Oxygen-derived free radicals are thought to be involved in the pathogenesis of a wide variety of neurological disorders. In the present work, the neurotoxic effects of reactive oxygen species provided the opportunity to study two different aspects of neurodegeneration. The first part of my work uses the central nervous system dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as a tool to study reactive gliosis. Although it is widely thought that reactive gliosis may be due to the release of cytokines such as interleukin-1 (IL-1) from brain microglia/macrophages, O'Callaghan et al have reported that MPTP-induced reactive gliosis in mice is unique compared to other models of experimentally-induced gliosis in that there does not appear to be an attendant increase in IL-1. To better understand the role of various glial cells in this exceptional model of gliosis, I have studied the reactive responses of both astrocytes and microglia to dopaminergic denervation of the striatum by MPTP. Following MPTP treatment, increased glial fibrillary acidic protein (GFAP) immunoreactivity reached a peak at two days and persisted for at least six weeks. Immunoreactivity to vimentin was also markedly increased in astrocytes 48 hours after MPTP treatment. Striatal laminin immunoreactivity, however, appeared to be unaffected by drug treatment. GFAP protein levels increased to 196% and 287% of control 24 and 48 hours after MPTP treatment, respectively. Concomitantly, GFAP mRNA levels increased to 470% and 1700% of control, respectively. These reactive changes in striatal astrocytes in response to MPTP treatment were also accompanied by a reactive microglial response as evidenced by increased immunohistochemical visualization of striatal microglia using antibodies to Mac-1. My results and those reported previously by O'Callaghan et al strongly suggest that MPTP-induced reactive gliosis in mouse striatum is associated with reactive microglia, albeit without increased interleukin-1beta. The second part and main emphasis of my work involves the initial characterization of a genetically-engineered hybrid protein which may prove to be useful in preventing/ameliorating free radical damage to neurons. Increased levels of Cu/Zn superoxide dismutase (SOD-1) are cytoprotective in experimental models for free radical-induced neurological disorders. Targeted delivery of SOD-1 to central nervous system neurons may therefore provide therapeutic benefit. The nontoxic C-fragment of tetanus toxin (TTC) possesses the nerve cell binding/transport properties of tetanus holotoxin, and has been used as a vector to enhance the neuronal uptake of proteins including enzymes. I have produced a recombinant hybrid protein in E. coli tandemly joining human SOD-1 to TTC. The expressed hybrid protein (SOD:Tet451) has a subunit molecular weight of 68 kD and is recognized by both anti-SOD-1 and anti-TTC antibodies. Calculated per mole, SOD:Tet451 has approximately 60% of the expected SOD-1 enzymatic activity. Analysis of the hybrid protein's interaction with the neuron-like cell line, N18-RE-105, and cultured hippocampal neurons by enzyme immunoassay for human SOD-1 revealed that SOD:Tet451 association with cells was neuron-specific and dose-dependent. The hybrid protein was also internalized, but substantial washout of internalized hybrid protein occurred over the first 24 hours. There was a modest elevation of total SOD enzyme activity in N18-RE-105 cells treated with relatively high concentrations of SOD:Tet451. These results suggest that human SOD-1 and TTC retain their respective functional properties when expressed together as a single peptide. SOD:Tet451 may therefore prove to be a useful agent for the targeted delivery of SOD-1 to neurons.