Abstract
Specific inhibitors of mitochondrial 2-oxoglutarate dehydrogenase (OGDH) are administered to animals to model the downregulation of the enzyme as observed in neurodegenerative diseases. Comparison of the effects of succinyl phosphonate (SP, 0.02 mmol/kg) and its uncharged precursor, triethyl succinyl phosphonate (TESP, 0.02 and 0.1 mmol/kg) reveals a biphasic response of the rat brain metabolism and physiology to increasing perturbation of OGDH function. At the low (TE)SP dose, glutamate, NAD+, and the activities of dehydrogenases of 2-oxoglutarate and malate increase, followed by their decreases at the high TESP dose. The complementary changes, i.e., an initial decrease followed by growth, are demonstrated by activities of pyruvate dehydrogenase and glutamine synthetase, and levels of oxidized glutathione and citrulline. While most of these indicators return to control levels at the high TESP dose, OGDH activity decreases and oxidized glutathione increases, compared to their control values. The first phase of metabolic perturbations does not cause significant physiological changes, but in the second phase, the ECG parameters and behavior reveal decreased adaptability and increased anxiety. Thus, lower levels of OGDH inhibition are compensated by the rearranged metabolic network, while the increased levels induce a metabolic switch to a lower redox state of the brain, associated with elevated stress of the animals.
Highlights
Introduction published maps and institutional affilThe pathogenic significance of impaired brain metabolism is acquiring increasing attention
Our study has revealed a biphasic response of the brain metabolism to increasing inhibition of oxoglutarate dehydrogenase complex (OGDHC), which is observed through changes in a number of enzymatic activities and metabolites of the brain
The metabolic changes induced by a low dose (0.02 mmol/kg) of the OGDHC inhibitors (SP or triethyl succinyl phosphonate (TESP)), are abrogated and in some cases reversed with increasing the inhibition (0.1 mmol/kg of TESP) (Figure 5)
Summary
Introduction published maps and institutional affilThe pathogenic significance of impaired brain metabolism is acquiring increasing attention. Metabolic impairments observed in these pathologies usually involve the deficient function of mitochondrial proteins, elevated oxidative and nitrosative stress, decreased oxidative phosphorylation, and altered Ca2+ homeostasis [5,6,7,8,9,10,11]. These changes form a vicious cycle causing neuronal death and a general decline in the physiological fitness of the organism. Neurological disorders caused by different molecular events may have similar manifestations. The therapeutic correction of impaired brain functions is often based on the regulation of neurotransmission by targeting receptor systems, ion channels, or iations
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