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Interferon Gamma-Mediated Oxidative Stress Induces Apoptosis, Neuroinflammation, Zinc Ion Influx, and TRPM2 Channel Activation in Neuronal Cell Line: Modulator Role of Curcumin

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Abstract

Host defenses in the brain are modulated by the activation of several factors such as oxygen free radical species (ROS), Ca2+ influx, and TRPM2 activation, and they are well-known adverse factors in neurotoxicity and neurodegenerative diseases. Importantly, recent data indicated a protective action of curcumin (CRC) via inhibition of TRPM2 on the inflammation factors, ROS, and apoptosis in hypoxia-induced SH-SY5Y neuronal cells. However, the relationship between interferon gamma (IFNg) exposure and TRPM2 activation in the SH-SY5Y cells are not fully identified. The SH-SY5Y cells as a neuronal cell line model were used in several neuroinflammation studies. Hence, we used the SH-SY5Y cells in the current study, and they were divided into four main groups as control, CRC, IFNg, and IFNg+CRC. The data presented here indicate that IFNg induced excessive Ca2+ influx via activation of TRPM2. The IFNg treatment further increased cell death, cell debris amount, apoptosis, and cytokine generations (IL-1β, IL-6, and TNF-α) which were due to increased cytosolic and mitochondrial ROS generations as well as increased activations of caspase-3 and caspase-9. The expression levels of TRPM2, PARP-1, Bax, caspase-3, and caspase-9 were increased in the cells by the IFNg treatment. However, CRC treatment reduced the increase of expression levels, cytokine generations, caspase activations, ROS release, Ca2+ influx, cell death, and apoptosis levels via inhibition of TRPM2 in the SH-SY5Y cells that were treated with IFNg. Moreover, the treatment of TRPM2 blockers (ACA and 2-APB) potentiated the modulator effects of CRC. In conclusion, these results suggest that neuroinflammation via IFNg lead to the TRPM2 activation in the SH-SY5Y cells, whereas CRC prevents IFNg-mediated TRPM2 activation, cell death, and cytokine generations.

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Data availability

The details of row data and materials are available on request from correspondence author (Prof. Dr. Mustafa Nazıroğlu). The graphics in the manuscript were prepared by the correspondence author.

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Acknowledgements

The authors wish thanks to Prof. Dr. Peter Butterworth (King’s College, London, UK) for polishing English of the manuscript.

Funding

This study was carried out with financial support from BSN Health, Analyses, Innovation, Consultancy, Organization, Agriculture, Industry Ltd. (Göller Bölgesi Teknokenti, Isparta, Turkey). (Project No: 2019-06).

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Authors and Affiliations

  1. Department of Medical Microbiology, Private Maltepe Medical Center, Istanbul, Turkey

    Mustafa Güzel

  2. Departmant of Neuroscience, Institute of Health Sciences, Suleyman Demirel University, Isparta, Turkey

    Mustafa Nazıroğlu & Ramazan Çınar

  3. Drug Discovery Unit, BSN Health, Analysis and Innovation Ltd. Inc., Isparta, Turkey

    Mustafa Nazıroğlu

  4. Unit of Medical Microbiology, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Suleyman Demirel University, Isparta, Turkey

    Orhan Akpınar

  5. Departmant of Medical Microbiology, Institute of Health Sciences, Suleyman Demirel University, Isparta, Turkey

    Orhan Akpınar

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  1. Mustafa Güzel
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  4. Ramazan Çınar
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Contributions

The cell culture, spectrophotometer (antioxidant), and plate reader (cell viability, apoptosis, and caspase) analyses in the current study were performed in 3rd International Brain Research School, 25 June-1 July 2018, Isparta, Turkey, by Dr. Mustafa Güzel and Assoc. Prof. Dr. Orhan Akpınar. (http://2018.brs.org.tr//). Western blot analyses were performed by Ramazan Çınar (PhD Student of Department of Neuroscience). Laser confocal microscope analyses were performed by the correspondence author.

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Correspondence to Mustafa Nazıroğlu.

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Güzel, M., Nazıroğlu, M., Akpınar, O. et al. Interferon Gamma-Mediated Oxidative Stress Induces Apoptosis, Neuroinflammation, Zinc Ion Influx, and TRPM2 Channel Activation in Neuronal Cell Line: Modulator Role of Curcumin. Inflammation 44, 1878–1894 (2021). https://doi.org/10.1007/s10753-021-01465-4

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