Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration

Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisirts are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNF alpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNF alpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFa increase that remained elevated for 10 months, while peripheral TNF alpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNF alpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNF alpha, MCP-1, IL-1 beta and NF-kappa B p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNF alpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevate roinflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease. (c) 2007 Wiley-Liss, Inc.