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Amantadine Attenuated Hypoxia-Induced Mitochondrial Oxidative Neurotoxicity, Apoptosis, and Inflammation via the Inhibition of TRPM2 and TRPV4 Channels

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Abstract

The hypoxia (HPX) acts the brain injury and apoptosis via the Ca2+ influx-induced excessive mitochondria free reactive oxygen species (mitROS) in neurons. The effective treatment of HPX is not possible yet. In addition to the antiviral and antiparkinsonian actions, amantadine (AMN) has been evaluated as a drug in treatments against brain injury. TRPM2 and TRPV4 channels are activated by mitROS. AMN attenuates NMDA receptor-induced Ca2+ influx, mitROS, inflammation, and apoptosis in the brain. However, the molecular pathways underlying AMN’s neuroprotection against HPX remain elusive. We investigated the protective role of AMN via attenuation of TRPM2 and TRPV4 on oxidative neurotoxicity, mitochondrial membrane potential (ΔΨm), inflammation, and apoptosis in neuronal cells (SH-SY5Y). The SH-SY5Y and HEK293 cells were divided into six groups as follows: control, AMN (750 µM for 48 h), HPX (200 µM CoCl2 for 24 h), HPX + AMN, HPX + TRPM2 blockers (25 µM ACA or 100 µM 2APB for 30 min), and HPX + TRPV4 blocker (ruthenium red (RuR)-1 µM for 30 min). The HPX caused to upregulation of Ca2+ influx with an upregulation of ΔΨm and mitROS. The changes were not observed in the absence of TRPM2 and TRPV4 in the HEK293 cells. When HPX induction, TRPV4 agonist (GSK1016790A) and TRPM2 agonists (ADP-ribose and H2O2)-induced channel activity were diminished by the incubation of AMN and channel antagonists (RuR, ACA, and 2APB). The changes of mitROS, apoptotic markers (caspase-3 and -9), cell death rate, cell viability, cytokine (IL-1β, IL-6, and TNF-α), ΔΨm, and Zn2+ concentrations were also restored by the incubation of AMN. In conclusion, the treatment of AMN attenuated HPX-mediated mitROS, apoptosis, and TRPM2/TRPV4-mediated overload Ca2+ influx and may provide an avenue for protecting the HPX-mediated neurodegenerative and cerebrovascular diseases associated with the upregulation of mitROS, Ca2+, and Zn2+ concentration.

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Data Availability

The present analyses were performed in BSN Health, Analyses, Innov., Consult., Org., Agricul., and Indust. Ltd, (Göller Bölgesi Teknokenti, Isparta, Turkey), and they are available from the Prof. Dr. M. Nazıroğlu on reasonable request.

Abbreviations

2APB:

2-Aminoethyl diphenyl borinate

ACA:

N-(p-amylcinnamoyl) anthranilic acid

AMN:

Amantadine

CASP-3:

Caspase-3

CASP-9:

Caspase-9

CNT:

Control

cytCa2 + :

Cytosolic free calcium ion

cytROS:

Cytosolic reactive oxygen species

cytZn2 + :

Cytosolic free zinc ion

GSK:

GSK1016790A

HPX:

Hypoxia

LSCM:

Laser scanning confocal microscope

LSM/800:

Laser scan confocal microscope

mitPOT:

Mitochondrial membrane potential

mitROS:

Mitochondrial reactive oxygen species

NMDA:

N-Methyl-D-aspartate

RuR:

Ruthenium red

TRP:

Transient receptor potential

TRPM2:

Transient receptor potential melastatin 2

TRPV4:

Transient receptor potential vanilloid 4

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Acknowledgements

The cell culture, apoptosis, caspases, cytokine, and cell viability analyses in the current study in 4th International Brain Research School, 24 and 30 June 2019, Isparta, Turkey, by Dr. Özgür Öcal and Dr. Aymer Coşar (http://2019.brs.org.tr/). The authors wish to thank technician Fatih Şahin (BSN Health LTD., Isparta, Turkey) for helping the patch-clamp analyses.

Funding

The study was supported by BSN Health, Analysis and Innovation Ltd. Inc. Göller Bölgesi Teknokenti, Isparta, Turkey (Project No: 2019–06).

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Authors and Affiliations

  1. Department of Neurosurgery, Ankara City State Hospital, Ankara, Turkey

    Özgür Öcal

  2. Department of Neurosurgery, Polatlı Duatepe State Hospital, Ankara, Turkey

    Aymer Coşar

  3. Neuroscience Research Center, Suleyman Demirel University, Isparta, Turkey

    Mustafa Nazıroğlu

  4. Drug Discovery and Development Research Group in Neuroscience, BSN Health, Analysis and Innovation, Goller Bolgesi Teknokenti, Isparta, Turkey

    Mustafa Nazıroğlu

  5. Departments of Biophysics and Neuroscience, Faculty of Medicine, Suleyman Demirel University, Isparta, TR-32260, Turkey

    Mustafa Nazıroğlu

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  1. Özgür Öcal
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Contributions

Dr. Özgür Öcal: conceptualization, validation, formal analysis, investigation, visualization, project administration, funding acquisition, writing — review and editing. Dr. Aymer Coşar: conceptualization, validation, formal analysis, investigation, visualization. Prof. Dr. Mustafa Nazıroğlu: conceptualization, methodology, validation, formal analysis, investigation, resources, data curation, graphic preparations, writing — review and editing.

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Correspondence to Mustafa Nazıroğlu.

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Öcal, Ö., Coşar, A. & Nazıroğlu, M. Amantadine Attenuated Hypoxia-Induced Mitochondrial Oxidative Neurotoxicity, Apoptosis, and Inflammation via the Inhibition of TRPM2 and TRPV4 Channels. Mol Neurobiol 59, 3703–3720 (2022). https://doi.org/10.1007/s12035-022-02814-6

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