ИСТИНА

Impaired metabolism causes brain pathologies, but therapeutic corrections of brain dysfunction are mostly based on targeting receptor systems and ion channels. Metabolic syndrome is a side effect of such treatments, manifesting both the interplay between metabolism and neurotransmission, and therapeutic potential of metabolic regulation in the brain. The present study aimed at characterizing behavioral and physiological effects of inhibitors of mitochondrial metabolism. Membrane-permeable precursors of the inhibitors of the pyruvate and 2-oxoglutarate dehydrogenases, acetylphosphonate and glutarylphosphonate, respectively, were employed. The fully esterified phosphonates (dimethyl acetylphosphonate - AcPMe2, and triethyl glutarylphoshonate - TEGP) were directed to the rat brain through intranasal application of the water solutions. TEGP decreased anxiety and increased number of highly active animals (p < 0.05), whereas its effects on specific parameters of exploratory behavior, locomotion and electrocardiogram were less expressed (p > 0.05). In contrast, AcPMe2 had the strongest effect on electrocardiogram (40% decrease in RMSSD, p < 0.05), with less expressed action on the anxiety and exploratory/locomotor activity (p > 0.1). Although inhibition of either of the enzymes may decrease the flux through the same pathway (tricarboxylic acid cycle), specific behavioral and electrocardiographic effects of the two inhibitors correspond to decreased synthesis of acetylcholine upon inhibition of pyruvate dehydrogenase and perturbed metabolism of glutamate at impairment of 2-oxoglutarate dehydrogenases. Indeed, the known indicators of the inhibition of 2-oxoglutarate dehydrogenase, glutamate and aspartate, decreased (p < 0.05) in the TEGP-treated animals only. Statistical analysis of the correlations of cerebral cortex amino acids with behavioral and electrocardiographic parameters revealed the compensatory and marker relationships between the metabolic and behavioral changes. The former corresponds to metabolic perturbations normalizing behavior. The latter manifests metabolic perturbations associated with behavioral ones. Thus, the brain-directed inhibitors of 2–oxoacid dehydrogenases demonstrate a number of behavioral effects in rats, including anxiolytic action of TEGP.