title: Mechanism of maprotiline-induced apoptosis: role of [Ca2+](i), ERK, JNK and caspase-3 signaling pathways.
abstract: Antidepressants are generally used for treatment of various mood and anxiety disorders. Several studies have shown the anti-tumor and cytotoxic activities of some antidepressants, but the underlying mechanisms were unclear. Maprotiline is a tetracyclic antidepressant and possesses a highly selective norepinephrine reuptake ability. We found that maprotiline decreased cell viability in a concentration- and time-dependent manner in Neuro-2a cells. Maprotiline induced apoptosis and increased caspase-3 activation. The activation of caspase-3 by maprotiline appears to depend on the activation of JNK and the inactivation of ERK. Maprotiline also induced [Ca(2+)](i) increases which involved the mobilization of intracellular Ca(2+) stored in the endoplasmic reticulum. Pretreatment with BAPTA/AM, a Ca(2+) chelator, suppressed maprotiline-induced ERK phosphorylation, enhanced caspase-3 activation and increased maprotiline-induced apoptosis. In conclusion, maprotiline induced apoptosis in Neuro-2a cells through activation of JNK-associated caspase-3 pathways. Maprotiline also evoked an anti-apoptotic response that was both Ca(2+)- and ERK-dependent.
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Jan
authors.forename: Jian-An
authors.initials: JA
authors.lastname: Su
authors.forename: Chih-Chuan
authors.initials: CC
authors.lastname: Teng
authors.forename: Meei-Ling
authors.initials: ML
authors.lastname: Sheu
authors.forename: Paul-Yann
authors.initials: PY
authors.lastname: Lin
authors.forename: Miao-Ching
authors.initials: MC
authors.lastname: Chi
authors.forename: Chia-Hao
authors.initials: CH
authors.lastname: Chang
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Liao
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Kuo
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chou
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008376:Maprotiline / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D018759:Adrenergic Uptake Inhibitors; D018687:Antidepressive Agents, Second-Generation; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D008376:Maprotiline; D004533:Egtazic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D002118:Calcium