Ethanol Induces Microglial Cell Death via the NOX/ROS/PARP/TRPM2 Signalling Pathway

Antioxidants

Syahida Ahmad¹  Sharani Rathakrishnan¹  IffaNadhira Hazanol¹  MohdEzuan Khayat¹  MuhammadSyahreel Azhad Sha’fie¹  MohdHaziq Izzazuddin Dali¹  SharifahAlawieyah Syed Mortadza¹  NoorjahanBanu Alitheen²  Yazmin Hussin²  Lin-Hua Jiang³ 

[1] Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province and Department of Physiology and Pathophysiology, Xinxiang Medical University, Xinxiang 453003, China;

关键词: alcoholism;    microglia;    cell death;    ROS;    oxidative stress;    PARP;   

DOI  :  10.3390/antiox9121253

来源: DOAJ

【 摘 要 】

Microglial cells are the primary immune cell resident in the brain. Growing evidence indicates that microglial cells play a prominent role in alcohol-induced brain pathologies. However, alcohol-induced effects on microglial cells and the underlying mechanisms are not fully understood, and evidence exists to support generation of oxidative stress due to NADPH oxidases (NOX_-mediated production of reactive oxygen species (ROS). Here, we investigated the role of the oxidative stress-sensitive Ca²⁺-permeable transient receptor potential melastatin-related 2 (TRPM2) channel in ethanol (EtOH)-induced microglial cell death using BV2 microglial cells. Like H₂O₂, exposure to EtOH induced concentration-dependent cell death, assessed using a propidium iodide assay. H₂O₂/EtOH-induced cell death was inhibited by treatment with TRPM2 channel inhibitors and also treatment with poly(ADP-ribose) polymerase (PARP) inhibitors, demonstrating the critical role of PARP and the TRPM2 channel in EtOH-induced cell death. Exposure to EtOH, as expected, led to an increase in ROS production, shown using imaging of 2’,7’-dichlorofluorescein fluorescence. Consistently, EtOH-induced microglial cell death was suppressed by inhibition of NADPH oxidase (NOX) as well as inhibition of protein kinase C. Taken together, our results suggest that exposure to high doses of ethanol can induce microglial cell death via the NOX/ROS/PARP/TRPM2 signaling pathway, providing novel and potentially important insights into alcohol-induced brain pathologies.

【 授权许可】

Unknown