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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and the accumulation of alpha-synuclein. Both traumatic brain injury (TBI) and pesticides are risk factors for PD, but whether TBI causes nigrostriatal dopaminergic cell loss in experimental models and whether it acts synergistically with pesticides is unknown. We have examined the acute and long-term effects of TBI and exposure to low doses of the pesticide paraquat, separately and in combination, on nigrostriatal dopaminergic neurons in adult male rats. In an acute study, rats received moderate TBI by lateral fluid percussion (LFP) injury, were injected with saline or paraquat (10 mg/kg IP) 3 and 6 days after LFP, were sacrificed 5 days later, and their brains processed for immunohistochemistry. TBI alone increased microglial activation in the substantia nigra, and caused a 15% loss of dopaminergic neurons ipsilaterally. Paraquat increased the TBI effect, causing a 30% bilateral loss of dopaminergic neurons, reduced striatal tyrosine hydroxylase (TH) immunoreactivity more than TBI alone, and induced alpha-synuclein accumulation in the substantia nigra pars compacta. In a long-term study, rats received moderate LFP, were injected with saline or paraquat at 21 and 22 weeks post-injury, and were sacrificed 4 weeks later. At 26 weeks post injury, TBI alone induced a 30% bilateral loss of dopaminergic neurons that was not exacerbated by paraquat. These data suggest that TBI is sufficient to induce a progressive degeneration of nigrostriatal dopaminergic neurons. Furthermore, TBI and pesticide exposure, when occurring within a defined time frame, could combine to increase the PD risk.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the accumulation of proteinaceous inclusions in defined pathological stages, the degeneration of nigrostriatal dopaminergic neurons and chronic central nervous system inflammation. PD is generally considered a disease of mixed etiology that strikes the aged. Age, genetic mutations, pesticide exposure, and traumatic brain injury (TBI) have been documented to increase the risk for developing PD. Rare genetic mutations that induce familial forms of PD all show incomplete penetrance. Epidemiological studies on environmental risk factors for PD have been unable to consistently document the same risk factors. The 'multiple-hit' hypothesis is a direct result of the inability of present research to identify a single factor or even a group of factors that cause PD. The 'multiple-hit' hypothesis suggests that PD is the result of multiple neuronal insults over a lifetime. In this work, I sought to evaluate the 'multiple-hit' hypothesis in rodent models of PD. Using immunohistochemistry and unbiased stereology it was determined that the overexpression of alpha-synuclein in transgenic mice does not increase the susceptibility of nigrostriatal dopaminergic neurons to paraquat or LPS induced toxicity. However, it was determined that paraquat induced the degeneration of nigrostriatal dopaminergic neurons in a ventral > medial > lateral gradient, mimicking the degenerative pattern in PD. Paraquat exposure from postnatal day 5-19 in mice had no effect on the nigrostriatal dopaminergic system at 3 or 6 months of age. The lateral fluid percussion injury (LFP) model of TBI in rats caused 15% loss of nigrostriatal dopaminergic neurons, ipsilateral to the side of injury. LFP also induced the bilateral activation of microglia in the substantia nigra (SN) and a bilateral reduction of tyrosine hydroxylase immunofluorescent intensity (TH-i) in the striatum. Subthreshold paraquat exposure 3 days post TBI induced a 30% bilateral a loss of nigrostriatal dopaminergic neurons and further reduced TH-i in the striatum. The combination of TBI and paraquat also induced the accumulation of alpha-synuclein in the SNc. Paraquat exposure did not induce nigrostriatal pathology in naïve animals. At 20 weeks post injury, TBI animals displayed deficits in gait marked by a decrease in stride length and an increase in stride width. At 26 weeks post injury, TBI induced a 30% bilateral loss of nigrostriatal dopaminergic neurons. Although subthreshold paraquat exposure at week 20 did not exacerbate dopaminergic cell loss, paraquat did reduce TH-i in the striatum of TBI animals 26 weeks post injury. Paraquat exposure did not increase TBI induced behavioral deficits at 26 weeks post injury. Pediatric TBI at postnatal day 19 induced the accumulation of alpha-synuclein and longterm microglial activation in the SNc 20 weeks post injury, well into adulthood. In a second cohort of animals, pediatric TBI induced deficits in gait; increased stride width and decreased stride length 20 weeks post injury. Pediatric TBI also induced preferences in paw use and motor deficits on the beam traversal; increasing the time to traverse the beam and the number of foot slips. Subthreshold paraquat exposure in pediatric TBI animals decreased stride width and increased the number of steps to traverse the balance beam. In summary, the experimental findings presented in this thesis support the 'multiple-hit' hypothesis. The data presented in this thesis are similar to epidemiological data on PD, where some combinations of risk factors can increase the risk for PD while other combinations of risk factors do not. This work has important implications in the study of PD as it is the first set of experiments describing the sensitization and degeneration of nigrostriatal dopaminergic neurons in an animal model of TBI.