Dimebon, an antihistamine drug, inhibits glutamate release in rat cerebrocortical nerve terminals

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Abstract

The excessive release of glutamate is a critical element in the neuropathology of acute and chronic brain disorders. The purpose of the present study was to investigate the effect and possible mechanism of dimebon, an antihistamine with a neuroprotective profile, on endogenous glutamate release in the nerve terminals (synaptosomes) of the rat cerebral cortex. Dimebon inhibited the release of glutamate that was evoked by exposing the synaptosomes to the K+ channel blocker 4-aminopyridine, and this effect was prevented by chelating extracellular Ca2+ ions, and the vesicular transporter inhibitor bafilomycin A1. Dimebon inhibited depolarization-evoked increase in cytosolic free Ca2+ concentration, and the dimebon-mediated inhibition of glutamate release was prevented by the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC. The inhibitory action of dimebon on glutamate release was not due to its decreasing synaptosomal excitability, because dimebon did not alter the resting synaptosomal membrane potential or 4-aminopyridine-mediated depolarization. Furthemore, the dimebon effect on 4-aminopyridine-evoked glutamate release was prevented by the protein kinase C inhibitor, and dimebon substantially reduced the 4-AP-induced phosphorylation of protein kinase C. However, the dimebon-mediated inhibition of glutamate release was unaffected by the N-methyl-D-aspartate receptor agonist or antagonist. These results suggest that dimebon inhibits glutamate release from rat cortical synaptosomes by suppressing presynaptic voltage-dependent Ca2+ entry and protein kinase C activity. This implies that the inhibition of glutamate release is an additional pharmacological activity of dimebon that may play a critical role in the apparent clinical efficacy of this compound.

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