Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction

The inhibition of gamma-butyrobetaine (GBB) hydroxylase, a key enzyme in the biosynthesis of carnitine, contributes to lay ground for the cardioprotective mechanism of action of mildronate. By inhibiting the biosynthesis of carnitine, mildronate is supposed to induce the accumulation of GBB, a substrate of GBB hydroxylase. This study describes the changes in content of carnitine and GBB in rat plasma and heart tissues during long-term (28 days) treatment of mildronate [i.p. (intraperitoneal) 100 mg/kg/daily]. Obtained data show that in concert with a decrease in carnitine concentration, the administration of mildronate caused a significant increase in GBB concentration. We detected about a 5-fold increase in GBB contents in the plasma and brain and a 7-fold increase in the heart. In addition, we tested the cardioprotective effect of mildronate in isolated rat heart infarction model after 3, 7, and 14 days of administration. We found a statistically significant decrease in necrotic area of infarcted rat hearts after 14 days of treatment with mildronate. The cardioprotective effect of mildronate correlated with an increase in GBB contents. In conclusion, our study, for the first time, provides experimental evidence that the long-term administration of mildronate not only decreases free carnitine concentration, but also causes a significant increase in GBB concentration, which correlates with the cardioprotection of mildronate.publishersversionPeer reviewe

Metabolic cardioprotection: new concepts in implementation of cardioprotective effects of meldonium

Recent studies confirm the need to find means to correct ischemic / reperfusion injury due to the hemodynamic medicine, which are already known do not have the proper cardioprotective effects. Key issue is the possibility of drug effects on the mitochondria of cardiomyocytes that controls the aerobic metabolism and maintenance of ATP admission into cardiomyocyte

Use of Meldonium in the Treatment of Patients with Coronary Artery Disease and Concomitant Arterial Hypertension

Coronary artery disease (CAD) remains one of the leading causes of mortality and disability in Ukraine. Arterial hypertension (AH) is one of the most common diseases and a leading risk factor for coronary artery disease.The aim of the work is to evaluate the antianginal activity of meldonium in the complex therapy in patients with CAD with stable angina and concomitant AH.Materials and methods. The study included 82 patients with CAD, stable angina pectoris II–III functional class, including 52 patients with concomitant AH stage II. The patients were divided into 2 groups. Patients in group 1 were prescribed meldonium at a dose of 750 mg/d for 2 months in addition to basic therapy for the underlying disease. Patients in group 2 continued basic antianginal, disaggregant, hypolipidemic therapy.Results. The use of meldonium led to a decrease in the frequency of angina attacks and the need for nitroglycerin. From the 1st month of therapy and up to 2 months treatment decreased it consumption by 63 and 82.3 % respectively. Adding meldonium to basic therapy led to a likely reduction in shortness of breath, episodes of palpitations, tinnitus, and headache. In all patients, after the treatment, an increase in exercise tolerance was observed, which was more pronounced in the group where patients were receiving meldonium. In the group of patients receiving meldonium, normalisation of blood pressure was faster and more pronounced.Conclusions. Meldonium has antianginal activity, which is manifested by an increase in the physical tolerance of patients, a decrease in the frequency of angina attacks, the need for sublingual nitroglycerin intake and improvement in the well-being of patients. Additional use of meldonium promotes faster and better normalization of blood pressure. The use of meldonium in the complex therapy of patients with stable angina and concomitant AH allows to increase the effectiveness of traditional antianginal therapy and to improve the quality of life of such patients

Mildronate and its Neuroregulatory Mechanisms : Targeting the Mitochondria, Neuroinflammation, and Protein Expression

This review for the first time summarizes the data obtained in the neuropharmacological studies of mildronate, a drug previously known as a cardioprotective agent. In different animal models of neurotoxicity and neurodegenerative diseases, we demonstrated its neuroprotecting activity. By the use of immunohistochemical methods and Western blot analysis, as well as some selected behavioral tests, the new mechanisms of mildronate have been demonstrated: a regulatory effect on mitochondrial processes and on the expression of nerve cell proteins, which are involved in cell survival, functioning, and inflammation processes. Particular attention is paid to the capability of mildronate to stimulate learning and memory and to the expression of neuronal proteins involved in synaptic plasticity and adult neurogenesis. These properties can be useful in neurological practice to protect and treat neurological disorders, particularly those associated with neurodegeneration and a decline in cognitive functions.publishersversionPeer reviewe

Pharmacological correction of L-NAME-induced oxide deficiency with derivatives of 3-(2,2,2-trimethylhydrazinium) propionate

This paper deals with the study of correction of L-NAME-induced endothelial dysfunction by means of 3-(2,2,2-trimethylhydrazinium) propionate derivative

Elevated vascular γ-butyrobetaine levels attenuate the development of high glucose-induced endothelial dysfunction

The aim of the present study was to investigate the effects of vascular tissue levels of l-carnitine and its precursor, γ-butyrobetaine (GBB), on the development of endothelial dysfunction induced by 5 μmol/L lysophosphatidylcholine (LPC), 10 mmol/L triglycerides (TG) or a high glucose concentration (44 mmol/L). Changes in vascular tissue levels of l-carnitine and GBB were induced by administration of l-carnitine (100 mg/kg), mildronate (100 mg/kg; an inhibitor of l-carnitine synthesis) or their combination to male Wistar rats for 2 weeks. Treatment with l-carnitine elevated vascular tissue levels of l-carnitine, whereas administration of mildronate reduced l-carnitine levels and increased GBB levels. Experimental animals that received the combination of both drugs showed elevated tissue levels of GBB. The results from organ bath experiments demonstrated that increased GBB levels with preserved l-carnitine content in vascular tissues attenuated the development of endothelial dysfunction induced by high glucose. However, changes in vascular tissue l-carnitine and GBB levels had no impact on endothelial dysfunction induced by TG or LPC. The results demonstrate that increased levels of GBB with preserved l-carnitine content in vascular tissue attenuate the development of endothelial dysfunction induced by high glucose concentrations.publishersversionPeer reviewe

Mildronate's protective effects in the peripheral nervous system : Stavudine-induced neuropathy and formalin-induced inflammation

Funding Information: This work was supported by the Latvian Council of Science Grant Nr. 05-1418; ESF Grant ESS2004/3; Contract No. 453, between the Latvian Institute of Organic Synthesis and the Joint Stock Company “Grindex”; Contract No. 2377, between the University of Latvia and the Joint Stock Company “Grindex”; and a L’ORÉAL Latvian “For Women In Science” fellowship with the support of the Latvian National Commission for UNESCO and the Latvian Academy of Sciences.Mildronate, previously known as a cardioprotective drug, recently was found to normalise mitochondrial processes by preventing the dysfunction of complex I in rat liver mitochondria. Previously we have shown also the ability of mildronate to prevent pathologies in the central nervous system by normalizing the expression of different signalling molecules in brain tissue. This allowed us to suggest that mildronate may possess a beneficial role also in peripheral nervous system pathologies. The present study was designed to assess the peripheral tissue damage caused by anti-HIV drug stavudine, as well as pain and inflammation caused by formalin. For this demonstration, we investigated the influence of mildronate: (1) on decreased myelin expression and increased neuron degeneration in rat sciatic nerve tissue caused by stavudine; and (2) on formalin-induced inflammation in mice. We found that mildronate protected the stavudine-induced degeneration of neurons in rat peripheral sciatic nerve without a significant influence on demyelination. In a formalin test, mildronate showed anti-inflammatory action comparable to that of indomethacin, a reference drug. The present results show that mildronate is capable of regulating peripheral nerve damage and peripheral inflammatory responses. We suggest that the multifunctional effects of mildronate can be attributed to its ability to regulate mitochondrial processes. The obtained data indicate protective effects of mildronate in different peripheral neurological pathologies.publishersversionPeer reviewe

Meldonium: drug which brought disrepute to sport

World of sports have been rocked by doping scandals every now and then and World Anti-Doping Agency(WADA) has banned several offending drugs at different times to counter this menace. Meldonium is the recent addition to the long list of drugs banned by WADA to prevent its misuse among the athletes. Meldonium is a carnitine synthesis inhibitor and has been approved by some European countries for the management of cardiac diseases like angina pectoris and congestive cardiac failure. Apart from these, it has numerous other indications like bronchial asthma, bronchitis and retinopathies. It had also been used by athletes across the world because of its presumptive role in increasing the performance

biobibliogrāfija II

Latvijas Zinātņu akadēmijas akadēmiķe profesore Vija Zaiga Kluša : biobibliogrāfija II / Latvijas Universitātes Akadēmiskā bibliotēka; sast. Dagnija Ivbule; korektore Gita Bērziņa; maketu veidojusi Baiba Lazdiņa. - Rīga: LU Akadēmiskais apgāds, 2015. - 137, [1] lpp. : il. - (Latvijas zinātnieki). ISBN 978-9934-18-040-8.Akadēmiķes V. Z. Klušas biobibliogrāfijas otrā daļa aptver viņas darbības posmu no 2005. līdz 2015. gada