USE AND DRUG DEPENDENT NEUROPROTECTION--TROPIC FACTORS

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Parkinson's disease (PD) poses a serious threat to the health of a large segment of our society. Having focused on the compensatory changes that underlie the preclinical phase of PD, we are now concentrating our efforts on the issue of neuroprotection. The present project is one component of this effort and focuses on strategies for inducing endogenous neuroprotective mechanisms in animal models of PD. The work derives from recent evidence from our labs indicating that the contralateral motor neglect normally following unilateral damage to the nigrostriatal dopamine (DA) projection can be ameliorated by forced use of the contralateral limb. Moreover, we find that this behavioral sparing is accompanied by a dramatic reduction in the loss of DA. We hypothesize that forced execution of a motor act that is otherwise compromised by PD is neuroprotective, and that this results from an interaction between the motor act, injury, and concomitant increase in the availability of one or more trophic factors (e.g., GDNF) and hormones (e.g. estrogen). Our project utilizes 6-hydroxydopamine (6-OHDA)-treated rodent models of PD and has five specific aims: (1) We will determine the impact of forced use/disuse on the anatomical and functional state of DA neurons, including the use of microdialysis to measure in vivo DA efflux. (2) We will determine the relationship between use-dependent neuroprotection and increased trophic factor expression by using antisense oligonucleotides to reduce expression, fusion proteins to serve as decoys for the factors, and animals deficient in a protein key to trophic factor signaling. (3) We will examine the ability of estrogen to exert a neuroprotective influence and the possible role of that influence on the impact of exercise. (4) We will use microarrays together with more classical techniques to examine changes in other trophic factors and their receptors in striatum of animals subjected to lesions and/or casting. Later we will also look at substantia nigra and at regions where no neuroprotection is seen. (5) Finally, we will examine the impact of age on neuroprotection induced by trophic factors by first determining whether neuroprotection induced in young adult rats continues to be effective as animals reach old age, and then ask whether neuroprotective strategies that work in young adults can also be used to reduce the impact of 6-OHDA in aged rats.