Acute Prenatal Hypoxia in Rats Affects Physiology and Brain Metabolism in the Offspring, Dependent on Sex and Gestational Age

Граф, А. В.; Maslova, M. V.; Artiukhov, Artem V.; Ksenofontov, Alexander L.; Aleshin, Vasily A.; Bunik, Victoria I.

doi:10.3390/ijms23052579

Cited by 12 publications

(9 citation statements)

References 80 publications

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“…Regulation of proteins by post-translational modifications (PTM) participates in adaptive reprogramming of metabolic fluxes. While epigenetic mechanisms involving acetylation of histones are long-known, lately also other types of acylation, and acylation of metabolic proteins have drawn increasing attention regarding metabolic regulation [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

The Brain Protein Acylation System Responds to Seizures in the Rat Model of PTZ-Induced Epilepsy

Zavileyskiy

Aleshin²,

Kaehne³

et al. 2022

IJMS

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Abnormal energy expenditure during seizures and metabolic regulation through post-translational protein acylation suggest acylation as a therapeutic target in epilepsy. Our goal is to characterize an interplay between the brain acylation system components and their changes after seizures. In a rat model of pentylenetetrazole (PTZ)-induced epilepsy, we quantify 43 acylations in 29 cerebral cortex proteins; levels of NAD+; expression of NAD+-dependent deacylases (SIRT2, SIRT3, SIRT5); activities of the acyl-CoA-producing/NAD+-utilizing complexes of 2-oxoacid dehydrogenases. Compared to the control group, acylations of 14 sites in 11 proteins are found to differ significantly after seizures, with six of the proteins involved in glycolysis and energy metabolism. Comparing the single and chronic seizures does not reveal significant differences in the acylations, pyruvate dehydrogenase activity, SIRT2 expression or NAD+. On the contrary, expression of SIRT3, SIRT5 and activity of 2-oxoglutarate dehydrogenase (OGDH) decrease in chronic seizures vs. a single seizure. Negative correlations between the protein succinylation/glutarylation and SIRT5 expression, and positive correlations between the protein acetylation and SIRT2 expression are shown. Our findings unravel involvement of SIRT5 and OGDH in metabolic adaptation to seizures through protein acylation, consistent with the known neuroprotective role of SIRT5 and contribution of OGDH to the Glu/GABA balance perturbed in epilepsy.

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Section: Introductionmentioning

confidence: 99%

The Brain Protein Acylation System Responds to Seizures in the Rat Model of PTZ-Induced Epilepsy

Zavileyskiy

Aleshin²,

Kaehne³

et al. 2022

IJMS

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“…Estimation of behavioral activity was performed using the “Open Field” test as described previously [ 43 , 45 ]. ECG was recorded for 3 min using a non-invasive electrode placement [ 43 ].…”

Section: Methodsmentioning

confidence: 99%

Phosphonate Inhibitors of Pyruvate Dehydrogenase Perturb Homeostasis of Amino Acids and Protein Succinylation in the Brain

Artiukhov

Aleshin

Karlina

et al. 2022

IJMS

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Mitochondrial pyruvate dehydrogenase complex (PDHC) is essential for brain glucose and neurotransmitter metabolism, which is dysregulated in many pathologies. Using specific inhibitors of PDHC in vivo, we determine biochemical and physiological responses to PDHC dysfunction. Dose dependence of the responses to membrane-permeable dimethyl acetylphosphonate (AcPMe2) is non-monotonous. Primary decreases in glutathione and its redox potential, methionine, and ethanolamine are alleviated with increasing PDHC inhibition, the alleviation accompanied by physiological changes. A comparison of 39 brain biochemical parameters after administration of four phosphinate and phosphonate analogs of pyruvate at a fixed dose of 0.1 mmol/kg reveals no primary, but secondary changes, such as activation of 2-oxoglutarate dehydrogenase complex (OGDHC) and decreased levels of glutamate, isoleucine and leucine. The accompanying decreases in freezing time are most pronounced after administration of methyl acetylphosphinate and dimethyl acetylphosphonate. The PDHC inhibitors do not significantly change the levels of PDHA1 expression and phosphorylation, sirtuin 3 and total protein acetylation, but increase total protein succinylation and glutarylation, affecting sirtuin 5 expression. Thus, decreased production of the tricarboxylic acid cycle substrate acetyl-CoA by inhibited PDHC is compensated by increased degradation of amino acids through the activated OGDHC, increasing total protein succinylation/glutarylation. Simultaneously, parasympathetic activity and anxiety indicators decrease.

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“…The “open field” test ( Sestakova et al, 2013 ; Díaz-Morán et al, 2014 ) was performed in an arena of 97 cm diameter (“OpenScience,” Moscow, Russia). The test was used to quantify animal behavior as described before ( Aleshin et al, 2021 ; Graf et al, 2022 ). Anxiety level was characterized, based on the duration and number of grooming acts, duration of freezing, and number of defecation acts.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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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.

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Acute Prenatal Hypoxia in Rats Affects Physiology and Brain Metabolism in the Offspring, Dependent on Sex and Gestational Age

Cited by 12 publications

References 80 publications

The Brain Protein Acylation System Responds to Seizures in the Rat Model of PTZ-Induced Epilepsy

The Brain Protein Acylation System Responds to Seizures in the Rat Model of PTZ-Induced Epilepsy

Phosphonate Inhibitors of Pyruvate Dehydrogenase Perturb Homeostasis of Amino Acids and Protein Succinylation in the Brain

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

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