Attenuation of Inflammatory Response in Progressive Neurodegeneration in Parkinson's Disease

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Parkinson's disease (PD), a progressive degenerative disorder, affects almost 80,000 Veterans. Since there is no cure, new therapies must be developed to halt disease progression. While the mechanisms of this degen- erative process remain elusive, chronic inflammation may be involved. Calpain activates microglia and T cells, induces T cell migration/chemotaxis, plays a pivotal role in spinal cord (SC) degeneration, and may be a driver of inflammation and disease progression. Preliminary data from MPTP mice and human PD samples showed infiltration of CD4+ and CD8+ T cells into SC and SN, increased CD4+ T cells in mouse splenocytes, and elevated serum cytokines/chemokines. An expanded subpopulation of cytotoxic CD4+ T cells was detected in splenocytes from MPTP mice and DSP-4/6OHDA-induced rats. Calpeptin (calpain inhibitor) treatment abolished this CD4+ subtype in MPTP mice, suggesting calpain's role in T cell activation and the CD4+ subtype may be critical in the inflammatory process. Chemokine receptor CCR-1 is a Ca2+ mobilizer and, importantly, can activate calpain. Since CCR-1 ligands (MIP-1α, RANTES) promote trafficking of T cells in SC, their role in inflammation was assessed. They were significantly reduced following treatment of MPTP mice with calpeptin, and behavioral function was remarkably improved. SC from PD patients revealed activation of microglia and astrocytes, infiltration of CD4+/CD8+ T cells, and increased calpain. Inhibition of primary microglia activation by Ca2+ ionophore by calpeptin and CCR-1 antagonist (BX471) produced marked reduction in cytokines/ chemokines, suggesting their potential as agents for treatment of MPTP-induced neurotoxicity. Thus, we hypothesize that calpain activation, infiltration of inflammatory T cells (Th1/Th17, CD8+), and released cytokines/chemokines are involved in progressive degeneration in PD, and calpain inhibitor and CCR-1 antagonist treatment may reduce degeneration, slow disease progression, and improve function. Three specific aims are proposed: (1) investigate the role of calpain regulation and T cell infiltration in SC degenera- tion and disease progression in MPTP mice, characterize infiltrating T cells, assess cytokine/chemokine levels in sera, and determine cell death parameters and calpain activation in SC; (2) examine infiltration of T cells and activation of microglia in SC from PD patients, characterize T cell subpopulations, and correlate with Specific Aim 1, determine chemokines/cytokines in serum from PD patients; and (3) examine whether treatment of MPTP mice with calpain inhibitors (calpeptin, SNJ1945) and BX471 alone or in combination will reduce inflam- matory events and degeneration and improve function, correlate with DigiGait analysis, and examine whether primary microglia activated by calcium ionophore upregulate chemokines/cytokines and can be controlled by calpeptin and BX471. The key finding of a CD4-subtype in MPTP mice will also be verified in rotenone and DSP-4/6OHDA rat models. The goal is to develop strategies for PD therapy with agents that block the inflam- matory process, protect neurons, control disease progression, and improve function.