Mechanism of maprotiline-induced apoptosis: Role of [Ca2+]i, ERK, JNK and caspase-3 signaling pathways

Chung Ren Jan, Jian An Su, Chih Chuan Teng, Meei Ling Sheu, Paul Yann Lin, Miao Ching Chi, Chia Hao Chang, Wayne C. Liao, Chun Chi Kuo, Chiang Ting Chou*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

24 Scopus citations

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 [Ca2+]i increases which involved the mobilization of intracellular Ca2+ stored in the endoplasmic reticulum. Pretreatment with BAPTA/AM, a Ca2+ 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 Ca2+- and ERK-dependent.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalToxicology
Volume304
DOIs
StatePublished - 08 02 2013
Externally publishedYes

Keywords

  • Apoptosis
  • Calcium
  • JNK
  • Maprotiline
  • Neuro-2a cells

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