Entacapone

Entacapone is a potent, reversible, peripherally acting and orally active inhibitor of catechol-O-methyltransferase (COMT), which effectively inhibits rat liver total COMT with IC₅₀ and K_i values of 20.1nM and 10.7nM, respectively^[1]. Entacapone has IC₅₀ values of 14.3nM and 73.3nM for rat liver soluble COMT (S-COMT) and rat liver membrane-bound COMT (MB-COMT), respectively^[1]. Entacapone is a weak uncoupler of oxidative phosphorylation^[2]. Entacapone is commonly used in combination with levodopa (L-DOPA) to treat Parkinson's disease^[3]. Entacapone is a ferroptosis inhibitor that can enhance antioxidant capacity^[4].

In vitro, treatment of esophageal cancer cell lines (KYSE-30 and YM-1 cells) with Entacapone (25-150μM) for 48h reduced cell viability in a dose-dependent manner, and induced apoptosis and altered the cell cycle at a concentration of 140μM^[5]. Treatment of Hep-G2 cells with Entacapone (50μM) for 48h increased the amount of m6A on mRNA in cells^[6].

In vivo, oral treatment of C57BL/6J mice with Entacapone (10, 50, 200mg/kg/day) for 21 days significantly improved ANA-12-induced memory impairment and the reduction of hippocampal brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) expression, and significantly increased the number of Ki67-positive proliferating cells, doublecortin-positive immature neurons, and phosphorylated cAMP response element binding protein (pCREB)-positive cells in the dentate gyrus of the hippocampus^[7]. Oral treatment of C57BL/6J mice with Entacapone (50mg/kg) for 21 days induced changes in the expression of proteins involved in synaptic transmission, cellular processes, cell signaling, cytoskeletal structure regulation, energy metabolism, and various other cellular responses in the mouse hippocampus^[8].

References:
[1] Forsberg M, Lehtonen M, Heikkinen M, et al. Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat[J]. Journal of Pharmacology and Experimental Therapeutics, 2003, 304(2): 498-506.
[2] Nissinen E, Kaheinen P, Penttilä K E, et al. Entacapone, a novel catechol-O-methyltransferase inhibitor for Parkinson's disease, does not impair mitochondrial energy production[J]. European journal of pharmacology, 1997, 340(2-3): 287-294.
[3] Stocchi F, Rascol O, Kieburtz K, et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE‐PD study[J]. Annals of neurology, 2010, 68(1): 18-27.
[4] Yang J, Sun X, Huang N, et al. Entacapone alleviates acute kidney injury by inhibiting ferroptosis[J]. The FASEB Journal, 2022, 36(7): e22399.
[5] Ramedani F, Jafari S M, Saghaeian Jazi M, et al. Anti‐cancer effect of entacaponeon esophageal cancer cells via apoptosis induction and cell cycle modulation[J]. Cancer Reports, 2023, 6(3): e1759.
[6] Peng S, Xiao W, Ju D, et al. Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1[J]. Science Translational Medicine, 2019, 11(488): eaau7116.
[7] Yoo D Y, Jung H Y, Kim W, et al. Entacapone promotes hippocampal neurogenesis in mice[J]. Neural Regeneration Research, 2021, 16(6): 1005-1010.
[8] Yoo D Y, Jung H Y, Kim W, et al. Entacapone treatment modulates hippocampal proteins related to synaptic vehicle trafficking[J]. Cells, 2020, 9(12): 2712.