Oxidative stress and dopamine depletion in an intrastriatal 6-hydroxydopamine model of Parkinson’s disease

Abstract

Although the etiology of Parkinson's disease (PD) is unknown, a common element of most theories is the involvement of oxidative stress, either as a cause or effect of the disease. There have been relatively few studies that have characterized oxidative stress in animal models of PD. In the present study a 6-hydroxydopamine (6-OHDA) rodent model of PD was used to investigate the in vivo production of oxidative stress after administration of the neurotoxin. 6-OHDA was injected into the striatum of young adult rats and the production of protein carbonyls and 4-hydroxynonenal (HNE) was measured at 1, 3, 7, and 14 days after administration. A significant increase in both markers was found in the striatum 1 day after neurotoxin administration, and this increase declined to basal levels by day 7. There was no significant increase found in the substantia nigra at any of the time points investigated. This same lesion paradigm produced dopamine depletions of 90-95% in the striatum and 63-80% in the substantia nigra by 14 to 28 days post 6-OHDA. Protein carbonyl and HNE levels were also measured in middle-aged and aged animals 1 day after striatal 6-OHDA. Both protein carbonyl and HNE levels were increased in the striatum of middle-aged and aged animals treated with 6-OHDA, but the increases were not as great as those observed in the young adult animals. Similar to the young animals, there were no increases in either marker in the substantia nigra of the middle-aged and aged animals. There was a trend for an age-dependent increase in basal amounts of oxidative stress markers when comparing the non-lesioned side of the brains of the three age groups. These results support that an early event in the course of dopamine depletion following intrastriatal 6-OHDA administration is the generation of oxidative stress. Keywordsreactive oxygen species; protein carbonyls; 4-hydroxynonenal; striatum; substantia nigra; aging; Fischer-344 rat Parkinson's disease (PD) stems from the loss of dopamine (DA) caused by the degeneration of the dopaminergic neurons of the substantia nigra. The nature of this degeneration remains unclear, although current theories suggest that reactive oxygen species (ROS) are involved in some capacity early in the disease process (Jenner, 2003). One of the earliest changes in patients with PD and incidental Lewy body disease is the loss of glutathione (Sian et al., 1994,Owen et al., 1996. Post mortem tissue from PD patients has been shown to contain elevated levels Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Yoritaka et al., 1996), protein carbonyls (Alam et...

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