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Manipulation of membrane potential modulates malonate-induced striatal excitotoxicity in vivo
1Department of Neurobiology and Anatomy, University of Rochester Medical Center, New York, USA.
Abstract:
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 mumol of malonate by approximately 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.
Insights
Malonate neurotoxicity is worsened by membrane depolarization and lessened by hyperpolarization. This effect is mediated by the N-methyl-D-aspartate (NMDA) receptor, suggesting potential therapeutic targets for neuroprotection.
Area of Science:
- Neuroscience
- Neuropharmacology
- Biochemistry
Background:
- Malonate inhibits succinate dehydrogenase (SDH), causing neurotoxicity via N-methyl-D-aspartate (NMDA) receptors.
- The role of cellular membrane potential in malonate's neurotoxicity is not fully understood.
Purpose of the Study:
- To investigate how manipulating membrane potential affects striatal malonate toxicity in vivo.
- To explore the involvement of NMDA receptors in the observed effects.
Main Methods:
- In vivo studies in rats using lesion volume analysis.
- Pharmacological agents to alter membrane potential: ouabain (Na+,K+-ATPase inhibitor), high potassium, and minoxidil (K+ channel activator).
- Administration of malonate, NMDA, and the NMDA antagonist MK-801.
Main Results:
- Membrane depolarization (via ouabain or high K+) significantly exacerbated malonate toxicity, an effect blocked by MK-801.
- Ouabain also potentiated NMDA toxicity, and MK-801 protected against ouabain toxicity.
- Hyperpolarization (via minoxidil) attenuated malonate toxicity by ~60% without affecting ATP depletion.
Conclusions:
- Membrane depolarization enhances malonate-induced neurotoxicity, while hyperpolarization offers protection.
- These findings support a hypothesis that NMDA receptor activity, influenced by both voltage and agonists, mediates the impact of membrane potential on malonate neurotoxicity.
