Historically, fetal dopamine tissue grafts used to treat parkinsonism have been transplanted into the striatum, the site of action for dopamine, which is normally transmitted from the substantia nigra (SN) through the nigrostriatal pathway. Simply resupplying the striatum with dopamine through fetal ventral mesencephalic (VM) tissue transplants has had marginal success in treating Parkinson's disease (PD) possibly because appropriate circuits for the control of dopamine release are not established. Replacing the lost cells in the SN and reconstructing the nigrostriatal pathway may provide consistent long-lasting improvements. We propose to test this hypothesis in a rodent model of PD, using VM tissue transplanted into the SN, the Functionally correct location, followed by a degradable polymer hydrogel containing microparticles of neurotrophins (GDNF and BDNF). This polymer will bridge the SN to the striatum, the terminal end of the pathway. The purpose of the polymer hydrogel is to provide a solid and temporary surface on which neurite outgrowth from the transplanted tissue can attach and follow to the striatum, thus recreating the neural circuitry which regulates dopamine release. The neurotrophins, GDNF and BDNF, have been shown to enhance transplant survival and encourage neurite outgrowth. Because they will be incorporated into the polymer, neurotrophic delivery will be in a site specific and timed manner. The polymer will be degradable, therefore no permanent foreign presence will remain to interfere with future pathway functioning or to affect surrounding tissue. Previous studies indicate that biodegradable polymers have good biocompatibility with neural tissue. The proposed studies will create polymer hydrogel bridges with neurotrophin containing microparticles. The neurotrophin concentrations and combinations which best suit cell survival and neuritic growth first will be determined in vitro using VM explants. Then the most optimal combination in vitro will be studied in vivo as polymer bridges transplanted in conjunction with VM tissue into the 6-hydroxydopamine rat model. The ability of the hydrogel bridges to reconstruct a functional nigrostriatal path will be determined as indicated by improved behavioral function, reduced dopamine-induced dyskinesias, and a neuroanatomical presence of a pathway. The success of these studies may alter the focus of neural transplantation from neurotransmitter replacement therapies to neural circuitry reconstruction. While we are using an animal model of PD to test this hypothesis, if successful, it could have implications for other neurodegenerative disorders, including Huntington's Disease or stroke. ? ? ?
