Domoic acid neurotoxicity in cultured cerebellar granule neurons is controlled preferentially by the NMDA receptor Ca(2+) influx pathway

Brain Res. 2002 Jan 4;924(1):20-9. doi: 10.1016/s0006-8993(01)03221-8.

Abstract

We have monitored real-time alterations in [Ca(2+)](i) in fluo-3-loaded cerebellar granule neurons exposed to domoate, and ascertained the influence of pharmacological blockers of various Ca(2+) entry pathways on intracellular Ca(2+) accumulation, excitatory amino acid (EAA) release and neuronal death. Domoate produced a rapid and concentration-dependent increase in [Ca(2+)](i), the magnitude of which correlated closely with the severity of neuron loss. The increase in [Ca(2+)](i) was derived from activation of NMDA receptors, L-type voltage-sensitive calcium channels (VSCC) and the reversed mode of operation of the Na(+)/Ca(2+) exchanger. When the level of neuroprotection conferred by pharmacological manipulation of these calcium entry pathways was regressed with the corresponding reductions in [Ca(2+)](i) load, it was observed that neuronal vulnerability is controlled preferentially by NMDA receptors. This observation is consistent with our previous study of brevetoxin-induced autocrine excitotoxicity and with the source specificity hypothesis of others [J. Neurochem. 71 (1998) 2349], which suggests that elevation of [Ca(2+)](i) in the vicinity of the NMDA receptor ion channel activates processes leading to neuronal death.

MeSH terms

  • Aniline Compounds
  • Animals
  • Animals, Newborn
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / drug effects*
  • Calcium Channels / metabolism
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cells, Cultured
  • Cerebellar Cortex / drug effects
  • Cerebellar Cortex / metabolism
  • Cerebellar Cortex / physiopathology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Amino Acids / metabolism
  • Fluorescent Dyes
  • Kainic Acid / analogs & derivatives*
  • Kainic Acid / toxicity*
  • L-Lactate Dehydrogenase / metabolism
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / physiopathology
  • Neuromuscular Depolarizing Agents / toxicity*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurotoxins / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / drug effects*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Sodium-Calcium Exchanger / antagonists & inhibitors
  • Sodium-Calcium Exchanger / metabolism
  • Xanthenes

Substances

  • Aniline Compounds
  • Calcium Channel Blockers
  • Calcium Channels
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Excitatory Amino Acids
  • Fluorescent Dyes
  • Neuromuscular Depolarizing Agents
  • Neurotoxins
  • Receptors, N-Methyl-D-Aspartate
  • Sodium-Calcium Exchanger
  • Xanthenes
  • Fluo-3
  • L-Lactate Dehydrogenase
  • domoic acid
  • Kainic Acid