Mildronate (hydrate)

Mildronate is a structural analog of γ-butyrobetaine (γBB), an intermediate in the biosynthesis of carnitine. It blocks carnitine synthesis by inhibiting γBB hydroxylase (IC₅₀ = 62 µM) and, less potently, carnitine acetyltransferase (K_i = 1.6 mM).^1,2,3 Through these actions, mildronate reduces the levels of free carnitine and long chain acyl carnitine.^4,5 This leads to suppressed fatty acid metabolism and mitochondrial uncoupling during oxidative conditions, resulting in cardioprotective and neuroprotective effects.^4,5,6 Mildronate also improves cognition and reduces amyloid-β pathology in a mouse model of Alzheimer’s disease.⁷

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1. Tars, K., Leitans, J., Kazaks, A., et al. Targeting carnitine biosynthesis: Discovery of new inhibitors against γ-butyrβne hydroxylase. J. Med. Chem. 57(6), 2213-2236 (2014).

2. Leung, I.K., Krojer, T.J., Kochan, G.T., et al. Structural and mechanistic studies on γ-butyrβne hydroxylase. Chem. Biol. 17(12), 1316-1324 (2010).

3. Jaudzems, K., Kuka, J., Gutsaits, A., et al. Inhibition of carnitine acetyltransferase by mildronate, a regulator of energy metabolism. J. Enzyme Inhib. Med. Chem. 24(6), 1269-1275 (2009).

4. Simkhovich, B.Z., Shutenko, Z.V., Meirena, D.V., et al. 3-(2,2,2-Trimethylhydrazinium)propionate (THP)—a novel γ-butyrβne hydroxylase inhibitor with cardioprotective properties. Biochem. Pharmacol. 37(2), 195-202 (1988).

5. Makrecka, M., Svalbe, B., Volska, K., et al. Mildronate, the inhibitor of L-carnitine transport, induces brain mitochondrial uncoupling and protects against anoxia-reoxygenation. Eur. J. Pharmacol. 723, 55-61 (2014).

6. Klusa, V., Beitnere, U., Pupure, J., et al. Mildronate and its neuroregulatory mechanisms: Targeting the mitochondria, neuroinflammation, and protein expression. Medicina (Kaunas) 49(7), 301-309 (2013).

7. Beitnere, U., van Groen, T., Kumar, A., et al. Mildronate improves cognition and reduces amyloid-β pathology in transgenic Alzheimer’s disease mice. J. Neurosci. Res. 92(3), 338-346 (2014).

Singh, S.R., Zeng, X., Zhao, J., et al. The lipolysis pathway sustains normal and transformed stem cells in adult Drosophila. Nature 538(7623), 109-113 (2016).