Taxol stabilizes [Ca]i and protects hippocampal neurons against excitotoxicity |
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Authors: | Katsutoshi Furukawa Mark P Mattson |
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Institution: | Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536-0230, USA |
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Abstract: | Elevation of intracellular calcium levels Ca2+]i induces microtubule depolymerization, a process which plays roles in regulation of cell motility and axonal transport. However, excessive Ca2+ influx, as occurs in neurons subjected to excitotoxic conditions, can kill neurons. We now provide evidence that the polymerization state of microtubules influences neuronal Ca2+]i homeostasis and vulnerability to excitotoxicity. The microtubule-stabilizing agent taxol significantly attenuated glutamate neurotoxicity in cultured rat hippocampal neurons. Experiments in which Ca2+]i was monitored using the Ca2+ indicator dye fura-2 showed that the elevation of Ca2+]i induced by glutamate was significantly attenuated in neurons pretreated with taxol. Experiments using selective glutamate receptor agonists suggested that taxol suppressed Ca2+ influx through α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors, but not through N-methyl-D-aspartate (NMDA) receptors. Taxol attenuated the neurotoxicity of the microtubule-depolymerizing agent colchicine; colchicine neurotoxicity was, in part, dependent on Ca2+ influx. These findings suggest that microtobules play a role in the mechanism of excitotoxicity and suggest that taxol and related compounds may be useful as antiexcitotoxic agents. |
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Keywords: | Alzheimer's disease Calcium Colchicine Excitototoxicity Fura-2 Glutamate Microtubule Taxol |
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