It is well known that autopsied brains from patients with Parkinson's disease (PD) show evidence of inflammation within the region of the brain thought to be responsible for PD Ã¢â‚¬" the substantia nigra (SN). This region of the brain contains nerves that secrete the chemical dopamine (DA). The nerve death process in the SN of PD patients leads to continued loss of DA neurons until the patient dies. The inflammation seen in the SN of these patients is thought to result from that cell death. Thus, when DA nerves die, they release other chemicals called proinflammatory cytokines that activate other cells called microglia cells that then engulf the nerve cell debris left when the DA nerves die. What is not known is if this inflammation leads to additional DA nerve cell death. More importantly, it is not known if inflammation actually precedes DA nerve cell death. If this were the case, treatments focused on reducing inflammation could be developed to prevent, or at least, reduce DA neuron death, and thereby extend the functional life of the PD patient. Preliminary data from animals in our laboratory suggest that inflammation actually precedes and contributes to DA nerve death. We contend that the brain is able to adjust to low levels of inflammation. As a result, there would be little DA nerve cell death. However, we believe that the brains of patients with PD already have a low level of inflammation as a result of prior exposure to certain environmental neurotoxins. As a result, a second neurotoxin exposure leads to a more profound inflammation response that cannot be adjusted to by the brain and this leads to further DA nerve cell death. This nerve death leads to further inflammation which leads to further DA nerve cell death and so on in a spiraling fashion. Each spiral turn leads to further DA nerve cell death producing further inflammation leading to further DA cell loss until sufficient cell loss occurs and PD symptoms emerge. This proposal will test this spiral inflammatory hypothesis of PD in rats exposed to common environmental toxins that could underlie the cause of PD. We will then monitor DA cell loss and several indices of inflammation in their brains in the weeks after that second exposure to determine if the brain adjusts to it, or exhibits a spiral pattern of inflammation and further DA neuron loss. If our results support the spiral inflammatory hypothesis, then therapies designed to break the cycling of this spiral should prevent PD progression.