Objectives: The objective of this study was to investigate the effects of a new derivative of GABA, RGPU-207 compound, on the mitochondrial functions of stressed animals.
Methods: RGPU-207 and the comparator drugs (phenibut and piracetam) were administered intraperitoneally to unstressed and stressed male rats at a dose of 9.4, 25 and 400 mg/kg, respectively. The oxygen consumption by cardiac and cerebral mitochondria in state 3 and 4 and Chance's respiratory control ratio (RCR) was investigated. The concentration of lipid peroxidation products (LPO) such as malondialdehyde (MDA), conjugated dienes (CD) and diketones was evaluated in the isolated mitochondria, as well as the activity of the antioxidant system (AOS) enzymes (superoxide dismutase (SOD), glutathione peroxidase (GP) and catalase).
Key findings: A new cyclic GABA derivative, RGPU-207 compound, at the dose of 9.4 mg/kg promotes a decline in MDA, diketone and CD concentrations in mitochondria and increases the levels of SOD, GP and catalase activity. Mitochondrial functional activity increases: oxygen consumption by cerebral mitochondria in state 4 decreases when complex I of the respiratory chain is activated, while malate-dependent state 3 respiration of cardiac mitochondria tends to increase. RCR of cardiac mitochondria increases when complexes I and II are involved. In cerebral mitochondria, malate-dependent and succinate-dependent RCR rise.
Conclusions: Twenty-four-hour immobilization and pain stress activate LPO processes inhibit the activity of the aos enzymes and decrease the functional activity of cardiac and cerebral mitochondria. RGPU-207 restricts LPO, enhances the antioxidant enzyme activity and improves the mitochondrial respiration. The efficacy of RGPU-207 is comparable with phenibut and piracetam.
Keywords: GABA derivatives; mitochondria; oxidative stress.
© 2019 Royal Pharmaceutical Society.