title: Duloxetine Reduces Oxidative Stress, Apoptosis, and Ca2+Entry Through Modulation of TRPM2 and TRPV1 Channels in the Hippocampus and Dorsal Root Ganglion of Rats.
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.
authors.affiliation: Department of Psychiatry, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey.
authors.forename: Arif
authors.initials: A
authors.lastname: Demirdaş
authors.affiliation: Department of Neuroscience, Health Science Institute, Suleyman Demirel University, Isparta, Turkey. mustafanaziroglu@sdu.edu.tr.|Neuroscience Research Center, Suleyman Demirel University, 32260, Isparta, Turkey. mustafanaziroglu@sdu.edu.tr.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Nazıroğlu
authors.affiliation: Department of Neuroscience, Health Science Institute, Suleyman Demirel University, Isparta, Turkey.
authors.forename: İshak Suat
authors.initials: İS
authors.lastname: Övey
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D000068736:Duloxetine Hydrochloride / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D050053:TRPM Cation Channels / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D050053:TRPM Cation Channels; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C557080:Trpm2 protein, rat; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D000068736:Duloxetine Hydrochloride; D053148:Caspase 3; D053453:Caspase 9; C071423:capsazepine; D002211:Capsaicin; D002118:Calcium
keywords: Apoptosis; Duloxetine; Oxidative stress; Pain; TRPV1