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Duloxetine Reduces Oxidative Stress, Apoptosis, and Ca2+ Entry Through Modulation of TRPM2 and TRPV1 Channels in the Hippocampus and Dorsal Root Ganglion of Rats

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Abstract

Overload of Ca2+ entry and excessive oxidative stress in neurons are the two main causes of depression. Activation of transient receptor potential (TRP) vanilloid type 1 (TRPV1) and TRP melastatin 2 (TRPM2) during oxidative stress has been linked to neuronal survival. Duloxetine (DULOX) in neurons reduced the effects of Ca2+ entry and reactive oxygen species (ROS) through glutamate receptors, and this reduction of effects may also occur through TRPM2 and TRPV1 channels. In order to better characterize the actions of DULOX in peripheral pain and hippocampal oxidative injury through modulation of TRPM2 and TRPV1, we tested the effects of DULOX on apoptosis and oxidative stress in the hippocampal and dorsal root ganglion (DRG) neurons of rats. Freshly isolated hippocampal and DRG neurons were incubated for 24 h with DULOX. In whole-cell patch-clamp and intracellular-free calcium ([Ca2+]) concentration (Fura-2) experiments, cumene hydroperoxide and ADP-ribose-induced TRPM2 currents in the neurons were inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and capsaicin-induced TRPV1 currents were inhibited by capsazepine (CPZ) incubations. TRPM2 and TRPV1 channel current densities, [Ca2+] concentration, apoptosis, caspase 3, caspase 9, mitochondrial depolarization, and intracellular ROS production values in the neurons were lower in the DULOX group than in controls. In addition, the above values were further decreased by DULOX + CPZ and DULOX + ACA treatments. In conclusion, TRPM2 and TRPV1 channels are involved in Ca2+ entry-induced neuronal death and modulation of the activity of these channels by DULOX treatment may account for their neuroprotective activity against apoptosis, excessive ROS production, and Ca2+ entry.

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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

DULOX:

Duloxetine

EGTA:

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

FBS:

Fetal bovine serum

HBSS:

Hank’s buffered salt solution

NMDG:

N-methyl-d-aspartate receptors

PEG:

Polyethylene glycol

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 submitted to the 6th World Congress of Oxidative Stress, Calcium Signaling, and TRP Channels, held 24 and 27 May 2016 in Isparta, Turkey (www.cmos.org.tr).

Authorship Contributions

MN and AD formulated the hypothesis and were responsible for writing the report. İSÖ was responsible for the Ca2+ analyses, animal experiments, and neuronal incubations with DULOX. The authors wish to thank technicians Fatih Şahin and Muhammet Şahin (Neuroscience Research Center, SDU, Isparta, Turkey) for helping with patch-clamp, lipid peroxidation, and antioxidant analyses.

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Authors and Affiliations

  1. Department of Psychiatry, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey

    Arif Demirdaş

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

    Mustafa Nazıroğlu & İshak Suat Övey

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

    Mustafa Nazıroğlu

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  1. Arif Demirdaş
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Correspondence to Mustafa Nazıroğlu.

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Demirdaş, A., Nazıroğlu, M. & Övey, İ.S. Duloxetine Reduces Oxidative Stress, Apoptosis, and Ca2+ Entry Through Modulation of TRPM2 and TRPV1 Channels in the Hippocampus and Dorsal Root Ganglion of Rats. Mol Neurobiol 54, 4683–4695 (2017). https://doi.org/10.1007/s12035-016-9992-1

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  • DOI: https://doi.org/10.1007/s12035-016-9992-1

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