Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
Toxicology. 2013 Feb 8;304:1-12. doi: 10.1016/j.tox.2012.11.013. Epub 2012 Dec 3.
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+) 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.
抗抑郁药通常用于治疗各种情绪和焦虑障碍。一些研究表明，一些抗抑郁药具有抗肿瘤和细胞毒性活性，但潜在的机制尚不清楚。马普替林是一种四环抗抑郁药，具有高度选择性的去甲肾上腺素再摄取能力。我们发现马普替林在Neuro-2a 细胞中以浓度和时间依赖的方式降低细胞活力。马普替林诱导细胞凋亡并增加半胱天冬酶-3 的激活。马普替林激活半胱天冬酶-3似乎依赖于 JNK 的激活和 ERK 的失活。马普替林还诱导 Ca(2+)增加，涉及内质网中储存的细胞内 Ca(2+)的动员。用 BAPTA/AM（一种 Ca(2+)螯合剂）预处理可抑制马普替林诱导的 ERK 磷酸化，增强半胱天冬酶-3 的激活，并增加马普替林诱导的细胞凋亡。总之，马普替林通过激活 JNK 相关的半胱天冬酶-3 途径诱导 Neuro-2a 细胞凋亡。马普替林还引发了一种抗细胞凋亡反应，该反应既依赖于 Ca(2+)又依赖于 ERK。
