Cyclophosphamide promotes cell survival via activation of intracellular signaling in cultured cortical neurons

• Published in: Neuroscience letters Vol. 470; no. 2; pp. 139 - 144
• Main Authors: Kitazawa, Hiromi, Numakawa, Tadahiro, Adachi, Naoki, Kumamaru, Emi, Tuerxun, Tuerhong, Kudo, Motoshige, Kunugi, Hiroshi
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 12-02-2010; Elsevier
• Subjects: 1-Phosphatidylinositol 3-kinase; Animals; Bcl2; Biological and medical sciences; Cell death; Cell survival; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - physiology; Cyclophosphamide; Cyclophosphamide - pharmacology; Enzyme Inhibitors - pharmacology; ERK; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Fundamental and applied biological sciences. Psychology; MAP Kinase Signaling System - drug effects; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Neurons - drug effects; Neurons - physiology; Neuroprotective Agents - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; PI3K; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Signal Transduction - drug effects; Signal Transduction - physiology; Vertebrates: nervous system and sense organs; Bcl2; Cyclophosphamide; Cell survival; PI3K; Cell death; ERK; Signal transduction; Extracellular signal-regulated protein kinase; Enzyme; Intracellular; In vitro
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2009.12.073

Cyclophosphamide (CP) has been used as an antitumour agent or immunosuppressant clinically, though the potential biological role of CP in the central nervous system (CNS) has not been clarified. In the present study, we found that pretreatment with CP prevented neuronal cell death caused by serum deprivation in cultured cortical neurons. Interestingly, CP stimulated activation of PI3K (phosphatidylinositol 3 kinase) and MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathways, which are known as survival-promoting intracellular signalings. Furthermore, CP increased the expression of Bcl2, an anti-apoptotic factor. In the presence of inhibitors for PI3K or MAPK/ERK pathways, the CP-dependent neuronal survival and Bcl-2 up-regulation were both abolished. Importantly, significant increase in BDNF (brain-derived neurotrophic factor) expression was induced by CP application, implying that BDNF up-regulation is involved in the CP effect. We propose that CP has a protective effect on CNS neurons via the activation of intracellular signalings, and up-regulation of Bcl2 and BDNF.