Meldonium is a metabolic drug used for treatment of coronary heart disease. The effect of the drug lies in its ability to inhibit synthesis and transport of L-carnitine. At the same time, a long-term deficiency of L-carnitine can theoretically negatively affect the activity of the transcription factor Nrf2, which is extremely important for maintaining mitochondrial balance in cells. We have shown that meldonium therapy for 3 months at a dose of 100 mg/kg in mice causes a decrease in the expression of the Nrf2 gene in the brain. A decrease in the Nrf2 level causes suppression of mitochondrial biogenesis, which is manifested in a decrease in the level of mtDNA and the level of Cox1 expression. However, no negative effect of meldonium on the bioenergetics parameters of mitochondria was found, as evidenced by the maintenance of a stable mitochondrial potential and the level of production of reactive oxygen species. Jne mohth after the end of the meldonium therapy, expression of the genes responsible for mitochondrial biogenesis and mitophagy (p62, Pink1, Tfam) was observed and the expression level of genes responsible for mitochondrial fusion returned to control values. These changes may be associated with the normalization of the level of L-carnitine in brain cells.
Mel'doniĭ — éto metabolicheskiĭ preparat, ispol'zuiushchiĭsia dlia lecheniia ishemicheskikh bolezneĭ serdtsa. Ego éffekt zakliuchaetsia v sposobnosti ingibirovat' sintez i transport L-karnitina. Pri étom dlitel'nyĭ defitsit L-karnitina teoreticheski mozhet negativno skazyvat'sia na aktivnosti transkriptsionnogo faktora Nrf2, kotoryĭ kraĭne vazhen dlia podderzhaniia mitokhondrial'nogo balansa v kletkakh. My pokazali, chto vvedenie mel'doniia mysham v techenie 3 mesiatsev v doze 100 mg/kg (peroral'no s vodoĭ) vyzyvaet snizhenie ékspressii gena Nrf2 v mozge. Éto privodit k podavleniiu mitokhondrial'nogo biogeneza, chto proiavliaetsia v snizhenii urovnia mtDNK i urovnia ékspressii Cox1. Pri étom ne otmecheno negativnogo éffekta mel'doniia na bioénergeticheskie parametry mitokhondriĭ, chto proiavliaetsia v podderzhanii stabil'nogo mitokhondrial'nogo potentsiala i urovnia produktsii aktivnykh form kisloroda. Veroiatno, v kachestve kompensatornogo éffekta aktiviruetsia protsess sliianiia mitokhondriĭ, chto pozvoliaet mitokhondriiam podderzhivat' osnovnye bioénergeticheskie kharakteristiki. Cherez mesiats posle prekrashcheniia priema mel'doniia nabliudaetsia, naprotiv, uvelichenie ékspressii genov, otvetstvennykh za mitokhondrial'nyĭ biogenez i mitofagiiu, i vozvrashchenie urovnia ékspressii genov, otvetstvennykh za sliianie mitokhondriĭ, k kontrol'nym znacheniiam. Veroiatno, éto sviazano s normalizatsieĭ urovnia L-karnitina v kletkakh mozga. Takim obrazom, polozhitel'nyĭ éffekt mel'doniia na tsentral'nuiu nervnuiu sistemu vyzyvaetsia sposobnost'iu aktivirovat' sliianie mitokhondriĭ v mozge, chto iavliaetsia kompensatornym éffektom na podavlenie mitokhondrial'nogo biogeneza, vyzvannogo defetsitom L-karnitina i dezaktivatsii Nrf2.
Keywords: L-carnitine; Nrf2; meldonium; mitochondrial biogenesis; mitochondrial fusion/fission; mitophagy.