The role of catecholamine oxidation in neuronal cell degeneration.

摘要

Oxidative stress has become increasingly important in the pathogenesis of many diseases. The etiology of Idiopathic Parkinson's disease has not been elucidated but there is a growing body of evidence that oxidative stress may play a prominent role. Much of the current support for an oxidative mechanism of neurodegeneration comes from non-human models of Parkinson's disease (PD) that utilize neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to generate a Parkinson-like syndrome. Similar to PD the exact mechanism of cell death and the role of oxidative stress in these models remain controversial. There is significant evidence establishing the participation of catecholamine oxidation as a promoter of oxidative stress. Most of the evidence is indirect and the precise role that catecholamines play in oxidative stress has not yet been determined.; Identifying and quantifying the products of catecholamine oxidation could better clarify the exact role of oxidative stress in both the neurotoxin-induced models of PD and clinical PD itself. We propose that the oxidation of dopamine to dopaminochrome plays a critical role in the toxic mechanism of cell death caused by 1-methyl-4-phenylpyridinium (MPP+). We believe that the loss of dopamine and the neuronal cell death associated with PD and MPTP toxicity is attributable to dopamine oxidation. Our hypothesis is that dopamine oxidation to dopaminochrome (DaC) leads to dopamine's inactivation and subsequent loss and provides a means by which oxidative conditions within the cell can propagate and ultimately cause cell death. By measuring the formation of DaC in models of neuronal cell death we may be able to elucidate a more accurate mechanism of MPP+ toxicity and the cause of cell death associated with PD.; To examine the role that dopamine oxidation plays in neuronal cell death we have used nerve growth factor (NGF)-differentiated pheochromocytoma (PC12) cells. NGF-differentiated PC12 cells have been used as in vitro models to study the effects of dopaminergic toxins. First we examined the toxicity of dopaminochrome. Second we developed a novel method for the separation and quantification of aminochromes, specifically dopaminochrome, from biological samples. Finally we evaluated the formation of DaC in an in vitro model oxidative stress.