The mechanism of pesticide rotenone-induced cell death in models of Parkinson's disease.

摘要

Parkinson's disease (PD) is characterized by progressive loss of neuromelanin pigmented dopaminergic neurons in the substantia nigra pars compacta. Though the underlying mechanism of neurodegeneration remains poorly understood, epidemiological studies indicate that environmental factors increase the risk of developing PD. Evidence from a number of epidemiological studies demonstrates a positive correlation between exposure to pesticides and development of PD in humans. Several groups have validated this finding, showing that chronic complex I inhibition caused by the commonly used pesticide rotenone induces features of PD in rats, including loss of the nigrostriatal dopaminergic pathway. Understanding why primary dopaminergic neurons succumb to pesticide toxicity may give insights in the principal mechanism of neurodegeneration in PD.; This thesis investigates the mechanism underlying rotenone-induced death of dopamine neurons using primary cultures of ventral mesencephalon from E15 rats. We demonstrate that the dopaminergic neurons succumb to rotenone-induced apoptosis mediated by the activation of caspase-3. This is the first study to implicate apoptosis as a principal mechanism underlying the rotenone-induced death of primary dopamine neurons. Next, we demonstrate that the relative contribution of the two forms of death observed: apoptosis and necrosis, depends on the energy level in the affected cells. We established that at lower doses, rotenone induces a partial depletion of ATP leading to apoptosis in dopaminergic neurons. By contrast, at higher concentrations of rotenone, ATP depletion by more than 75% results in necrosis. We also show that dopamine renders dopaminergic neurons more vulnerable to rotenone-induced toxicity resulting in caspase-3 dependent apoptosis. Moreover, mitochondrial superoxide dismutase mimetic, MnTBAP, prevented caspases-3 activation, implicating upstream peroxynitrite generation as the initiating factor for apoptosis.; In summary, these data imply that rotenone-induced apoptosis of dopaminergic neurons may be exacerbated by the metabolism of cytoplasmic DA and chronic mitochondria-associated energy failure. Elucidating why primary dopaminergic neurons succumb to rotenone toxicity might reveal the primary mechanism of neurodegeneration and how the pesticide exposure affects the etiology of PD. Such knowledge should lead to new protective strategies targeting specific pathways involved in the demise of dopaminergic neurons.