REGNERATION IN THE AGED AND INJURED DOPAMINE SYSTEM

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Dopamine (DA) neurons of the ventral mesencephalon which innervate the striatum show age-related deterioration in rodents, monkeys and humans. Severe degeneration of this nigrostriatal DA system yields the motor dysfunctions characteristic of Parkinson's disease in humans. Recent evidence from our laboratory indicates that exposure of embryonic rat DA neurons to diffusible products derived from an explanted peripheral nerve segment, or cultured Schwann cells, enhances survival and neurite outgrowth of these DA neurons in culture. Similar enhancement of DA neuron survival and growth is obtained when embryonic DA neurons are co- grafted with a peripheral nerve segment to the striatum of DA-depleted rats. In addition, intraventricular implantation of the peripheral nerve segment in 25 month old rats upregulates tyrosine hydroxylase (TH) staining in the entire nigrostriatal system ipsilateral to the implant. Finally, we have isolated a low molecular weigh fraction of Schwann cell conditioned medium that contains DA neuron survival and growth-promoting activity, referred to in this application as dopamine neurotrophic factor (DNTF). The current proposal seeks to extend these preliminary finding s to document whether compensatory growth and/or activity of nigrostriatal DA neurons can be induced in young adult and aging rats with variable degrees of damage to the DA system via exposure to products of grafted Schwann cells or intraventricular infusion of the conditioned medium fraction (DNTF). Since identification DNTF is ongoing and incomplete, we will also test the relative efficacy of DNTF to promote DA neuron survival and growth as compared to four known growth factors which have demonstrated positive effects on the viability of cultured DA neurons: bFGF, BDNF,IGF-1 and EGF. Both culture and animals studies will collect information on the magnitude of factor induced compensatory changes in the DA system, the relationship to the number and location of DA neurons information on cellular mechanisms of DA neuron growth promotion. Evidence from behavioral measures, immunocytochemical morphology, neurotransmitter and metabolite assays, and measurements of TH mRNA expression will combine to address these issues of interest. In addition, we will pursue our initial finding of enhanced efficacy of embryonic DA neuron grafts in the presence of co-grafted peripheral nerve, by comparing embryonic DA neuron grafts to mixed co-grafts of young and aged rats with short-term (3 weeks) or long-standing (12 months) lesions of the nigrostriatal DA pathway. Further study of Schwann cells and their products as a source of survival and growth- promoting activity for DA neurons may provide insights into the biology of aging as it influences mechanisms of central nervous system plasticity, as well as having exciting implications for experimental therapeutics in aging and Parkinson's disease.