Mildronate protects heart mtDNA from oxidative stress toxicity induced by exhaustive physical exercise

Gureev, Artem P.; Sadovnikova, Irina S.; Shaforostova, Ekaterina A.; Starkov, Anatoly A.; Popov, Vasily N.

doi:10.1016/j.abb.2021.108892

Cited by 6 publications

(5 citation statements)

References 45 publications

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“…However, in this study, we did not find a significant positive effect of Mildronate on NO system parameters in the myocardium of animals undergoing PH. It was found that Mildronate significantly increased iNOS mRNA expression and significantly decreased nitrotyrosine concentration, which is more evidence of its antioxidative properties [49].…”

Section: Discussionmentioning

confidence: 91%

Cardioprotective Activity of Pharmacological Agents Affecting NO Production and Bioavailability in the Early Postnatal Period after Intrauterine Hypoxia in Rats

Popazova,

Belenichev,

Bukhtiyarova

et al. 2023

Biomedicines

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Intrauterine hypoxia in newborns leads to a multifaceted array of alterations that exert a detrimental impact on the cardiovascular system. The aim of this research was to assess the cardioprotective effects of modulators of the nitric oxide (NO) system, including L-arginine, Thiotriazoline, Angiolin, and Mildronate, during the early postnatal period following intrauterine hypoxia. Methods: The study involved 50 female white rats. Pregnant female rats were given a daily intraperitoneal dose of 50 mg/kg of sodium nitrite starting on the 16th day of pregnancy. A control group of pregnant rats received saline instead. The resulting offspring were divided into the following groups: Group 1—intact rats; Group 2—rat pups subjected to prenatal hypoxia (PH) and daily treated with physiological saline; and Groups 3 to 6—rat pups exposed to prenatal hypoxia and treated daily from the 1st to the 30th day after birth. Nitrotyrosine levels, eNOS, iNOS, and NO metabolites were evaluated using ELISA; to measure the expression levels of iNOS mRNA and eNOS mRNA, a PCR test was utilized. Results: Angiolin enhances the expression of eNOS mRNA and boosts eNOS activity in the myocardium of rats with ischemic conditions. Arginine and particularly Thiotriazoline exhibited a consistent impact in restoring normal parameters of the cardiac nitroxidergic system following PH. Mildronate notably raised iNOS mRNA levels and notably reduced nitrotyrosine levels, providing further support for its antioxidative characteristics.

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Section: Discussionmentioning

confidence: 91%

Cardioprotective Activity of Pharmacological Agents Affecting NO Production and Bioavailability in the Early Postnatal Period after Intrauterine Hypoxia in Rats

Popazova,

Belenichev,

Bukhtiyarova

et al. 2023

Biomedicines

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“…Intense and recurrent physical exertion can have negative effects on the cardiac muscle, ranging from left ventricular hypertrophy to increased ventricular dysrhythmias and diastolic ventricular dysfunction, a phenomenon known as "athletic heart syndrome" [ 22 ]. Although there is no consensus in the scientific literature regarding the dose, intensity, and type of physical exercise that can have negative effects on cardiac metabolism, it is unanimously accepted that under these conditions, myocardial adaptation occurs through an increase in the number of mitochondria and intensification of fatty acid β-oxidation for energy purposes.…”

Section: Reviewmentioning

confidence: 99%

Meldonium Supplementation in Professional Athletes: Career Destroyer or Lifesaver?

Pușcaș,

Buț,

Vari

et al. 2024

Cureus

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Meldonium is a substance with known anti-anginal effects demonstrated by numerous studies and human clinical trials; however, it does not possess marketing authorization within the European Union, only in ex-Soviet republics. Since 2016, meldonium has been included by the World Anti-doping Agency (WADA) on the S4 list of metabolic modulators. In performance athletes, meldonium is now considered a doping agent due to its capacity to decrease lactate production during and after exercise, its capability to enhance the storage and utilization of glycogen, and its protective action against oxidative stress. Together, these attributes can significantly improve aerobic endurance, cardiac function, and capacity as well as shorten recovery times (allowing higher intensity training), thereby enhancing performance. The purpose of this review is to highlight the most important mechanisms underlying the protective effect of meldonium against mitochondrial dysfunction (MD), which is responsible for oxidative stress, inflammation, and the cardiac changes known as "athletic heart syndrome." Meldonium acts as an inhibitor of γ-butyrobetaine hydroxylase (BBOX), preventing the de novo synthesis of carnitine and its absorption at the intestinal level via the organic cation/carnitine transporter 2 (OCTN2) and directing the oxidation of fatty acids to the peroxisomes. The decrease in mitochondrial β-oxidation of fatty acids leads to a reduction in lipid peroxidation products that cause oxidative stress and prevent the formation of acyl/acetyl-carnitines involved in numerous pathological disorders. Given the recent findings of the potentially detrimental effects of prolonged high-intensity exercise on cardiovascular health and coronary atherosclerosis, there may be legitimate arguments for the justification of the use of substances like meldonium as protective supplements for athletes.

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“…It is par-ticularly noteworthy the specific effect aimed at improving NO synthesis, such as replacement therapy with L-arginine, which is a substrate for endothelial nitric oxide synthase (eNOS), as well as tetrahydrobiopterin, a cofactor of eNOS, which determines the activity of this enzyme [6,15,22]. Additionally, there is a scientific evidence confirming that the currently used cytoprotective agents of metabolic action Trimetazidine (Table 1) and Mildronate (Meldonium, Table 2) not only block betaoxidation of fatty acids in mitochondria and, on an alternative basis, stimulate glucose oxidation (Tables 1 and 2), but also affect the induction of nitric oxide biosynthesis by increasing gamma-butyrobetaine levels [19][20][21].…”

Section: Pharmacological Approaches To Ed Managementmentioning

confidence: 99%

Nitric oxide-dependent mechanism of endothelial dysfunction formation is a promising target link for pharmacological management

et al. 2022

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Herein, we presented a review to show that the main mechanism underlying endothelial dysfunction is a decrease in the formation and bioavailability of NO against the background of inhibition of eNOS expression and reduced equivalents of the thiol-disulfide system with a simultaneous increase in the levels of cytotoxic forms of NO and the production of powerful vasoconstrictors. Based on the foregoing, the conjugated complex eNOS-L-arginine-NO/SH can be undoubtedly claimed in the near future as a promising target for the pharmacological correction of endothelial dysfunction. Since it is a nitrosative stress that plays the role in the development of endothelial dysfunction, it is topical to search for potential endothelial protectors in the series of S-substituted 1,2,4-triazole, which have the properties of antioxidanitts and NO scavengers. A striking representative of this cohort is Thiotriazolin which is a drug with cardioprotective, anti-ischemic and antioxidant properties, though does not possesses endothelial protective activity. As a result of chemical modification of the molecule of the latter, we obtained the compound (S)-2,6-diaminohexanoic acid 3-methyl-1,2,4-triazolyl-5-thioacetate (Angiolin), which manifests endothelium-protective properties against the background of cardioprotective, anti-ischemic and antioxidant activities.

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Mildronate protects heart mtDNA from oxidative stress toxicity induced by exhaustive physical exercise

Cited by 6 publications

References 45 publications

Cardioprotective Activity of Pharmacological Agents Affecting NO Production and Bioavailability in the Early Postnatal Period after Intrauterine Hypoxia in Rats

Cardioprotective Activity of Pharmacological Agents Affecting NO Production and Bioavailability in the Early Postnatal Period after Intrauterine Hypoxia in Rats

Meldonium Supplementation in Professional Athletes: Career Destroyer or Lifesaver?

Nitric oxide-dependent mechanism of endothelial dysfunction formation is a promising target link for pharmacological management

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