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Modulation of Diabetes-Induced Oxidative Stress, Apoptosis, and Ca2+ Entry Through TRPM2 and TRPV1 Channels in Dorsal Root Ganglion and Hippocampus of Diabetic Rats by Melatonin and Selenium

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Abstract

Neuropathic pain and hippocampal injury can arise from the overload of diabetes-induced calcium ion (Ca2+) entry and oxidative stress. The transient receptor potential (TRP) melastatin 2 (TRPM2) and TRP vanilloid type 1 (TRPV1) are expressed in sensory neurons and hippocampus. Moreover, activations of TRPM2 and TRPV1 during oxidative stress have been linked to neuronal death. Melatonin (MEL) and selenium (Se) have been considered potent antioxidants that detoxify a variety of reactive oxygen species (ROS) in neurological diseases. In order to better characterize the actions of MEL and Se in diabetes-induced peripheral pain and hippocampal injury through modulation of TRPM2 and TRPV1, we tested the effects of MEL and Se on apoptosis and oxidative stress in the hippocampal and dorsal root ganglion (DRG) neurons of streptozotocin (STZ)-induced diabetic rats. Fifty-eight rats were divided into six groups. The first group was used as control. The second group was used as the diabetic group. The third and fourth groups received Se and MEL, respectively. Intraperitoneal Se and MEL were given to diabetic rats in the fifth and sixth groups. On the 14th day, hippocampal and DRG neuron samples were freshly taken from all animals. The neurons were stimulated with a TRPV1 channel agonist (capsaicin) and a TRPM2 channel agonist (cumene hydroperoxide). We observed a modulator role of MEL and Se on intracellular free Ca2+ concentrations, current densities of TRPM2 and TRPV1 channels, apoptosis, caspase 3, caspase 9, mitochondrial depolarization, reduced glutathione, glutathione peroxidase, lipid peroxidation, and intracellular ROS production values in the neurons. In addition, procaspase 3 and 9 activities in western blot analyses of the brain cortex were also decreased by MEL and Se treatments. In conclusion, in our diabetes experimental model, TRPM2 and TRPV1 channels are involved in the Ca2+ entry-induced neuronal death and modulation of this channel activity by MEL and Se treatment may account for their neuroprotective activity against apoptosis and Ca2+ entry.

Possible molecular pathways of involvement of melatonin and selenium in diabetes-induced apoptosis, oxidative stress, and calcium accumulation through TRPM2 and TRPV1 channels in the hippocampus and DRG neurons of rats. The TRPM2 channel is activated by ADP-ribose and oxidative stress although it is inhibited by ACA. The TRPV1 channel is activated by oxidative stress and capsaicin and it is blocked by capsazepine (CPZ). Diabetes can result in augmented ROS release in hippocampal and DRG neurons through polyol reactions, leading to Ca2+ uptake through TRPM2 and TRPV1 channels. Mitochondria were reported to accumulate Ca2+ provided intracellular Ca2+ rises, thereby leading to the depolarization of mitochondrial membranes and release of apoptosis-inducing factors such as caspase 3 and caspase 9. Melatonin and selenium reduce TRPM2 and TRPV1 channel activation through the modulation of polyol oxidative reactions and selenium-dependent glutathione peroxidase (GSH-Px) antioxidant pathways.

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Abbreviations

[Ca2+]i :

Intracellular free calcium ion

ACA:

N-(p-amylcinnamoyl) anthranilic acid

ADPR:

ADP-ribose

CAP:

Capsaicin

CHPx:

Cumene hydroperoxide

CPZ:

Capsazepine

DMSO:

Dimethyl sulfoxide

DRG:

Dorsal root ganglion

EGTA:

Ethylene glycol-bis[2-aminoethyl-ether]-N,N,N,N-tetraacetic acid

GSH:

Reduced glutathione

GSH-Px:

Glutathione peroxidase

HBSS:

Hank’s buffered salt solution

ROS:

Reactive oxygen species

TRP:

Transient receptor potential

TRPM2:

Transient receptor potential Mu

TRPV1:

Transient receptor potential vanilloid 1

WC:

Whole cell

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Acknowledgments

The abstract of the study was partially published in the “5th International Congress on Cell Membranes and Oxidative Stress: Focus on Calcium Signaling and TRP Channels, 9–12 September 2014, Isparta, Turkey” (http://www.cmos.org.tr/2014/). The authors declare that there is no conflict of interest in the current study.

Authorship Contributions

MN and MCK formulated the hypothesis and was responsible for writing the report. MCK was also responsible for the Ca2+ analyses and animal experiments such as the induction of diabetes and injection of melatonin and selenium. İSÖ performed the Western blot, apoptosis, and mitochondrial depolarization analyses. The authors wish to thank Fatih Şahin and Muhammet Şahin (Neuroscience Research Center, SDU, Isparta, Turkey) for helping with the patch-clamp, lipid peroxidation, and antioxidant analyses.

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Authors and Affiliations

  1. Department of Biophysics, Faculty of Medicine, University of Izmir Katip Celebi, Izmir, Turkey

    Mehmet Cemal Kahya

  2. Department of Neuroscience, Health Science Institute, University of Suleyman Demirel, Isparta, Turkey

    Mustafa Nazıroğlu & İshak Suat Övey

  3. Neuroscience Research Center, University of Suleyman Demirel, Isparta, TR-32260, Turkey

    Mustafa Nazıroğlu

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  1. Mehmet Cemal Kahya
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Correspondence to Mehmet Cemal Kahya or Mustafa Nazıroğlu.

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Financial Disclosure

The study was supported by the Unit of Scientific Research Project (BAP), İzmir Katip Çelebi University, İzmir, Turkey (Project Number: BAP: 2014-1-TIP-02). There is no financial disclosure for the current study.

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Kahya, M.C., Nazıroğlu, M. & Övey, İ.S. Modulation of Diabetes-Induced Oxidative Stress, Apoptosis, and Ca2+ Entry Through TRPM2 and TRPV1 Channels in Dorsal Root Ganglion and Hippocampus of Diabetic Rats by Melatonin and Selenium. Mol Neurobiol 54, 2345–2360 (2017). https://doi.org/10.1007/s12035-016-9727-3

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