Succinate increases neuronal post-synaptic excitatory potentials in vitro and induces convulsive behavior through N-methyl-d-aspartate-mediated mechanisms.

摘要

Succinate is a dicarboxylic acid that accumulates due to succinate dehydrogenase inhibition by malonate and methylmalonate exposure. These neurotoxins cause increased excitability and excitotoxic damage, which can be prevented by administering high amounts of succinate. In the present study we investigated whether succinate alters hippocampal field excitatory post-synaptic potentials. Bath application of succinate at intermediate concentrations (0.3-1 mM) increased the slope of field excitatory post-synaptic potentials in hippocampal slices, and at high concentrations (above 1 mM) did not alter or decrease field excitatory post-synaptic potentials slope. Succinate-induced enhancement of field excitatory post-synaptic potentials slope was abolished by the addition of d-2-amino-5-phosphonovaleric acid (50 microM) to the perfusate, supporting the involvement of N-methyl-d-aspartate receptors in the excitatory effect of this organic acid. Accordingly, succinate (0.8-7.5 micromol) i.c.v. administration caused dose-dependent convulsive behavior in mice. The i.c.v. co-administration of MK-801 (7 nmol) fully prevented succinate-induced convulsions, further suggesting the involvement of N-methyl-d-aspartate receptors in the convulsant action of succinate. Our data indicate that accumulation of moderate amounts of succinate may contribute to the excitotoxicity induced by succinate dehydrogenase inhibitors, through the activation of N-methyl-d-aspartate receptors.