TRPM2 channel protective properties of N-acetylcysteine on cytosolic glutathione depletion dependent oxidative stress and Ca²⁺ influx in rat dorsal root ganglion

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• 作者：C &#214 ; zg&#252 ; l ^{cmlozgl@gmail.com} ; M Nazı ; ro&#287 ; lu ; ^{naziroglum@hotmail.com}
• 关键词：2-APB ; 2-aminoethyl diphenylborinate ; ADPR ; adenosine diphosphatase ribose ; DRG ; dorsal root ganglion ; LP ; lipid peroxidation ; NMDG+ ; N-methyl-D-glucamine ; ROS ; reactive oxygen species ; TRP ; transient receptor potential ; TRPM2 ; melastatin-like transient r
• 刊名：Physiology and Behavior
• 出版年：2012
• 期刊代码：220_00319384
• 类别：med
• 出版时间：15 May, 2012
• 卷：106
• 期：2
• 页码：122-128
• 文件大小：478 K

摘要

N-acetylcysteine (NAC) is a thiol-containing (sulphydryl donor) antioxidant, which contributes to regeneration of glutathione (GSH) and also acts through a direct reaction with free radicals. Thiol depletion has been implicated in the neurobiology of sensory neurons and pain. We reported recently an activator role of intracellular GSH depletion on calcium influx through transient receptor potential melastatin-like 2 (TRPM2) channels in rat dorsal root ganglion (DRG). NAC may have a protective role on calcium influx through regulation of TRPM2 channels in the neurons. Therefore, we tested the effects of NAC on TRPM2 channel currents in cytosolic GSH depleted DRG in rats.

DRG neurons were freshly isolated from rats and the neurons were incubated for 24 h with buthionine sulfoximine (BSO). In whole-cell patch clamp experiments, TRPM2 currents in the DRG incubated with BSO were gated by H₂O₂. TRPM2 channels current densities, cytosolic free Ca²⁺ content, and lipid peroxidation values in the neurons were higher in H₂O₂ and BSO + H₂O₂ group than in controls; however GSH and GSH peroxidase (GSH-Px) values were decreased. BSO + H₂O₂-induced TRPM2 channel gating was totally inhibited by extracellular NAC and partially inhibited by 2-aminoethyl diphenylborinate. GSH-Px activity, lipid peroxidation and GSH levels in the DRG neurons were also modulated by NAC.

In conclusion, we observed a modulator role of NAC on Ca²⁺ influx through a TRPM2 channel in intracellular GSH depleted DRG neurons. NAC incubation before BSO exposure appears to be more protective than NAC incubation after BSO exposure. Since cytosolic thiol group depletion is a common feature of neuropathic pain, our findings are relevant to the etiology and treatment of pain neuropathology in DRG neurons.