GDNF reduces oxidative stress in a 6-hydroxydopamine model of Parkinson's disease

Abstract

Many current theories of Parkinson's disease (PD) suggest that oxidative stress is involved in the neurodegenerative process. Potential neuroprotective agents could protect neurons through inherent antioxidant properties or through the upregulation of the brain's antioxidant defenses. Glial cell linederived neurotrophic factor (GDNF) has been shown to protect and restore dopamine neurons in experimental models of PD and to improve motor function in human patients. This study was designed to investigate GDNF's effect on oxidative stress in a model of PD. GDNF or vehicle was injected into the right striatum of male Fischer-344 rats. Three days later 6-OHDA or saline was injected into the same striatum. The striatum and substantia nigra from both sides of the brain were removed 24 hours after 6-OHDA or saline injection and analyzed for the oxidative stress markers protein carbonyls and 4-hydroxynonenal. Both markers were significantly reduced in GDNF + 6-OHDA treated animals compared to vehicle + 6-OHDA treated animals. In addition, in animals allowed to recover for 3.5 to 4 weeks after the 6-OHDA administration, the GDNF led to significant protection against loss of striatal and nigral tissue levels of dopamine. These results suggest that the protective effects of GDNF against 6-OHDA involve a reduction in oxidative stress. KeywordsGDNF; reactive oxygen species; protein carbonyls; 4-hydroxynonenal; striatum; substantia nigra; dopamine Oxidative stress is a common characteristic of many of the current theories of the etiology of Parkinson's disease (PD). It is implicated either as a cause or result of the neurodegeneration associated with PD [4,29,36,38] Glial cell line-derived neurotrophic factor (GDNF) has been shown to have both protective and restorative properties in vivo, particularly regarding the dopaminergic neurons of the substantia nigra [12,16,22]. In addition to its effects in models of PD, GDNF has demonstrated similar protective and restorative effects in other models of neurodegeneration [6,17,26,48]. 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. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAlthough the protective and restorative properties of GDNF have been well documented, the mechanisms behind these properties are still relatively unknown.Increases in oxidative stress can be detected before signs of neuronal degeneration [15,47], suggesting that oxidative stress may be an early component of neuronal loss. This study was designed to investigate GDNF's ability to reduce the generation of oxidative str...

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