Melatonin is protective in necrotic but not in caspase-dependent, free radical-independent apoptotic neuronal cell death in primary neuronal cultures

To assess the neuroprotective potential of melatonin in apoptotic neuronal cell death, we investigated the efficacy of melatonin in serum-free primary neuronal cultures of rat cortex by using three different models of caspase -dependent apoptotic, excitotoxin-independent neurodegeneration and com par ed it to that in necrotic neuronal damage. Neuronal apoptosis was induced b y either staurosporine or the neurotoxin ethylcholine aziridinium (AF64A) w ith a delayed occurrence of apoptotic cell death (within 72 h). The apoptot ic component of oxygen-glucose deprivation (OGD) unmasked by glutamate anta gonists served as a third model. As a model for necrotic cell death, OGD wa s applied. Neuronal injury was quantified by LDH release and loss of metabo lic activity. Although melatonin (0.5 mM) partly protected cortical neurons from OGD-induced necrosis, as measured by a significant reduction in LDH r elease, it was not effective in all three models of apoptotic cell death. I n contrast, exaggeration of neuronal damage by melatonin was observed in na tive cultures as well as after induction of apoptosis. The present data sug gest that the neuroprotectiveness of melatonin strongly depends on the mode l of neuronal cell death applied. As demonstrated in three different models of neuronal apoptosis, the progression of the apoptotic type of neuronal c ell death cannot be withhold or is even exaggerated by melatonin, in contra st to its beneficial effect in the necrotic type of cell death.