Aged mice exhibit greater mortality concomitant to increased brain and plasma TNF-alpha levels following intracerebroventricular injection of lipopolysaccharide

Background: Age-related defects in the development of peripheral inflammato ry responses have been observed in rodents and humans. Objective: We examin ed the effects of age on a centrally injected endotoxin-induced cytokine pr oduction and cellular activation in mice. Methods: Male C57BL/6J (B6) mice, C3H/HeN mice, and C3H/HeJ mice received an intracerebroventricular injecti on of lipopolysaccharide (LPS) and were sacrificed at various times (2, 4, 8 h) thereafter. ELISA for IL-1 beta, IL-6, IL-12, and TNF-alpha were condu cted on forebrain tissue homogenates as well as plasma samples, and lectin staining to detect activated microglia was prepared for selected brain slic es. Results: Intracerebroventricular injection of LPS in B6 mice produced a n age-associated increase in mortality which was paralleled with a signific ant increase in brain and plasma levels of TNF-alpha. Anti-TNF-alpha-and IL -6-immunoreactive cells possessed macrophage-like morphologies and were obs erved along the LPS injection tract and scattered throughout the hilus of t he dorsal hippocampus and cerebral cortices. This LPS-mediated response was found to be specific in that the LPS-hyporesponsive mouse strain (C3H/HeJ) failed to demonstrate significant brain or plasma levels of TNF-alpha afte r LPS administration compared to C3H/HeN mice. Conclusion: These results su ggest that the age-related increases in TNF-alpha production and mortality following the intracerebroventricular administration of LPS may be due to a n increased endotoxin hypersensitivity of brain microglia/macrophages withi n aged animals. Copyright (C) 2000 S. Karger AG, Basel.