What is the mechanism of Meldonium hydrate?

Meldonium hydrate, also known simply as meldonium, is a pharmacological agent first synthesized in the 1970s by Ivars Kalviņš at the Latvian Institute of Organic Synthesis. It is commonly known by its brand name, Mildronate. Meldonium is a structural analog of gamma-butyrobetaine (GBB), a substance that is a precursor to the nutrient carnitine in the human body. Though initially developed for the treatment of ischemic heart disease and other cardiovascular disorders, meldonium has gained attention for its performance-enhancing properties, leading to its inclusion on the World Anti-Doping Agency (WADA) banned list in 2016.

The mechanism of action of meldonium primarily involves its ability to inhibit the enzyme gamma-butyrobetaine dioxygenase (GBB dioxygenase). This enzyme is critical in the biosynthesis of carnitine from GBB. Carnitine is essential for the transport of long-chain fatty acids into the mitochondria, where they undergo beta-oxidation to generate energy. By inhibiting GBB dioxygenase, meldonium reduces carnitine levels in the body, subsequently leading to a decrease in the transport and oxidation of fatty acids.

This reduction in fatty acid oxidation results in several physiological effects. Firstly, there is an increased reliance on glucose oxidation for energy production. Glucose oxidation is more oxygen-efficient compared to fatty acid oxidation, meaning that the myocardium (heart muscle) can produce the same amount of energy with less oxygen. This is particularly beneficial under ischemic conditions, where oxygen supply to the heart is limited.

Additionally, the inhibition of fatty acid oxidation reduces the accumulation of harmful intermediates such as long-chain acylcarnitines and acyl-CoA derivatives. These intermediates can have detrimental effects on cellular functions, including the induction of apoptosis (programmed cell death) and increased oxidative stress. By reducing their accumulation, meldonium helps to protect cells from ischemic damage and improve overall cellular health.

Meldonium also exhibits cardioprotective properties through its effects on nitric oxide (NO) synthesis. Nitric oxide is a crucial signaling molecule that helps to regulate vascular tone, blood flow, and platelet aggregation. Meldonium has been shown to enhance the bioavailability of NO, leading to vasodilation and improved blood flow, further contributing to its therapeutic benefits in cardiovascular diseases.

Moreover, meldonium's modulation of energy metabolism extends beyond the cardiovascular system. It has been noted to improve physical endurance and recovery by optimizing the energy utilization of skeletal muscles. This is achieved through the same mechanisms of shifting energy substrate preference from fatty acids to glucose, thereby enhancing the efficiency of energy production under stress or high-intensity exercise conditions.

In summary, meldonium hydrate exerts its effects by inhibiting gamma-butyrobetaine dioxygenase, leading to decreased carnitine levels and a subsequent reduction in fatty acid oxidation. This shift towards glucose oxidation enhances energy production efficiency, particularly under ischemic conditions, and protects cells from metabolic stress. Additionally, meldonium's positive effects on nitric oxide bioavailability and energy metabolism in skeletal muscles further underscore its broad range of therapeutic applications. Despite its benefits, the drug's potential for misuse in sports has led to stringent regulations on its use.