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Manipulation of Membrane Potential Modulates Malonate‐Induced Striatal Excitotoxicity In Vivo
Author(s) -
Greene James G.,
Greenamyre J. Timothy
Publication year - 1996
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1996.66020637.x
Subject(s) - malonate , excitotoxicity , nmda receptor , depolarization , chemistry , ouabain , membrane potential , pharmacology , toxicity , agonist , biophysics , biochemistry , biology , receptor , sodium , organic chemistry
Malonate is a reversible inhibitor of succinate dehydrogenase (SDH) that produces neurotoxicity by an N ‐methyl‐ d ‐aspartate (NMDA) receptor‐dependent mechanism. We have examined the influence of pharmacological manipulation of membrane potential on striatal malonate toxicity in rats in vivo by analysis of lesion volume. Depolarization caused by coinjection of the Na + ,K + ‐ATPase inhibitor ouabain or a high concentration of potassium greatly exacerbated malonate toxicity; this combined toxicity was blocked by the noncompetitive NMDA antagonist MK‐801. The toxicity of NMDA was also exacerbated by ouabain. The overt toxicity of a high dose of ouabain (1 nmol) was largely prevented by MK‐801. Coinjection of the K + channel activator minoxidil (4 nmol) to reduce depolarization attenuated the toxicity of 1 µmol of malonate by ∼60% without affecting malonate‐induced ATP depletion. These results indicate that membrane depolarization exacerbates malonate neurotoxicity and that membrane hyperpolarization protects against malonate‐induced neuronal damage. We hypothesize that the effects of membrane potential on malonate toxicity are mediated through the NMDA receptor as a result of its combined agonist‐ and voltage‐dependent properties.