Curcumin diminishes cisplatin-induced apoptosis and mitochondrial oxidative stress through inhibition of TRPM2 channel signaling pathway in mouse optic nerve

Abstract

Background: Cisplatin (CiSP), a chemotherapeutic agent, is widely used to treat several types of cancers. However, its clinical use is limited due to adverse side effects caused by excessive production of reactive oxygen species (ROS) and death of neurons. The transient receptor potential (TRP) melastatin 2 (TRPM2) cation channel is activated by ADP-ribose (ADPR) and ROS. The protective effect of curcumin (CURCU) against CiSP-induced apoptosis and mitochondrial ROS through inhibition of TRP channels in several types of neuron except optic nerve, was recently reported. The aim of the current study is to clarify the protective effect of CURCU on CiSP-induced mitochondrial oxidative injury and TRPM2 activation in the mice optic nerve and SH-SY5Y human derived neuronal cells.

Material and methods: The SH-SY5Y cells and mice were divided into four groups: Control, CURCU, CiSP, and CURCU + CiSP. The mice were treated for 14 days and the cells were incubated with CiSP and CURCU for 24 h.

Results: CURCU and PARP-1 inhibitor (PJ34) treatments ameliorated CiSP-induced mitochondrial membrane depolarization, mitochondrial and cytosolic ROS levels and neuronal death in the optic nerve. In the patch-clamp of SH-SY5Y cells and laser confocal microscopy experiments of optic nerve, CURCU and TRPM2 blocker treatments also decreased ADPR-induced TRPM2 currents and cytosolic free calcium ion (Ca²⁺) concentration, suggesting a suppression of Ca²⁺ influx and neuronal death.

Conclusion: CURCU prevents CiSP-induced optic nerve oxidative injury and cell death by suppressing mitochondrial ROS production via regulating TRPM2 signaling pathways. CURCU may serve as a potential therapeutic target against CiSP-induced toxicity in the optic nerve of CiSP-treated patients.

Keywords:

• Cisplatin
• optic nerve
• mitochondria
• oxidative stress
• TRPM2 channel
• cell death

Acknowledgements

The authors thank technician Hulusi Gül (BSN Health, Analyses, Innovation, Consultancy, Organization, Agriculture, Industry and Trade Limited Company, Göller Bölgesi Teknokenti, Isparta, Turkey) for helping with the animal experiments, laser confocal microscopy, and patch-clamp analyses. The authors also thank Dr. Xinhua Shu (Department of Life Sciences, Glasgow Caledonian University, Glasgow, UK) for polishing the English of the manuscript.

Author contributions

D.Ö. and M.N. formulated the present hypothesis. M.N. wrote the report. D.Ö. was responsible for isolation of the optic nerve and M.N. was responsible for cell culture and analyzing the laser confocal microscope and patch-clamp data. D.Ö. made critical revisions to the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The study was supported by BSN Health, Analyses, Innovation, Consultancy, Organization, Agriculture, Industry, and Trade Limited Company, Göller Bölgesi Teknokenti, Isparta, Turkey [Project No: 2019-01].