Physiological and Biochemical Markers of the Sex-Specific Sensitivity to Epileptogenic Factors, Delayed Consequences of Seizures and Their Response to Vitamins B1 and B6 in a Rat Model

Aleshin, Vasily A.; Граф, А. В.; Artiukhov, Artem V.; Boyko, Alexandra; Ksenofontov, Alexander L.; Maslova, M. V.; Nogués, Isabel; Salvo, Martino L. di; Bunik, Victoria I.

doi:10.3390/ph14080737

Cited by 15 publications

(36 citation statements)

References 89 publications

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“…Manipulating the brain glutathione redox status by specific OGDH-directed inhibitors, we not only have reproduced the increased anxiety in the animal model but demonstrated the causal link between the OGDHC function and glutathione redox state. Our results on the biochemical and physiological effects of the brain OGDHC inhibition unravel molecular mechanisms underlying the known benefits of therapeutic applications of a physiological OGDHC activator, thiamine, and its pharmacological derivatives, in patients with Alzheimer's disease [72,73], in animal models of neurodegeneration [74][75][76][77], brain and spinal cord injuries [20,21], enhanced stress [78][79][80], and other neurological conditions [81][82][83][84][85][86][87].…”

Section: Discussionmentioning

confidence: 83%

“…The treated groups included animals administered with 0.02 mmol/kg SP (12 animals), with 0.02 mmol/kg TESP (13 animals), and with 0.1 mmol/kg TESP (14 animals). Twenty-four hours after the substance administration, the rats were subjected to physiological tests and killed by decapitation as described before [82,89]. Taking into account that anaesthetics influence mitochondrial and brain function [88,[93][94][95][96][97][98], rats were killed by decapitation with a guillotine (OpenScience, Moscow, Russia) without anaesthetics.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…Estimation of behavioral activity was performed in the "Open Field" test (OpenScience, Moscow, Russia) 24 h after the administration of phosphonates. Animal behavior in the circular arena was recorded for 3 min as described before [82]. The estimated parameters (duration and number of grooming acts, duration of freezing, number of defecation acts, number of rearing acts, number of crossings for each type of lines (outer circle, inner circle, and sector borders)) served as indicators of anxiety level, locomotor, or exploratory activity according to established views [100].…”

Section: Physiological Testsmentioning

confidence: 99%

“…ECG was recorded using non-invasive electrode placement as previously described [82]. The following parameters were assessed through ECG within the registration time of 3 min: the average interval between the heartbeats (R-R interval, ms), the standard deviation of the average R-R interval values (SD, ms), the range of R-R interval values, i.e., the difference between the maximal and minimal values (dX, ms), the root mean square of successive differences in R-R intervals (RMSSD, ms), and stress index (SI, arbitrary units).…”

Section: Physiological Testsmentioning

confidence: 99%

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Increasing Inhibition of the Rat Brain 2-Oxoglutarate Dehydrogenase Decreases Glutathione Redox State, Elevating Anxiety and Perturbing Stress Adaptation

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 83%

Section: Animal Experimentsmentioning

confidence: 99%

Section: Physiological Testsmentioning

confidence: 99%

Section: Physiological Testsmentioning

confidence: 99%

See 2 more Smart Citations

Increasing Inhibition of the Rat Brain 2-Oxoglutarate Dehydrogenase Decreases Glutathione Redox State, Elevating Anxiety and Perturbing Stress Adaptation

et al. 2022

Self Cite

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“…The "Open Field" test ("OpenScience", Moscow, Russia) was used to quantify anxiety level, exploratory, and locomotor activities 24 h after exposure to SP or hypoxia. Exploratory activity and anxiety were assessed cumulatively as described previously (20).…”

Section: Behavioral Parametersmentioning

confidence: 99%

Inhibition of 2-Oxoglutarate Dehydrogenase as a Chemical Model of Acute Hypobaric Hypoxia

2021

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Both hypoxia and inhibition of 2-oxoglutarate dehydrogenase complex (OGDHC) are known to change cellular amino acid pools, but the quantitative comparison of the metabolic and physiological outcomes has not been done. We hypothesize that OGDHC inhibition models metabolic changes caused by hypoxia, as both perturb the respiratory chain function, limiting either the NADH (OGDHC inhibition) or oxygen (hypoxia) supply. In the current study, we quantify the changes in the amino acid metabolism after OGDHC inhibition in the highly sensitive to hypoxia cerebellum and compare them to the earlier characterized changes after acute hypobaric hypoxia. In addition, the associated physiological effects are characterized and compared. A specific OGDHC inhibitor succinyl phosphonate (SP) is shown to act similar to hypoxia, increasing levels of many amino acids in the cerebellum of non-pregnant rats, without affecting those in the pregnant rats. Compared with hypoxia, stronger effects of SP in non-pregnant rats are observed on the levels of cerebellar amino acids, electrocardiography (ECG), and freezing time. In pregnant rats, hypoxia affects ECG and behavior more than SP, although none of the stressors significantly change the levels of cerebellar amino acids. The biochemical differences underlying the different physiological actions of SP and hypoxia are revealed by correlation analysis of the studied parameters. The negative correlations of cerebellar amino acids with OGDHC and/or tryptophan, shown to arise after the action of SP and hypoxia, discriminate the overall metabolic action of the stressors. More negative correlations are induced in the non-pregnant rats by hypoxia, and in the pregnant rats by SP. Thus, our findings indicate that the OGDHC inhibition mimics the action of acute hypobaric hypoxia on the cerebellar amino acid levels, but a better prediction of the physiological outcomes requires assessment of integral network changes, such as increases in the negative correlations among the amino acids, OGDHC, and/or tryptophan.

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Inhibition of pyruvate dehydrogenase affects the brain protein acylation stronger than PDHA phosphorylation at Ser293

Aleshin

Sibiryakina

Kazantsev

et al. 2022

Preprint

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Adaptation of an organism to metabolic challenges requires mechanisms coupling metabolism to gene expression. Acylations of metabolic and histone proteins acquire significant attention in this regard. We hypothesize that adaptive response to inhibition of a key metabolic process, catalyzed by the acetyl-CoA-generating pyruvate dehydrogenase (PDH) complex, may be mediated by changed protein acylations. The hypothesis is tested by intranasal administration to animals of PDH-specific inhibitors acetylmethylphosphinate (AcMeP) or methyl ester of acetylphosphonate (AcPMe), followed by assessment of physiological parameters, brain protein acylation system and expression/phosphorylation of PDHA subunit. At a fixed dose, AcMeP, but not AcPMe, decreases acetylation and increases succinylation of the brain proteins of apparent molecular mass of 15-20 kDa. Regarding the 30-50 kDa proteins, a strong inhibitor AcMeP affects acetylation only, while a less efficient AcPMe mostly increases succinylation. No increase in the succinylation of the 30-50 kDa proteins by AcMeP coincides with its induction of desuccinylase SIRT5, not observed in the AcPMe-treated animals. The brain PDHA expression or phosphorylation, the animal behavior or ECG do not significantly differ between the studied animal groups. The data indicate that a short-term inhibition of the brain PDH affects acetylation and/or succinylation of the brain proteins, dependent on the inhibitor potency, protein molecular mass and acylation type. Homeostatic nature of these changes is implied by stability of physiological parameters after the PDH inhibition.

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Physiological and Biochemical Markers of the Sex-Specific Sensitivity to Epileptogenic Factors, Delayed Consequences of Seizures and Their Response to Vitamins B1 and B6 in a Rat Model

Cited by 15 publications

References 89 publications

Increasing Inhibition of the Rat Brain 2-Oxoglutarate Dehydrogenase Decreases Glutathione Redox State, Elevating Anxiety and Perturbing Stress Adaptation

Increasing Inhibition of the Rat Brain 2-Oxoglutarate Dehydrogenase Decreases Glutathione Redox State, Elevating Anxiety and Perturbing Stress Adaptation

Inhibition of 2-Oxoglutarate Dehydrogenase as a Chemical Model of Acute Hypobaric Hypoxia

Inhibition of pyruvate dehydrogenase affects the brain protein acylation stronger than PDHA phosphorylation at Ser293

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