Parkinson's disease is characterized by the progressive degeneration of nigrostriatal dopaminergic neurons in the ventral midbrain. Although the basic underlying mechanisms of this debilitating movement disorder remain unknown, considerable efforts have centered on developing effective strategies for halting the neurodegenerative process and restoring normal function. One promising approach involves the use of neurotrophic factors, proteins that promote the survival and proper functioning of select populations of neurons. Preliminary findings from our laboratory show that receptor mRNA and protein for a relatively novel group of trophic factors called neuregulins are synthesized within the dopaminergic nigrostriatal system in rodents and primates. We find that supranigral administration of neuregulin induces increased dopamine overflow in the striatum, indicating functional effects upon the dopaminergic nigrostriatal system. Our recent data also indicate that neuregulin treatment protects dopaminergic cells against neurotoxin-induced degeneration in vivo, and against both oxidative and metabolic insults in vitro. In the proposed research, we will expand upon these findings to test the overall the hypothesis that neuregulins are neuroprotective and/ or neurorestorative for midbrain dopaminergic neurons upon selective neurotoxic damage.
Specific Aim #1 will determine the extent to which neuregulin receptors are expressed by dopaminergic cells in the ventral mesencephalon of normal and neurotoxin-lesioned rat and monkey using single- and double-labeling in situ hybridization and immunocytochemical techniques.
Specific Aim #2 will use a well-characterized rat model of Parkinson's disease coupled with specific neuregulin treatment regims to test if infusion of neuregulins (I) protects dopaminergic neurons from subsequent neurotoxic damage or (ii) promotes functional recovery of the injured nigrostriatal system after neurotoxic damage. Morphological, behavioral and neurochemical approaches will be used to analyze the extent of protection and/or functional restoration afforded by neuregulin treatment.
Specific aim #3 will (I) determine if neuregulin receptor expression is spatially or temporally deficient in the rat and monkey nigrostriatal system in aged animals, and (ii) using intracerebral microdialysis, evaluate the responsiveness of the dopaminergic nigrostriatal system to neuregulin administration in young, middle age and old rats.
Specific aim #4 will assess the potential mechanisms by which neuregulin protects dopaminergic cells from insults relevent to Parkinson's disease. Overall, these studies will assess the therapeutic value of neuregulin trophic factors for the treatment of Parkinson's disease and other neurodegenerative disorders of the nigrostriatal system.
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