Behavioral Impact of the Regulation of the Brain 2-Oxoglutarate Dehydrogenase Complex by Synthetic Phosphonate Analog of 2-Oxoglutarate: Implications into the Role of the Complex in Neurodegenerative Diseases

Abstract

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.

The effect of chronic tianeptine administration on the brain mitochondria: direct links with an animal model of depression

“…Some data demonstrated that malfunction of the OGDHC associated with mitochondrial dysfunction might be a crucial point in the pathogenesis of depression [33]. Consistent with this finding, the stimulation of the brain OGDHC complex by a synthetic analog of 2-oxoglutarate upregulated the activity of this enzymatic complex and affected behavioral changes, which were expressed as an increase in exploratory activity and diminished anxiety behavior in rats [32]. Based on this observation, it may be postulated that the ability of tianeptine to upregulate the OGDHC in the hippocampus may have a beneficial impact on the brain metabolism and on the behavioral disturbances observed in prenatally stressed animals.…”

“…Importantly, our data demonstrated that chronic tianeptine administration in prenatally stressed offspring increased the expression of a component of the 2-oxoglutarate dehydrogenase complex (OGDHC). The OGDHC comprises multiple copies of three catabolic components, the action of which is required for an important regulatory step in the mitochondrial Krebs cycle (the oxidative decarboxylation of 2-oxoglutarate, which generates energy in the form of NADH and the macroergic compound succinyl-CoA) [32]. Some data demonstrated that malfunction of the OGDHC associated with mitochondrial dysfunction might be a crucial point in the pathogenesis of depression [33].…”

Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models

“…This response may contribute to preconditioning effects. These and other data suggest that the action of the phosphonate analogs of 2‐oxoglutarate on OGDHC may provide the mechanistically defined model of chemically induced hypoxia. Currently, such models employ cyanide to inhibit respiration and iodoacetate to inhibit glycolysis .…”

“…Interestingly, low doses of SP induced preconditioning effects in animals exposed to hypoxia, which was associated with an increase in their brain OGDHC activity. The increase in OGDHC was ascribed to a compensatory response resulting from OGDHC inhibition by SP [36,149,150]. In this regard, a temporary increase in neuronal ATP which was observed under low SP doses in situ, may contribute to the preconditioning in vivo.…”

“…The fact that OGDHC is impaired in the brain of patients with neurodegenerative diseases [147,148] promoted the in situ [114,137,[141][142][143][144][145] and in vivo [36,149,150] application of the phosphonate analogs of 2-oxoglutarate to understand the role of the OGDHC impairment in the neuronal and brain function. These studies revealed a dual effect of OGDHC inhibitors on different physiological parameters in vivo and in situ.…”