In this study, the effects of melatonin on MPP+ -treated cerebellar granule neurons (CGNs) in culture were investigated. Results showed that MPP+ treatment significantly decreased cell viability and increased the apoptotic cell population at 24 and 48 hr. Calpain and caspase-3 activation was also determined, with results showing a strong increase in calpain (74%) and caspase 3 activity (70%), as measured by alpha-spectrin cleavage and fluorometric and colorimetric analysis, respectively. There are several studies suggesting that the activation of the cdk5/p35 pathway at its cleavage to cdk5/p25 may play a role in neuronal cell death in neurodegenerative diseases. Moreover, these studies indicate that this cleavage is mediated by calpains, and that MPP+ prompted an increase in cdk5 expression, as well as the cleavage of p35-p25, in a time-dependent manner. 1 mm Melatonin not only reduced the neurotoxic effects of MPP+ on cell viability, but also prevented apoptosis mediated by this Parkinsonian toxin in CGNs. 1 mm Melatonin reduced cdk5 expression, as well as the cleavage of p35-p25. These data indicate that melatonin possesses some neuro-protective properties against MPP+ -induced apoptosis. Moreover, these data suggest that the calpain/cdk5 signaling cascade has a potential role in the MPP+ -mediated apoptotic process in CGNs.