γ-butylbetaine (GBB) hydroxylase catalyses the hydroxylation of γ-butyrobetaine to carnitine. This is the final step in the biosynthesis of L-carnitine from 6-N-trimethyl-L-lysine.
Mildronate is an inhibitor of L-carnitine biosynthetic mediated by γ-butylbetaine (GBB) hydroxylase, and can be a competitive inhibitor of carnitine reabsorption in the kidney[3]. In vitro, Mildronate (40 μM) inhibited the reaction between γ-butyryl betaine hydroxylase and γ-butyryl betaine, and the Km and Vmax values were 36.8 μM and 0.08 nmol/min/mg proteins, respectively[3]. In vivo，Mildronate reduced the levels of free carnitine and long-chain acyl carnitine in myocardium by 63.7% and 74.3%, respectively, in rats after 10 days of oral administration (150 mg/kg). When treated with Mildronate (100 mg/kg, oral), the concentration of free carnitine decreased by 48.7% compared with the rats only treated with isoproterenol. Priority administration of Mildronate can effectively protect the myocardium from damage caused by isoproterenol-induced changes in ATP content and myocardial energy charge, and also prevent the increase of creatine phosphokinase and lactate dehydrogenase activity[3]. In mouse hearts, long-term treatment with Mildronate (200 mg/kg) significantly increased insulin stimulated glucose uptake by 35%, and increased the expression of glucose transporter IV(1.7-fold increase), hexokinase II (2.1-fold increase), insulin receptor protein (2.5-fold increase) and carnitine palmityl transferase IA (2.2-fold increase). Long-term treatment with Mildronate has statistically significantly reduced the blood glucose level in the supply state from 6 mM to 5 mM[4]. Mildronate has a protective effect on type 2 diabetes in rats with Goto-Kakizaki. Treatment with Mildronate (200mg/kg) also lowers the blood sugar level during feeding and fasting. Mildronate strongly inhibited the accumulation of fructosamine and the loss of pain sensitivity (by 75%), and also improved the increased systolic response of the aortic ring to phenylephrine in rats with Goto-Kakizaki. In addition, in the heart treated with Mildronate, the necrotic area of myocardial infarction was significantly reduced by 30%[5].
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