Taxol stabilizes [Ca2+]i and protects hippocampal neurons against excitotoxicity

Brain Res. 1995 Aug 14;689(1):141-6. doi: 10.1016/0006-8993(95)00537-z.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Axonal Transport / drug effects
  • Biopolymers
  • Calcium / metabolism*
  • Cell Movement / drug effects
  • Excitatory Amino Acid Agonists / pharmacology
  • Hippocampus / cytology
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Homeostasis / drug effects
  • Microtubules / drug effects
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Paclitaxel / pharmacology*
  • Rats
  • Receptors, AMPA / drug effects
  • Receptors, N-Methyl-D-Aspartate / drug effects

Substances

  • Biopolymers
  • Excitatory Amino Acid Agonists
  • Neuroprotective Agents
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Paclitaxel
  • Calcium