Kainic acid-mediated excitotoxicity as a model for neurodegeneration.
Neuronal excitation involving the excitatory glutamate receptors is recognized as an important underlying mechanism in neurodegenerative disorders. Excitation resulting from stimulation of the ionotropic glutamate receptors is known to cause the increase in intracellular calcium and trigger calcium-dependent pathways that lead to neuronal apoptosis. Kainic acid (KA) is an agonist for a subtype of ionotropic glutamate receptor, and administration of KA has been shown to increase production of reactive oxygen species, mitochondrial dysfunction, and apoptosis in neurons in many regions of the brain, particularly in the hippocampal subregions of CA1 and CA3, and in the hilus of dentate gyrus (DG). Systemic injection of KA to rats also results in activation of glial cells and inflammatory responses typically found in neurodegenerative diseases. KA-induced selective vulnerability in the hippocampal neurons is related to the distribution and selective susceptibility of the AMPA/kainate receptors in the brain. Recent studies have demonstrated ability of KA to alter a number of intracellular activities, including accumulation of lipofuscin-like substances, induction of complement proteins, processing of amyloid precursor protein, and alteration of tau protein expression. These studies suggest that KA-induced excitotoxicity can be used as a model for elucidating mechanisms underlying oxidative stress and inflammation in neurodegenerative diseases. The focus of this review is to summarize studies demonstrating KA-induced excitotoxicity in the central nervous system and possible intervention by anti-oxidants.
Wang
Qun
Q
Department of Medical Pharmacology, University of Missouri School of Medicine, Columbia, MO, USA.
Yu
Sue
S
Simonyi
Agnes
A
Sun
Grace Y
GY
Sun
Albert Y
AY
D000818:Animals; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism*; D006801:Humans; D007608:Kainic Acid / Q000378:metabolism*; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology
D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid