Effect of a new cyclic derivative of GABA, RGPU-207, on the functions of cardiac and cerebral mitochondria of stressed animals

Abstract

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.

Long‐term stiripentol administration, an anticonvulsant drug, does not impair sperm parameters in rats

“…GABA pretreatment also reduced ethanol‐induced gastric tissue and cells injury restraining oxidative stress by decreasing malondialdehyde level and increasing the activities of superoxide dismutase and catalase (Xie et al., 2017). In the study of mitochondria from stressed male rats treated with RGPU‐207, a cyclic derivative of GABA, the concentration of LPOs (malondialdehyde, conjugated dienes and diketones) in cardiac and brain mitochondria was lower than in the negative control (Mokrousov et al., 2019); however, in this last study the effects seemed to be rather centrally mediated. The results obtained in our study with stiripentol also suggest that the drug may have some inhibitory effect on LPO production in spermatozoa, which requires further studies focused predominantly on this aspect.…”

“…It has been reported that oxcarbazepine can also exert beneficial influence on the sperm parameters (Wu et al., 2018), whereas many other AEDs seem to be spermatotoxic (Asadi‐Pooya et al., 2015; Baysal et al., 2017; Hamed et al., 2015; Karaduman et al., 2019). It is well known that mitochondrial dysfunction leads to many changes within mitochondria and within mitochondrial membrane resulting first in so‐called mitoptosis and later to apoptosis (Mokrousov et al., 2019). However, in our study, the activity of mitochondria was the same in the control and the stiripentol‐treated group.…”