Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses

Abstract

In vitro and in cell cultures, succinyl phosphonate (SP) and adipoyl phosphonate (AP) selectively target dehydrogenases of 2-oxoglutarate (OGDH, encoded by OGDH/OGDHL) and 2-oxoadipate (OADH, encoded by DHTKD1), respectively. To assess the selectivity in animals, the effects of SP, AP, and their membrane-penetrating triethyl esters (TESP and TEAP) on the rat brain metabolism and animal physiology are compared. Opposite effects of the OGDH and OADH inhibitors on activities of OGDH, malate dehydrogenase, glutamine synthetase, and levels of glutamate, lysine, citrulline, and carnosine are shown to result in distinct physiological responses. ECG is changed by AP/TEAP, whereas anxiety is increased by SP/TESP. The potential role of the ester moiety in the uncharged precursors of the 2-oxo acid dehydrogenase inhibitors is estimated. TMAP is shown to be less efficient than TEAP, in agreement with lower lipophilicity of TMAP vs. TEAP. Non-monotonous metabolic and physiological impacts of increasing OADH inhibition are revealed. Compared to the non-treated animals, strong inhibition of OADH decreases levels of tryptophan and beta-aminoisobutyrate and activities of malate dehydrogenase and pyruvate dehydrogenase, increasing the R–R interval of ECG. Thus, both metabolic and physiological actions of the OADH-directed inhibitors AP/TEAP are different from those of the OGDH-directed inhibitors SP/TESP, with the ethyl ester being more efficient than methyl ester.

Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death

“…TPP synthesized in cytoplasm from TH is the coenzyme of not only OGDHC, but also PDH. In contrast, SP selectivity inhibits OGDHC [ 25 ]. Remarkably, actions of SP and TH interact in such a way that OGDHC inhibition may be compensated by increased TH transport to the brain [ 38 ].…”

“…Previously, we have demonstrated that the mitochondrial OGDHC is crucial in glutamate excitotoxicity [ 23 , 24 ]. Our previous studies have also identified succinyl phosphonate (SP) as a highly selective inhibitor of the isoenzymes of the first component of the complex [ 25 , 26 ]. The involvement of OGDHC was dissected in neuronal culture using its coenzyme thiamine (TH) and inhibitor SP.…”