title: Agomelatine and duloxetine synergistically modulates apoptotic pathway by inhibiting oxidative stress triggered intracellular calcium entry in neuronal PC12 cells: role of TRPM2 and voltage-gated calcium channels.
abstract: Calcium ion (Ca(2+)) is one of the universal second messengers, which acts in a wide range of cellular processes. Results of recent studies indicated that ROS generated by depression leads to loss of endoplasmic reticulum-Ca(2+) homeostasis, oxidative stress, and apoptosis. Agomelatine and duloxetine are novel antidepressant and antioxidant drugs and may reduce oxidative stress, apoptosis, and Ca(2+) entry through TRPM2 and voltage-gated calcium channels. We tested the effects of agomelatine, duloxetine, and their combination on oxidative stress, Ca(2+) influx, mitochondrial depolarization, apoptosis, and caspase values in the PC-12 neuronal cells. PC-12 neuronal cells were exposed in cell culture and exposed to appropriate non-toxic concentrations and incubation times for agomelatine were determined in the neurons by assessing cell viability. Then PC-12 cells were incubated with agomelatine and duloxetine for 24 h. Treatment of cultured PC-12 cells with agomelatine, duloxetine, and their combination results in a protection on apoptosis, caspase-3, caspase-9, mitochondrial membrane depolarization, cytosolic ROS production, glutathione peroxidase, reduced glutathione, and lipid peroxidation, values. Ca(2+) entry through non-specific TRPM2 channel blocker (2-APB) and voltage-gated Ca(2+) channel blockers (verapamil and diltiazem) was modulated by agomelatine and duloxetine. However, effects of duloxetine on the Ca(2+) entry through TRPM2 channels were higher than in agomelatine. Results of current study suggest that the agomelatine and duloxetine are useful against apoptotic cell death and oxidative stress in PC-12 cells, which seem to be dependent on mitochondrial damage and increased levels of intracellular Ca(2+) through activation of TRPM2 and voltage-gated Ca(2+) channels.
authors.affiliation: Department of Psychiatry, Faculty of Medicine, University of Suleyman Demirel, Isparta, Turkey.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Akpinar
authors.forename: Abdülhadi Cihangir
authors.initials: AC
authors.lastname: Uğuz
authors.forename: Mustafa
authors.initials: M
authors.lastname: Nazıroğlu
mesh_terms: D000081:Acetamides / Q000627:therapeutic use*; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004357:Drug Synergism; D000068736:Duloxetine Hydrochloride; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D051381:Rats; D050053:TRPM Cation Channels / Q000378:metabolism*; D013876:Thiophenes / Q000627:therapeutic use*; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000928:Antidepressive Agents; D000975:Antioxidants; D002118:Calcium; D015220:Calcium Channels; D053148:Caspase 3; D053453:Caspase 9; D000068736:Duloxetine Hydrochloride; D005978:Glutathione; D005979:Glutathione Peroxidase; D050053:TRPM Cation Channels; D013876:Thiophenes; C557080:Trpm2 protein, rat; C084711:agomelatine; D009281:Naphthalenes