Parkinson's disease (PD) is a progressive and debilitating neurodegenerative disorder that affects over one million people in the United States. Current therapies for PD offer symptomatic relief but do not provide a cure or slow the disease process. Treatments that could halt progression of the disease or even restore function to damaged neurons would be of substantial benefit. Trophic factors, such as glial cell line-derived neurotrophic factor (GDNF), are promising therapeutic candidates because of their neuroprotective and neurorestorative effects on nigrostriatal dopamine (DA) neurons in animal models of PD. However, while the protective and restorative effects of GDNF have been well documented, the use of exogenous GDNF is problematic as it does not cross the blood brain barrier and must be administered directly into the brain. Thus, non-invasive treatments that can upregulate endogenous levels of trophic factors such as GDNF could be of significant benefit to individuals suffering from PD. Calcitriol, the active metabolite of vitamin D, has been shown to upregulate GDNF levels in the brain, including in the striatum and substantia nigra, and is partially protective against various CNS insults. The systemic administration of calcitriol may therefore be able to help restore normal function to DA neurons damaged by degenerative processes in patients with PD and may be able to slow down or halt progression of the disease. The proposed experiments will examine the effects of calcitriol in a 6-hydroxydopamine (6-OHDA) animal model of early PD. It is hypothesized that calcitriol will be effective in reversing 6-OHDA-induced behavioral changes and damage to nigrostriatal DA neurons in rats. The proposed experiments will determine the extent to which calcitriol treatment promotes recovery of behavior and striatal DA release and content in animals previously administered neurotoxic doses of 6-OHDA. Four weeks after administration of 6-OHDA rats will begin treatment with various doses and time courses of calcitriol. Behavior, in vivo microdialysis, and post- mortem analyses will be used to evaluate the restorative effects of calcitriol. As PD usually affects older individuals, young, middle-aged and aged rats will be examined to provide a more comprehensive evaluation of the effects of calcitriol in this model. These studies will begin to define the restorative effects of calcitriol on behavior and on functional measures of DA terminal integrity, and determine if the effects of calcitriol are dependent on the age of the animal. to Public Health: The proposed studies will determine if calcitriol can help restore normal behavior and normal levels of dopamine release and content in an animal model of Parkinson's disease. If calcitriol proves effective, the results of the experiments in this proposal may lead to novel and improved treatment strategies for persons suffering from this debilitating disease. In addition, as calcitriol is already approved for clinical use in humans for other diseases, evidence of efficacy in animal models of Parkinson's disease would facilitate initiation of clinical trials. ? ? ?
