Features of the antihypoxic action of mexidol associated with its specific effect on energy metabolism

Luk’yanova, L. D.; Romanova, V. E.; Chernobaeva, G. N.; Lukinykh, N. V.; Смирнов, Л. Д.

doi:10.1007/bf00766466

Cited by 5 publications

(6 citation statements)

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“…The most effective of these drugs are structural derivatives of vitamin B 6 , which belong to 3-oxypyridine derivatives (mexidol, proxipin). These drugs are used in the early phase of acute disorders related with oxygen shortage (Luk'yanova et al, 1990 ; Kondrashova, 1993 ; Lukyanova and Dudchenko, 1999 ; Lukyanova et al, 2009a , b , c ; Lukyanova, 2005 ; Nowak et al, 2008 ).…”

Section: Pharmacological Methods For Protection Of the Brain Respiratmentioning

confidence: 99%

“…However, the phosphorylation efficiency estimated by the ATP/O ratio was higher after than before long-term adaptation to hypoxia (Luk'yanova et al, 1990 , 1991 ; Lukyanova et al, 2009b ). The increased efficiency of NAD-dependent substrate oxidation together with the reduced electron transport function and the increased amount of mitochondria suggest economization of the energy production process in the brain of adapted rats.…”

Section: Features Of Respiratory Chain Reprogramming In Hypoxic Brainmentioning

confidence: 99%

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Mitochondria-controlled signaling mechanisms of brain protection in hypoxia

2015

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The article is focused on the role of the cell bioenergetic apparatus, mitochondria, involved in development of immediate and delayed molecular mechanisms for adaptation to hypoxic stress in brain cortex. Hypoxia induces reprogramming of respiratory chain function and switching from oxidation of NAD-related substrates (complex I) to succinate oxidation (complex II). Transient, reversible, compensatory activation of respiratory chain complex II is a major mechanism of immediate adaptation to hypoxia necessary for (1) succinate-related energy synthesis in the conditions of oxygen deficiency and formation of urgent resistance in the body; (2) succinate-related stabilization of HIF-1α and initiation of its transcriptional activity related with formation of long-term adaptation; (3) succinate-related activation of the succinate-specific receptor, GPR91. This mechanism participates in at least four critical regulatory functions: (1) sensor function related with changes in kinetic properties of complex I and complex II in response to a gradual decrease in ambient oxygen concentration; this function is designed for selection of the most efficient pathway for energy substrate oxidation in hypoxia; (2) compensatory function focused on formation of immediate adaptive responses to hypoxia and hypoxic resistance of the body; (3) transcriptional function focused on activated synthesis of HIF-1 and the genes providing long-term adaptation to low pO2; (4) receptor function, which reflects participation of mitochondria in the intercellular signaling system via the succinate-dependent receptor, GPR91. In all cases, the desired result is achieved by activation of the succinate-dependent oxidation pathway, which allows considering succinate as a signaling molecule. Patterns of mitochondria-controlled activation of GPR-91- and HIF-1-dependent reaction were considered, and a possibility of their participation in cellular-intercellular-systemic interactions in hypoxia and adaptation was proved.

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Section: Pharmacological Methods For Protection Of the Brain Respiratmentioning

confidence: 99%

Section: Features Of Respiratory Chain Reprogramming In Hypoxic Brainmentioning

confidence: 99%

Mitochondria-controlled signaling mechanisms of brain protection in hypoxia

2015

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“…A succinic acid derivative of 2-ethyl-6-methylpyridin-3-ol is used as a nootropic drug in medical practice (Voronina, 1992, and references therein). It is also known for its antioxidant (Klebanov et al, 2001), antihypoxant (Luk'yanova et al, 1990), cardioprotective (Golikov et al, 2004;Sidorenko et al, 2011) and antistressor (Tilekeyeva & Sitina, 2005;Sariev & Kravtsova, 2005) effects. As no crystal data are available for any succinic acid derivatives of 2-ethyl-6-methylpyridin-3-ol [Cambridge Structural Database (CSD), Version 5.32, November 2010; Allen, 2002], in the present work we intended to obtain such structural information.…”

Section: Commentmentioning

confidence: 99%

Two succinic acid derivatives of 2-ethyl-6-methylpyridin-3-ol

et al. 2011

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Crystals of bis(2-ethyl-3-hydroxy-6-methylpyridinium) succinate-succinic acid (1/1), C(8)H(12)NO(+)·0.5C(4)H(4)O(4)(2-)·0.5C(4)H(6)O(4), (I), and 2-ethyl-3-hydroxy-6-methylpyridinium hydrogen succinate, C(8)H(12)NO(+)·C(4)H(5)O(4)(-), (II), were obtained by reaction of 2-ethyl-6-methylpyridin-3-ol with succinic acid. The succinate anion and succinic acid molecule in (I) are located about centres of inversion. Intermolecular O-H···O, N-H···O and C-H···O hydrogen bonds are responsible for the formation of a three-dimensional network in the crystal structure of (I) and a two-dimensional network in the crystal structure of (II). Both structures are additionally stabilized by π-π interactions between symmetry-related pyridine rings, forming a rod-like cationic arrangement for (I) and cationic dimers for (II).

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“…Verification of this possibility showed that succinate-containing compounds of the hydroxypyridine series (mexidol) increase the tolerance to acute hypobaric hypoxia [3,6]. Further investigations of the mechanisms of action of mexidol showed that its protective effects are due to activation of the succinate oxidase oxidation pathway and utilization of the succinate molecule as the energy substrate [3,6]. In this study we examined the effect of the hydroxypyridine derivative yancarb on survival of rats after acute hypobaric hypoxia and on the specific changes in EEG power spectra in the cerebral cortex.…”

mentioning

confidence: 97%

“…Under such conditions activation of alternative metabolic pathways providing energy for the respiration (for example, the succinate oxidase oxidation pathway), may be effective against hypoxia [1,2,6]. Verification of this possibility showed that succinate-containing compounds of the hydroxypyridine series (mexidol) increase the tolerance to acute hypobaric hypoxia [3,6]. Further investigations of the mechanisms of action of mexidol showed that its protective effects are due to activation of the succinate oxidase oxidation pathway and utilization of the succinate molecule as the energy substrate [3,6].…”

mentioning

confidence: 99%

Antihypoxic effects of derivative on the EEG power spectra in rats with different susceptibility to oxygen deficiency

1997

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The succinate-containing hydroxypyridine derivative yancarb increases both the altitude tolerated by rats and their survival time at a high altitude, particularly in rats with low resistance to hypobaric hypoxia; it also prevents both phasic changes in the EEG characteristic of hypobaric hypoxia and hemispheric asymmetry and paroxysmal activity in the brain of highly resistant rats in the 5000-10,000 m range and in rats with low resistance in the 5000-11,000 m range. Antihypoxic effects of this substance are more pronounced in low-resistance rats and in the left hemisphere of both high-and low-resistant animals; in altitude range of 10,000-13,000 m these effects are weaker or absent. Key Words: cerebral cortex; Fourier EEG power spectra; hypobaric hypoxia; antihypoxants; succinate-containing hydrooxypyridine derivativeHypoxia inhibits the major NAD-dependent pathway of oxidation in the respiratory chain, particularly in the brain [1,2], which may impair the energy-synthesizing function of the cell. Under such conditions activation of alternative metabolic pathways providing energy for the respiration (for example, the succinate oxidase oxidation pathway), may be effective against hypoxia [1,2,6]. Verification of this possibility showed that succinate-containing compounds of the hydroxypyridine series (mexidol) increase the tolerance to acute hypobaric hypoxia [3,6]. Further investigations of the mechanisms of action of mexidol showed that its protective effects are due to activation of the succinate oxidase oxidation pathway and utilization of the succinate molecule as the energy substrate [3,6]. In this study we examined the effect of the hydroxypyridine derivative yancarb on survival of rats after acute hypobaric hypoxia and on the specific changes in EEG power spectra in the cerebral cortex. MATERIALS AND METHODSMale random-bred rats (body weight 180-200 g) were used. They were divided into two groups according to the resistance to hypoxia: high and low (HR and LR, respectively) [5]. Electrodes were inserted and EEG recorded in unrestrained animals as described previously [4].Control rats were placed in a flow altitude chamber, and EEG was recorded for 4 min before "elevation" (baseline EEG) and then at an altitude of 5000, 8000, 9000, 10,000, 11,000, 12,000, and 13,000 m. On each altitude the rats were left for 4 rain (8 rain at 11,000 m). Total period of elevation ranged from 25 to 35 min, depending on the time when agony began. At an altitude of 11,000 m, two 4-min EEGs were recorded. Experimental rats were injected with yancarb (40 mg/kg intraperitoneally) 20 min before elevation, and the EEG was recorded 15 min aRer the injection, after which EEG was recorded as in the control rats [4]. An additional EEG was recorded at 12,000 m in LR rats and at 13,000 m in HR rats because the hypoxia threshold was raised by yancarb.

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Features of the antihypoxic action of mexidol associated with its specific effect on energy metabolism

Cited by 5 publications

References 1 publication

Mitochondria-controlled signaling mechanisms of brain protection in hypoxia

Mitochondria-controlled signaling mechanisms of brain protection in hypoxia

Two succinic acid derivatives of 2-ethyl-6-methylpyridin-3-ol

Antihypoxic effects of derivative on the EEG power spectra in rats with different susceptibility to oxygen deficiency

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