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Involvement of TRPM7 Channel on the Induction of Diabetic Neuropathic Pain in Mice: Protective Role of Selenium and Curcumin

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Abstract

Excessive levels of the mitochondrial reactive oxygen radical (mitSOX) and Ca2+ influx were found to cause neuropathic pain in patients with diabetes mellitus (DM). Naltriben (NLT) and mitSOX activate the transient receptor (TRP) melastatin 7 (TRPM7) channel, but antioxidants and carvacrol inhibit it. Selenium (Se) and curcumin (CRC) have been thoroughly studied for their modulator effects on streptozotocin (STZ)-induced neuropathic pain, apoptosis, and oxidative stress through the blockage of TRP channels in dorsal root ganglion (DRG) neurons. It has not yet been fully understood how Se and CRC protect against STZ-induced neuropathic pain by modulating TRPM7. Here, we assessed how Se and CRC affected the Ca2+ influx, mitSOX-mediated oxidative damage, and apoptosis in the DRGs of mice through modifying TRPM7 activity. Seven groups (control, Se, CRC, STZ, STZ + Se, STZ + CRC, and STZ + Se + CRC) were induced from the 56 male mice. We observed that the STZ-induced stimulation of TRPM7 increased mechanical neuropathic pain (von Frey), thermal neuropathic pain (hot plate), cytosolic Ca2+, TRPM7 current density, TRPM7 expression, lipid peroxidation, mitSOX, cytosolic ROS, apoptosis, caspase-3, caspase-8, and caspase-9 concentrations, whereas Se and CRC therapies diminished the alterations. The STZ-mediated decreases of DRG viability, brain glutathione, glutathione peroxidase, vitamin A, and vitamin E concentrations were also upregulated in the treatment groups by the therapies. These findings collectively imply that an imbalance of neuropathic pain, oxidative neurotoxicity, and apoptosis in the mice is caused by the STZ-mediated activation of TRPM7. However, the downregulation of TRPM7 activity caused by the injections of Se and CRC reduced the neurotoxicity and apoptosis.

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Data Availability

The treatments and animal tissue samplings in the current study were induced in BMAU. The current analyses were performed in BSN Health, Analyses, Innovation, Consultancy, Organization, Agriculture, and Industry Ltd. (Göller Bölgesi Teknokenti, Isparta, Turkey), and they are available from the Professor M. Nazıroğlu on reasonable request. All graphics including graphical abstract in the manuscript were prepared by the correspondence author (MN).

Abbreviations

[Ca2+]i :

Cytosolic free calcium ion

AGS:

Human gastric adenocarcinoma cell line

CLSM:

Confocal laser scanning microscope

CNT:

Control

CRC:

Curcumin

CRV:

Carvacrol

cytROS:

Cytosolic free reactive oxygen radicals

DiNP:

Diabetic neuropathy

DM:

Diabetes mellitus

DRG:

Dorsal root ganglion

GSH:

Glutathione

GPx:

Glutathione peroxidase

LPO:

Lipid peroxidation

mitSOX:

Mitochondrial free reactive oxygen radicals

MMD:

Mitochondrial membrane depolarization

NLT:

Naltriben

Se:

Selenium

TRP:

Transient receptor potential

TRPM7:

Transient receptor potential melastatin 7

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Acknowledgements

The authors wish to thank technicians Fatih Şahin and Muhammet Şahin (BSN Health, Isparta, Turkey) for hel** patch-clamp and plate reader analyses.

Funding

The current study was financially supported by BSN Health, Analyses, Innov., Consult., Org., Agricul., Industry Ltd., Isparta, Turkey. (The number of the project is 2021–09. The owner of the project is Dr. Bünyamin Aydın.)

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Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kutahya Health Sciences University, Kutahya Evliya Çelebi Training and Research Hospital, TR-64100, Kutahya, Turkey

    Bünyamin Aydın

  2. Neuroscience Research Center (NOROBAM), Suleyman Demirel University, TR-32260, Isparta, Turkey

    Mustafa Nazıroğlu

  3. Drug Discovery Unit, Analyses, Innov, BSN Health, Org., Agricul., Ltd, Consult, TR-32260, Isparta, Turkey

    Mustafa Nazıroğlu

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Contributions

MN reviewed the current literature. MN and BA designed the project. BA performed animal care and plate reader tests in 7th International Brain Research School, 27 June and 3 July 2022, Isparta, Turkey (http://2022.brs.org.tr/). MN conceptualized this perspective piece, reviewed, and revised the manuscript. Laser confocal microscope analyses were performed in the DRG neurons by MN.

Corresponding author

Correspondence to Mustafa Nazıroğlu.

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The authors declare no competing interests.

Ethics Approval

This article does not contain human participants and human samples. All experimental procedures were reviewed and approved by Experimental Animal Ethics Committee of Burdur Mehmet Akif University (MAKU) Local Animal Care Committee in accordance with the guidelines set by the MAKU (Meeting number: 96. Decision number: 839. Owner: Dr. Bünyamin Aydın). The authors have no ethical conflicts to disclose.

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MN reviewed the current literature. MN and BA designed the project. BA performed animal care and plate reader tests. MN conceptualized this perspective piece, reviewed, and revised the manuscript. All authors approved the final manuscript as submitted.

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Aydın, B., Nazıroğlu, M. Involvement of TRPM7 Channel on the Induction of Diabetic Neuropathic Pain in Mice: Protective Role of Selenium and Curcumin. Biol Trace Elem Res 201, 2377–2395 (2023). https://doi.org/10.1007/s12011-022-03518-7

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