Taxol stabilizes [Ca2+]i and protects hippocampal neurons against excitotoxicity.
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 alpha-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 microtubules play a role in the mechanism of excitotoxicity and suggest that taxol and related compounds may be useful as antiexcitotoxic agents.
Furukawa
K
K
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
Mattson
M P
MP
D000818:Animals; D001370:Axonal Transport / Q000187:drug effects; D001704:Biopolymers; D002118:Calcium / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
D001704:Biopolymers; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D017239:Paclitaxel; D002118:Calcium