Curcumin inhibits activation of TRPM2 channels in rat hepatocytes

Abstract

Oxidative stress is a hallmark of many liver diseases including viral and drug-induced hepatitis, ischemia-reperfusion injury, and non-alcoholic steatohepatitis. One of the consequences of oxidative stress in the liver is deregulation of Ca ²⁺ homeostasis, resulting in a sustained elevation of the free cytosolic Ca ²⁺ concentration ([Ca ²⁺] _c) in hepatocytes, which leads to irreversible cellular damage. Recently it has been shown that liver damage induced by paracetamol and subsequent oxidative stress is, in large part, mediated by Ca ²⁺ entry through Transient Receptor Potential Melastatin 2 (TRPM2) channels. Involvement of TRPM2 channels in hepatocellular damage induced by oxidative stress makes TRPM2 a potential therapeutic target for treatment of a range of oxidative stress-related liver diseases. We report here the identification of curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a natural plant-derived polyphenol in turmeric spice, as a novel inhibitor of TRPM2 channel. Presence of 5 µM curcumin in the incubation medium prevented the H ₂O ₂- and paracetamol-induced [Ca ²⁺] _c rise in rat hepatocytes. Furthermore, in patch clamping experiments incubation of hepatocytes with curcumin inhibited activation of TRPM2 current by intracellular ADPR with IC ₅₀ of approximately 50 nM. These findings enhance understanding of the actions of curcumin and suggest that the known hepatoprotective properties of curcumin are, at least in part, mediated through inhibition of TRPM2 channels.

Graphical abstract

Highlights

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  Curcumin inhibits paracetamol- and H ₂O ₂- induced [Ca ²⁺] _c rise in rat hepatocytes.

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  Curcumin inhibits paracetamol- and H ₂O ₂-induced activation of TRPM2 current.

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  Curcumin inhibits activation of TRPM2 channels by intracellular ADP-ribose.

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  Liver-protective properties of curcumin are partly mediated through TRPM2 inhibition.