The long term goal of this work is to identify inflammatory mechanisms underlying the neurodegeneration of Parkinson's disease so that target-specific therapeutics can be designed. Emerging evidence has led investigators to the hypothesis that inflammatory processes are involved in nigrostriatal degeneration which is the pathological hallmark of Parkinson's disease. They propose to determine the relationship between inflammatory cytokine activation and dopaminergic cell damage in the model of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-induced mouse nigrostriatal degeneration. While there is accumulating post-mortem data suggesting an ongoing immune activation in the parkinsonian substantia nigra, the role of the inflammatory cytokines, the mediators of the immune response, as well as the identity of the immunoeffector cells that produce them remain unclear. These multifunctional cytokines that regulate the inflammatory cascade are interleukin-lBeta (IL-1Beta), tumor necrosis factor alpha (TNFalpha) and IL-6. These cytokines may have both immunotoxic and neuroprotective activities in the CNS. This proposal is a first step in determining their role in nigrostriatal degeneration. Specifically the investigators will correlate striatal dopamine depletion with the induction of IL-1Beta, TNFalpha and IL-6 proteins in response to MPTP. Further, they will identify and quantify the immunoeffector cell(s) responsible for specific cytokine production in the striatum where dopaminergic projections are damaged and in the substantia nigra where cytokine production could affect dopaminergic neuron cell bodies. To analyze the mechanisms through which astrogliosis and microglia infiltration occur, they will examine glial growth factors and chemoattractants in primary cultures of astrocytes and microglia treated with MPTP. An understanding of inflammatory induction in the MPTP model will provide important clues as to the role of cytokines in neurodegenerative processes. This knowledge could then be applied to cytokine- and cell-specific strategies for anti-inflammatory therapeutic intervention in Parkinson's disease.
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| Cardenas, Hernan; Bolin, Laurel M (2003) Compromised reactive microgliosis in MPTP-lesioned IL-6 KO mice. Brain Res 985:89-97 |
| Bolin, Laurel M; Strycharska-Orczyk, Iwona; Murray, Richard et al. (2002) Increased vulnerability of dopaminergic neurons in MPTP-lesioned interleukin-6 deficient mice. J Neurochem 83:167-75 |
