamate-related signalling outcomes as recently reviewed in [21].…”

Protective effects of peel and seed extracts of Citrus aurantium on glutamate-induced cytotoxicity in PC12 cell line

“…Glutamate cytotoxicity has been associated with the activation of glutamate receptors and non-receptor-mediated oxidative glutamate toxicity [4,35]. Recent studies have shown that glutamate-induced cytotoxicity could be mediated by oxidative stress, depletion of GSH, and down regulation of SOD activity that leads to apoptosis [18]. Reactive oxygen species are typically defined as molecules or ions formed by the incomplete one-electron reduction of oxygen.…”