Formyl-methionyl-leucyl-phenylalanine Induces Apoptosis in Murine Neurons: Evidence for NO-Dependent Caspase-9 Activation

Formyl-methionyl-leucyl-phenylalanine (fMLP) may be present in the brain in the course of some infectious diseases of the central nervous system (CNS), although little is known about its role. This investigation was performed to study the effect of fMLP on neuron apoptosis. Our results showed that fMLP treatment of primary cultures of neurons was able to induce morphological features of apoptosis in cell cultures, as well as activation of the intrinsic apoptotic pathway, through the upregulation of caspase-9 and caspase-3. This effect contextually occurred to the pro-apoptotic protein Bax activation and cytochrome c release. The in vitro fMLP treatment was also able to induce, in a dose-dependent manner, the increase of inducible nitric oxide synthase (iNOS) expression accompanied by an up-regulation of nitric oxide (NO) release. When neuron cultures were pre-treated with 1400 W, a selective iNOS inhibitor, all of the apoptotic features were significantly reversed. Overall, these results demonstrated that fMLP treatment of neurons leads to intrinsic apoptosis activation, through iNOS expression regulation, suggesting a role for fMLP in CNS neurodegenerative processes.