Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors

Abstract

Glutamate receptors play a crucial role in the central nervous system and are implicated in different brain disorders. They play a significant role in the pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although many studies on NDDs have been conducted, their exact pathophysiological characteristics are still not fully understood. In in vivo and in vitro models of neurotoxic-induced NDDs, neurotoxic agents are used to induce several neuronal injuries for the purpose of correlating them with the pathological characteristics of NDDs. Moreover, therapeutic drugs might be discovered based on the studies employing these models. In NDD models, different neurotoxic agents, namely, kainic acid, domoic acid, glutamate, β-N-Methylamino-L-alanine, amyloid beta, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenylpyridinium, rotenone, 3-Nitropropionic acid and methamphetamine can potently impair both ionotropic and metabotropic glutamate receptors, leading to the progression of toxicity. Many other neurotoxic agents mainly affect the functions of ionotropic glutamate receptors. We discuss particular neurotoxic agents that can act upon glutamate receptors so as to effectively mimic NDDs. The correlation of neurotoxic agent-induced disease characteristics with glutamate receptors would aid the discovery and development of therapeutic drugs for NDDs.

Keywords: glutamate receptors; nerve tissue; neurodegenerative diseases; neuronal toxicity; neurotoxic agents.

FIGURE 1

Glutamate receptor-mediated neurotoxic actions of glutamate, domoic acid, and kainic acid. Upon binding to glutamate receptors, all toxins produce an agonistic reaction that lead to cell death. Glu: Glutamate; KA: Kainic acid; DomA: Domoic acid; COX: Cyclooxygenase; ROS: Reactive oxygen species; and RNS: Reactive nitrogen species.

FIGURE 2

Amyloid beta-induced synaptic dysfunction through NMDAR. Binding of Aβ to the NMDAR causes calcium overload in the synapse leading to impairment in various signaling pathways. Finally, these impairments cause synaptic dysfunction. PSD-95: Postsynaptic density protein 95; MAPKs: Mitogen-activated protein kinases; GSK-3β: Glycogen synthase kinase-3 beta; CREB: cAMP-response element binding protein; BDNF: Brain-derived neurotrophic factor; CaMKII: Calcium/calmodulin-dependent protein kinase II