Güzel Elif, Sayın Şakul Ayşe Arzu, Nazıroğlu Mustafa
Department of Medical Pharmacology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Türkiye.
Department of Medical Pharmacology, Institute of Health Sciences, Istanbul Medipol University, Istanbul, Türkiye.
Pharmacol Res Perspect. 2025 Jun;13(3):e70105. doi: 10.1002/prp2.70105.
Parkinson's disease (PD) is the most prevalent neurodegenerative disease. Previously, it was believed that aberrant iron metabolism, leading to ferroptosis due to glutathione (GSH) depletion, excessive Ca influx, mitochondrial (mROS), and cytosolic (cROS) free reactive oxygen species in the brain, was a contributing factor to PD. ADP-ribose (ADPR), mROS, and cROS activate the TRPM2 cation channel. It is yet unclear how TRPM2 contributes to the development of neuronal damage induced by the rise in ferroptosis in PD. Our aim in this study was to examine the function of TRPM2 and the protective effect of GSH in the dopaminergic human SH-SY5Y neuronal cells that had been exposed to 1-methyl 4-phenylpyridinium (MPP) to produce parkinsonism. The SH-SY5Y cells were divided into six groups: control, MPP, MPP + erastin, MPP + erastin + ferrostatin-1, MPP + erastin + glutathione (GSH), and MPP + erastin + TRPM2 blocker (ACA). In the MPP and MPP + erastin groups, the concentrations of Ca, ADPR-induced TRPM2 current density, mitochondrial membrane dysfunction, mROS, cROS, lipid peroxidation, mitochondrial Zn, cytosolic Zn, and cytosolic Fe were increased, although glutathione peroxidase, GSH, cell viability, and cell number were decreased. The changes were higher in the MPP + erastin group than in MPP group only. However, their concentrations were modulated by the changes in the MPP + erastin + ferrostatin-1, MPP + erastin + GSH, and MPP + erastin + ACA groups. In conclusion, the increase in death and ferroptosis in parkinsonism (MPP)-induced SH-SY5Y cells was attributed to TRPM2 activation. By regulating cytosolic oxidant/antioxidant balance, GSH regulates TRPM2 channel activity and lowers neuronal death and ferroptosis.
帕金森病（PD）是最常见的神经退行性疾病。以前，人们认为异常的铁代谢会导致大脑中谷胱甘肽（GSH）耗竭、钙过度内流、线粒体（mROS）和胞质（cROS）游离活性氧引起铁死亡，这是帕金森病的一个促成因素。ADP-核糖（ADPR）、mROS和cROS会激活TRPM2阳离子通道。目前尚不清楚TRPM2如何促进帕金森病中铁死亡增加所诱导的神经元损伤的发展。我们在本研究中的目的是检测TRPM2的功能以及GSH对暴露于1-甲基-4-苯基吡啶鎓（MPP）以产生帕金森综合征的多巴胺能人SH-SY5Y神经元细胞的保护作用。将SH-SY5Y细胞分为六组：对照组、MPP组、MPP + 埃拉司亭组、MPP + 埃拉司亭 + 铁死亡抑制剂-1组、MPP + 埃拉司亭 + 谷胱甘肽（GSH）组和MPP + 埃拉司亭 + TRPM2阻滞剂（ACA）组。在MPP组和MPP + 埃拉司亭组中，钙浓度、ADPR诱导的TRPM2电流密度、线粒体膜功能障碍、mROS、cROS、脂质过氧化、线粒体锌、胞质锌和胞质铁增加，而谷胱甘肽过氧化物酶、GSH、细胞活力和细胞数量减少。MPP + 埃拉司亭组的变化比仅MPP组更高。然而，它们的浓度在MPP + 埃拉司亭 + 铁死亡抑制剂-1组、MPP + 埃拉司亭 + GSH组和MPP + 埃拉司亭 + ACA组中受到调节。总之，帕金森综合征（MPP）诱导的SH-SY5Y细胞死亡和铁死亡增加归因于TRPM2激活。通过调节胞质氧化还原平衡，GSH调节TRPM2通道活性并降低神经元死亡和铁死亡。
