Apoptotic signaling in dopamine-induced cell death: the role of oxidative stress, p38 mitogen-activated protein kinase, cytochrome c and caspases

Oxidative stress generated by dopamine (DA) oxidation could be one of the f actors underlying the selective vulnerability of nigral dopaminergic neuron s in Parkinson's diseases. Here we show that DA induces apoptosis in SH-SY5 Y neuroblastoma cells demonstrated by activation of caspase-9 and caspase-3 , cleavage of poly(ADP-ribose) polymerase as well as nuclear condensation. We also show that p38 mitogen-activated protein kinase is activated within 10 min of DA treatment, which precedes the onset of apoptosis because the p otent p38 kinase inhibitor SB203580 protects against DA-induced cell death as well as against caspase-9 and caspase-3 activation. In addition, the ant ioxidant N-acetyl-L-cysteine (NAC) effectively blocks DA-induced p38 kinase activation, caspase-9 and caspase-3 cleavage and subsequent apoptosis, ind icating that DA triggers apoptosis via a signaling pathway that is initiate d by the generation of reactive oxygen species (ROS). Dopamine exerts its t oxicity principally intracellularly as the DA uptake inhibitor, nomifensine significantly reduces DA-induced cell death as well as activation of p38 k inase and caspase-3. Furthermore, DA induces mitochondrial cytochrome c rel ease, which is dependent on p38 kinase activation and precedes the cleavage of caspases. These observations indicate that DA induces apoptosis primari ly by generating ROS, p38 kinase activation, cytochrome c release followed by caspase-9 and caspase-3 activation.