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.
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