Focal cerebral ischemia in the TNFalpha-transgenic rat.

Background: To determine if chronic elevation of the inflammatory cytokine, tumor necrosis factor-alpha (TNFalpha), will affect infarct volume or cortical perfusion after focal cerebral ischemia.

Methods: Transgenic (TNFalpha-Tg) rats overexpressing the murine TNFalpha gene in brain were prepared by injection of mouse DNA into rat oocytes. Brain levels of TNFalpha mRNA and protein were measured and compared between TNFalpha-Tg and non-transgenic (non-Tg) littermates. Mean infarct volume was calculated 24 hours or 7 days after one hour of reversible middle cerebral artery occlusion (MCAO). Cortical perfusion was monitored by laser-Doppler flowmetry (LDF) during MCAO. Cortical vascular density was quantified by stereology. Post-ischemic cell death was assessed by immunohistochemistry and regional measurement of caspase-3 activity or DNA fragmentation. Unpaired t tests or analysis of variance with post hoc tests were used for comparison of group means.

Results: In TNFalpha-Tg rat brain, the aggregate mouse and rat TNFalpha mRNA level was fourfold higher than in non-Tg littermates and the corresponding TNFalpha protein level was increased fivefold (p
Conclusion: Chronic elevation of TNFalpha protein in brain increases susceptibility to ischemic injury but has no effect on vascular density. TNFalpha-Tg animals are more susceptible to apoptotic cell death after MCAO than are non-Tg animals. We conclude that the TNFalpha-Tg rat is a valuable new tool for the study of cytokine-mediated ischemic brain injury.