Mildronate: Overview and Pharmacological Activity

General Description

Mildronate, a cardioprotective medication, effectively modulates l-carnitine levels, crucial for cellular energy metabolism and cardiovascular health. By inhibiting carnitine palmitoyltransferase-1, it reduces fatty acid oxidation within mitochondria, thereby enhancing energy metabolism and reducing toxic metabolite accumulation. This mechanism underpins its efficacy in treating cardiovascular diseases, showing significant benefits in reducing myocardial infarction sizes, managing heart failure, and attenuating atherosclerosis development. Furthermore, Mildronate has proven effective in managing metabolic syndrome and diabetes by lowering blood glucose levels, improving glucose uptake, and offering potential synergistic benefits when combined with metformin. Its unique action in reducing acylcarnitine availability presents a novel approach to improving insulin sensitivity and addressing diabetes-induced insulin resistance.

Figure 1. Mildronate

Overview

Mildronate is a clinically utilized cardioprotective medication that plays a crucial role in modulating body tissue levels of l-carnitine, a compound essential for cellular energy metabolism. Discovered over a century ago by Latvian biochemist Krimbergs, l-carnitine is derived from dietary sources and can also be synthesized from the amino acids lysine and methionine. Its concentration within the body is meticulously regulated through specific transporters. Mildronate's mechanism involves the inhibition of carnitine palmitoyltransferase-1, a key enzyme facilitating the transfer of fatty acids into mitochondria for β-oxidation, a process vital for energy production in muscle cells. By lowering l-carnitine content, Mildronate indirectly affects the transportation and oxidation of fatty acids within the mitochondria, thereby playing a significant role in maintaining cardiovascular health by ensuring efficient energy metabolism and reducing the accumulation of toxic fatty acid metabolites. ¹

Pharmacological activity

Cardiovascular diseases

Mildronate is a cardioprotective medication renowned for its efficacy in treating cardiovascular diseases. Its pharmacological activity is primarily attributed to its ability to lower l-carnitine levels, thereby regulating energy metabolism and enhancing adaptive responses akin to preconditioning. Extensive research has demonstrated Mildronate's effectiveness in various cardiovascular pathologies through multiple molecular mechanisms. It optimizes energy metabolism during hypoxia, preserving ATP production, and has shown significant reductions in infarct size in both in vitro and in vivo models. Notably, Mildronate also displays glucose-reducing effects and reduces myocardial infarction sizes in diabetic and non-diabetic rats, linking its anti-infarction properties to decreased l-carnitine pools in cardiac tissues, which in turn lowers fatty acid transport and protects mitochondrial membranes. Interestingly, Mildronate does not significantly affect haemodynamic parameters before or during ischemia reperfusion, highlighting its role as a metabolic regulator rather than a direct influencer of cardiac workload. This characteristic allows for its potential combination with agents targeting haemodynamic parameters for enhanced therapeutic efficacy. Studies have also shown its additive cardioprotective effects with orotic acid, suggesting a potent therapeutic combination for ischemia-reperfusion injury recovery and decreased arrhythmia duration and incidence. Moreover, Mildronate has been effective in experimental heart failure models, attenuating left ventricular hypertrophy and improving myocardial energy states, which contributes to prolonged survival and enhanced cardiac function adaptability. Clinical studies further support its use in chronic heart failure therapy, showing benefits in functional class improvement, exercise tolerance, and quality of life normalization when combined with standard therapies. Additionally, Mildronate's role extends to atherosclerosis management, where it significantly attenuates lesion development, potentially through lowering TMAO levels and exhibiting vasoprotective effects, including endothelial dysfunction prevention in hypertension and diabetes models. These multifaceted pharmacological activities underscore Mildronate's significant potential in cardiovascular disease treatment, emphasizing its metabolic regulation and cardioprotective mechanisms. ²

Metabolic syndrome and diabetes

Mildronate has emerged as a noteworthy pharmacological agent in managing metabolic syndrome and diabetes. Initially, it was observed that while acute and cardioprotective doses did not alter blood glucose levels in non-diabetic rodents, significant reductions were seen in diabetic models. Notably, an 800-mg/kg dose over 10 days significantly lowered blood glucose in fasted Wistar rats, showcasing its potential for hyperglycemia management. Further studies highlighted Mildronate's ability to enhance glucose uptake and modify glucose metabolism gene expression, leading to lowered blood glucose levels, particularly evident in type 2 diabetic Goto-Kakizaki rats without affecting insulin levels. Its efficacy extends to type 1 diabetes models, where it improved glucose tolerance and prevented neuropathy. Compared with metformin, Mildronate showed similar glucose-reducing effects and, when combined, offered synergistic benefits in liver insulin sensitivity and weight management, also reducing the risk of metformin-induced lactate acidosis. The drug's unique mechanism involves reducing acylcarnitine availability, presenting a novel approach to improving insulin sensitivity and managing diabetes-related insulin resistance. ²

Reference

1. Dambrova M, Liepinsh E, Kalvinsh I. Mildronate: cardioprotective action through carnitine-lowering effect. Trends Cardiovasc Med. 2002;12(6):275-279.

2. Dambrova M, Makrecka-Kuka M, Vilskersts R, Makarova E, Kuka J, Liepinsh E. Pharmacological effects of meldonium: Biochemical mechanisms and biomarkers of cardiometabolic activity. Pharmacol Res. 2016;113(Pt B):771-780.