Beneficial effects of MET-88, a γ-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction

Hayashi, Yukio; Kirimoto, Tsukasa; Asaka, Naomasa; Nakano, Masaya; Tajima, Kiyotaka; Miyake, Hidekazu; Matsuura, Naosuke

doi:10.1016/s0014-2999(00)00098-4

Cited by 31 publications

(34 citation statements)

References 35 publications

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“…33 Other data showed that mildronate improved cardiac sarcoplasmic reticulum Ca 2þ uptake activity in rats with congestive heart failure following myocardial infarction. 11 Therefore, previous and present data demonstrating mildronate's activity to inhibit H 2 O 2 production and MPT pore opening indicate mildronate's ability to halt apoptotic and necrotic processes at their early stages. It must be also noted that mildronate per se did not affect mitochondrial function either in glutamate/malate or succinate respiration.…”

Section: Discussionsupporting

confidence: 57%

“…11,12 It is suggested that mildronate's protective action is based on its ability to inhibit carnitine palmityoiltransferase-1 activity thus decreasing the amount of activated FFAs in mitochondria. 9 Since activated FFAs possess detergentlike activity damaging mitochondrial membranes, we suggest that mitochondria may serve as the target for midronate's cytoprotective action.…”

Section: Discussionmentioning

confidence: 99%

“…This suggestion is based on previous data showing that mildronate is capable of protecting mitochondrial membranes from damage by free fatty acids (FFAs), 9 as well as from AZT-induced morphological changes and activation of nuclear factor kBp65 in mice cardiac tissue. 10 Furthermore, it was also shown that mildronate decreases the concentration of lactic acid and increases ATP level in cardiac tissue after coronary artery occlusion; 11 as well as preventing the drop of ATP content during hypoxia of isolated rat heart . 12 A plausible mechanism to explain mildronate's protective action is related to its ability to regulate carnitine levels by acting as a competitive inhibitor of gammabutyrobetaine (GBB) hydroxylase, 13,14 thus inhibiting GBB transformation to carnitine.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondria as the target for mildronate's protective effects in azidothymidine (AZT)‐induced toxicity of isolated rat liver mitochondria

Pupure

Férnandes

Santos

et al. 2008

Cell Biochemistry & Function

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Previously mildronate, an aza-butyrobetaine derivative, was shown to be a cytoprotective drug, through its mechanism of action of inhibition of carnitine palmitoyltransferase-1, thus protecting mitochondria from long-chain fatty acid accumulation and subsequent damage. Recently in an azidothymidine (AZT)-induced cardiotoxicity model in vivo (in mice), we have found mildronate's ability of protecting heart tissue from nuclear factor kB abnormal expression. Preliminary data also demonstrate cerebro-and hepatoprotecting properties of mildronate in AZT-toxicity models. We suggest that mildronate may target its action predominantly to mitochondria. The present study in isolated rat liver mitochondria was designed to clarify mitochondrial targets for mildronate by using AZT as a model compound. The aim of this study was to investigate: (1) whether mildronate may protect mitochondria from AZT-induced toxicity; and (2) which is the most critical target in mitochondrial processes that is responsible for mildronate's regulatory action. The results showed that mildronate protected mitochondria from AZT-induced damage predominantly at the level of complex I, mainly by reducing hydrogen peroxide generation. Significant protection of AZT-caused inhibition of uncoupled respiration, ADP to oxygen ratio, and transmembrane potential were also observed. Mildronate per se had no effect on the bioenergetics, oxidative stress, or permeability transition of rat liver mitochondria. Since mitochondrial complex I is the first enzyme of the respiratory electron transport chain and its damage is considered to be responsible for different mitochondrial diseases, we may account for mildronate's effectiveness in the prevention of pathologies associated with mitochondrial dysfunctions.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondria as the target for mildronate's protective effects in azidothymidine (AZT)‐induced toxicity of isolated rat liver mitochondria

Pupure

Férnandes

Santos

et al. 2008

Cell Biochemistry & Function

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“…A significant 2-fold increase in the expression of both PDC enzymes, E1/E2, in mildronate-treated mouse hearts compared with non-treated controls was observed. In addition, in several studies, a decrease in lactate concentration in ischemic hearts of mildronate-treated animals has been noted, which indicates that long-term mildronate treatment not only facilitates glucose uptake but also enhances the aerobic oxidation of glucose (Asaka et al, 1998;Hayashi et al, 2000b;Liepinsh et al, 2011b). Besides the direct effects of insulin on glucose homeostasis, stimulation of the insulin receptor leads to the activation of signalling pathways such as the phosphatidylinositol-3-kinase and the mitogen-activated protein kinase cascades, which are involved in cardioprotection from reperfusion injury (Jonassen et al, 2001;Youngren, 2007).…”

Section: Effects On Insulin Signallingmentioning

confidence: 99%

“…In the past 10 years, cardioprotective effects of mildronate have been extensively studied in different models of heart infarction and heart failure (Hayashi et al, 2000b;Liepinsh et al, 2006;Sesti et al, 2006;Vilskersts et al, 2009a). It was shown that long-term treatment with mildronate preserved ATP production by optimisation of energy metabolism.…”

Section: Effects On Myocardial Infarctionmentioning

confidence: 99%

The Regulation of Energy Metabolism Pathways Through L-Carnitine Homeostasis

Liepinsh¹,

Kalvinsh²,

Dambrova³

2011

Role of the Adipocyte in Development of Type 2 Diabetes

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Pharmacokinetics and pharmacodynamics of meldonium in exercised thoroughbred horses

Knych

Stanley

McKemie

et al. 2017

Drug Testing and Analysis

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Although developed as a therapeutic medication, meldonium has found widespread use in human sports and was recently added to the World Anti-Doping Agency's list of prohibited substances. Its reported abuse potential in human sports has led to concern by regulatory authorities about the possible misuse of meldonium in equine athletics. The potential abuse in equine athletes along with the limited data available regarding the pharmacokinetics and pharmacodynamics of meldonium in horses necessitates further study. Eight exercised adult thoroughbred horses received a single oral dose of 3.5, 7.1, 14.3 or 21.4 mg/kg of meldonium. Blood and urine samples were collected and analyzed using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined using non-compartmental analysis. Maximum serum concentrations ranged from 440.2 to 1147 ng/mL and the elimination half-life from 422 to 647.8 h. Serum concentrations were below the limit of quantitation by days 4, 7, 12 and 12 for doses of 3.5, 7.1, 14.3 and 21.4 mg/kg, respectively. Urine concentrations were below the limit of detection by day 44 following administration of 3.5 mg/kg and day 51 for all other dose groups. No adverse effects were observed following meldonium administration. While the group numbers were small, changes in heart rate were observed in the 3.5 mg/kg dose group (n = 1). Glucose concentrations changed significantly in all dose groups studied (n = 2 per dose group). Similar to that reported for humans, the detection time of meldonium in biological samples collected from horses is prolonged, which should allow for satisfactory regulation in performance horses.

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Beneficial effects of MET-88, a γ-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction

Cited by 31 publications

References 35 publications

Mitochondria as the target for mildronate's protective effects in azidothymidine (AZT)‐induced toxicity of isolated rat liver mitochondria

Mitochondria as the target for mildronate's protective effects in azidothymidine (AZT)‐induced toxicity of isolated rat liver mitochondria

The Regulation of Energy Metabolism Pathways Through L-Carnitine Homeostasis

Pharmacokinetics and pharmacodynamics of meldonium in exercised thoroughbred horses

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