Glutathione Depletion and Parkinsonian Neurotoxin MPP+-Induced TRPM2 Channel Activation Play Central Roles in Oxidative Cytotoxicity and Inflammation in Microglia

Abstract

Parkinson’s disease (PD) is one of most common neurodegenerative diseases. Environmental stressors such as oxidative stress (OS), calcium ion influx, apoptosis, and inflammation mechanisms are linked to activated microglia in patients with PD. The OS-dependent activated transient receptor potential melastatin 2 (TRPM2) channel is modulated in several neurons by glutathione (GSH). However, the cellular and molecular effects of GSH alteration on TRPM2 activation, OS, apoptosis, and inflammation in the microglia remain elusive. The microglia of TRPM2 wild-type (TRPM2-WT) and knockout (TRPM2-KO) mice were divided into control, PD model (MPP), l-buthionine sulfoximine (BSO), MPP + BSO and MPP + BSO + GSH groups. MPP-induced increases in apoptosis, death, OS, lipid peroxidation, PARP1, caspase-3 and caspase-9, inflammatory cytokines (IL-1β, TNF-α, IL-6), and intracellular free Zn2+ and Ca2+ levels in the microglia of TRPM2-WT mice were further increased by the BSO treatment, although they were diminished by the GSH treatment. Their levels were further reduced by PARP1 inhibitors (PJ34 and DPQ) and TRPM2 blockers (ACA and 2-APB). However, the effects of MPP and BSO were not observed in the microglia of TRPM2-KO mice. Taken together, our data demonstrate that maintaining GSH homeostasis is not only important for quenching OS in the microglia of patients with PD but also equally critical to modulating TRPM2, thus suppressing inflammatory responses elicited by environmental stressors.

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Abbreviations

[Ca2+]i :

Intracellular free calcium ion

2-APB:

2-Aminoethoxydiphenyl borate

ACA:

N-(p-Amylcinnamoyl) anthranilic acid

BSO:

l-Buthionine-sulfoximine

CASP:

Caspase

DRG:

Dorsal root ganglion

GSH:

Glutathione

MDA:

Malondialdehyde

MPP:

1-Methyl-4-phenylpyridinium

OS:

Oxidative stress

PARP1:

Poly[ADP-ribose] polymerase 1

PD:

Parkinson’s disease

TRPM2:

Transient receptor potential melastatin 2

TRPM2-KO:

TRPM2 knockout

TRPM2-WT:

TRPM2 wild type

VGCC:

Voltage-gated calcium channels

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Acknowledgments

The patch-clamp and LSC microscope analyses of the current study were from BSN Health, Analyses, Innovation, Consultancy, Organization, Agriculture and Industry Ltd., (Göller Bölgesi Teknokenti, Isparta, Turkey) by MN. Results of the current study were summarized from a PhD thesis of Kenan Yıldızhan.

Funding

The study was supported by Scientific Project Unit (BAP) of SDU, Isparta, Turkey (Project No: TDK-2019-7321. The coordinator of the project was Prof. Dr. Mustafa Nazıroğlu). There is no financial disclosure of the current study.

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Contributions

MN and KE formulated the hypothesis and MN were responsible for writing the report. KY was responsible for isolating the microglia and analyzing the intracellular Ca2+ concentration. MN was responsible for the LSC microscope analyses. KE was also responsible from plate reader analyses.

Corresponding author

Correspondence to Mustafa Nazıroğlu.

Ethics declarations

This article does not contain any studies with human participants performed by any of the authors. This study was approved by the Local Ethical Committee of Burdur Mehmet Akif University (BMAU), Burdur, Turkey (date: 15.05.2019, permit number: 2019-521). The mice were cared in accordance with the guidelines of the Animal Care Committee of BMAU.

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The authors declare that they have no conflict of interest.

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Yıldızhan, K., Nazıroğlu, M. Glutathione Depletion and Parkinsonian Neurotoxin MPP+-Induced TRPM2 Channel Activation Play Central Roles in Oxidative Cytotoxicity and Inflammation in Microglia. Mol Neurobiol 57, 3508–3525 (2020). https://doi.org/10.1007/s12035-020-01974-7

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Keywords

  • Apoptosis
  • Glutathione depletion
  • Oxidative stress
  • Parkinson’s disease
  • TRPM2 channel