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Glutathione Decreases Parkinsonism‐Induced Ferroptosis and Oxidative Stress Through the Inhibition of the TRPM2 Channel in Neuronal Cells

Year: 2025

Type: article

Abstract: ABSTRACT 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 2+ 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 2+ , ADPR‐induced TRPM2 current density, mitochondrial membrane dysfunction, mROS, cROS, lipid peroxidation, mitochondrial Zn 2+ , cytosolic Zn 2+ , and cytosolic Fe 2+ 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.

Source: Pharmacology Research & Perspectives

DOI: 10.1002/prp2.70105

Authors: Elif Güzel, Ayşe Arzu Sayın Şakul, Mustafa Nazıroğlu

Institutions: Istanbul Medipol University, Süleyman Demirel Üniversitesi

Language: English

Topic: Parkinson's Disease Mechanisms and Treatments

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,160