INCREASED RELEASE OF TUMOR-NECROSIS-FACTOR-ALPHA INTO THE CEREBROSPINAL-FLUID AND PERIPHERAL-CIRCULATION OF AGED RATS

Background and Purpose. We earlier reported that risk factors for stroke prepare brain stem tissue for a modified Shwartzman reaction, including the development of ischemia and hemorrhage and the production of tumor necrosis factor-alpha, after a provocative dose of lipopolysaccharide. In the present study, we sought to determine whether blood and central nervous system cells of rats with the stroke risk factor of advanced age produce more proinflammatory and prothrombotic mediators than do those of young rats of the same strain. Methods: Levels of tumor necrosis factor-alpha and platelet activating factor in the cerebrospinal fluid and tumor necrosis factor-alpha in the serum of 2-year-old and 16-week-old Sprague-Dawley rats were monitored before and after challenge with lipopolysaccharide. Results: No consistent tumor necrosis factor-alpha activity was found in the cerebrospinal fluid or blood of control animals. Intravenous administration of lipopolysaccharide (1.8 mg/kg) increased serum tumor necrosis factor-alpha levels but had no effect on tumor necrosis factor-alpha in the cerebrospinal fluid. Serum tumor necrosis factor-alpha increased much more in aged rats than in young rats. When lipopolysaccharide was injected intracerebroventricularly, tumor necrosis factor-alpha activity in cerebrospinal fluid increased significantly more in old rats than in young rats. Baseline levels of platelet activating factor in cerebrospinal fluid were significantly higher in old rats than in young rats, and the levels increased to a greater degree in aged rats on stimulation. Conclusions. Rats with the stroke risk factor of advanced age respond to lipopolysaccharide with a more exuberant production of tumor necrosis factor-alpha and platelet activating factor than young rats of the same strain. These findings are consistent with our working hypothesis that perivascular cells are capable of exaggerated signaling of endothelium through cytokines such as tumor necrosis factor-alpha in animals with stroke risk factors. The effect of such signaling might be to prepare the endothelium of the local vascular segment for thrombosis or hemorrhage in accord with the local Shwartzman reaction paradigm.