As neurodegenerative diseases are a major challenge for aging societies, the development of small, non-peptidic molecules with neurotrophic activity is of vital importance as such compounds easily cross the blood-brain barrier. We recently reported that the fungal metabolite militarinone A (MiliA), from the entomopathogenic fungus Paecilomyces militaris [1], stimulates neuronal outgrowth in PC12 cells within 24 hours [2]. Application of MiliA to other cell lines such as the neuroblastoma cell line N2a, however, resulted in immediate onset of apoptosis.
Differentiation in PC12 cells is induced by persistent activation of the same pathways that are involved in the NGF-mediated differentiation. This is namely the PI3-K/PKB and the MEK/ERK pathways as well as the activation of the transcription factor CREB. The continuous activation of these pathways finally led to up-regulation of p53, release of AIF from mitochondria and activation of the c-Jun/AP-1 transcription factor. Consequently, PC12 cells succumbed to cellular death as well after 48 to 72 hours of treatment.
Application of MiliA to N2a cells resulted in immediate onset of apoptosis by nuclear translocation of AIF, activation of caspases and c-Jun/AP-1 transcription factors. The main difference between the two cell types was found to be the basal level of p53 expression, which was very high in N2a but low in PC12. Pre-treatment of N2a cells with the PI3-K inhibitor LY294.002 delayed onset of apoptosis as it lowered basal expression levels of p53 but could not prevent its activation.
References: [1] Schmidt, K. et al. (2002) Org Lett. 4: 197–199, [2] Riese, U. et al. (2004) FEBS Lett. 577: 455.
