Elucidating the dopaminergic neurotoxicity of kainic acid
Type of DegreeMaster's Thesis
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Dopamine is an essential catecholamine neurotransmitter in the central and peripheral nervous system. This monoaminergic neurotransmitters is required for the maintenance of several physiological functions (control of movement, mental functions (mood and decision making), prolactin secretion, emesis, appetite, cardiovascular system (heart/blood vessel), gastrointestinal tract motility, sexual function, and diuresis). Degeneration of dopaminergic neurons in the central and peripheral nervous system arises due to several highly complicated neurotoxic mechanisms and pathways. Among the various neurotoxic mechanisms, excitotoxicity has a great impact on the survival of the dopaminergic neurons. Most of the present neurotoxins primarily target tyrosine hydroxylase (rate limiting step) to exert its dopaminergic neurotoxicity. Since dopaminergic neurotoxicity is a complex endeavor, it will be appropriate to have a neurotoxin with multiple pharmacodynamic effects. Interestingly, kainic acid is an accepted and established excitatory neurotoxin which exerts its effect by binding to kainate (glutamate) receptor to enhance excessive calcium influx, increase proxidant generation, induce mitochondrial dysfunction and apoptosis or necrosis which triggers neurodegeneration leading to neuronal death. Currently, the neurotoxic potency of kainic acid as compared to the well-known dopaminergic neurotoxins are not clearly elucidated. Hence, this study compared the dopaminergic neurotoxicity of kainic acid with various endogenous and exogenous neurotoxins using valid in vitro dopaminergic neuronal models. Our finding clearly indicates that as compared to the existing valid and scientifically accepted dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+), kainic acid has significantly less dopaminergic neurotoxicity. Consequently, kainic acid can be used as an adjuvant to enhance the dopaminergic neurotoxicity. Further in vivo studies will be done in the future to investigate the potentiating / synergistic role of kainic acid on dopaminergic neurotoxicity.