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Decreased activity of the mitochondrial 2-oxoglutarate dehydrogenase complex (OGDHC) in brain accompanies neurodegenerative diseases. To reveal molecular mechanisms of this association, we treated rats with a specific inhibitor of OGDHC, succinyl phosphonate, or exposed them to hypoxic stress. In males treated with succinyl phosphonate and in pregnancy-sensitized females experiencing acute hypobaric hypoxia, we revealed upregulation of brain OGDHC (within 24 hours), with the activity increase presumably representing the compensatory response of brain to the OGDHC inhibition. This up-regulation of brain OGDHC was accompanied by an increase in exploratory activity and a decrease in anxiety of the experimental animals. Remarkably, the hypoxia-induced elevation of brain OGDHC and most of the associated behavioral changes were abrogated by succinyl phosphonate. The antagonistic action of hypoxia and succinyl phosphonate demonstrates potential therapeutic significance of the OGDHC regulation by the phosphonate analogs of 2-oxoglutarate.

We studied the effect of acute hypobaric hypoxia in early organogenesis on physiological and behavioral parameters of second-generation albino rats. Antenatal acute hypoxia was followed by physical and sexual retardation, increase in the mortality rate, and behavioral changes in second-generation animals (hypoactivity of males and females on day 22 of life and hyperactivity of males on day 57 of life). Second-generation animals exhibited no gender differences in body weight and horizontal and vertical locomotor activity.

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