Attenuation of intracerebral hemorrhage and thrombin-induced brain edema by overexpression of interleukin-1 receptor antagonist

Object. Adenovirus-mediated overexpression of interleukin-1 receptor antago nist (IL-1ra) attenuates the inflammatory reaction and brain injury that fo llows focal cerebral ischemia. Recently, an inflammatory reaction after int racerebral hemorrhage (ICH) was identified. In this study the authors exami ne the hypothesis that overexpression of IL-1ra reduces brain injury (speci fically edema formation) after ICH. Methods. Adenoviruses expressing IL-1ra (Ad.RSVIL-1ra) or LacZ, a control p rotein (Ad.RSVlacZ), or saline were injected into the left lateral cerebral ventricle in rats. On the 5th day after virus injection, 100 mul of autolo gous blood or 5 U thrombin was infused into the right basal ganglia. Rats w ith ICH were killed 24 or 72 hours later for measurement of brain water and ion content. Thrombin-treated rats were killed 24 hours later for edema me asurements and an assessment of polymorphonuclear leukocyte (PMNL) infiltra tion by myeloperoxidase (MPO) assay, as well as histological evaluation. Co mpared with saline-treated and Ad.RSVlacZ-transduced controls, Ad.RSVIL-1ra -transduced rats had significantly attenuated edema in the ipsilateral basa l ganglia 3 days after ICH (81.5 +/- 0.3% compared with 83.4 +/- 0.4% and 8 3.3 +/- 0.5% in control animals). Thrombin-induced brain edema was also red uced in Ad.RSVIL-1ra-treated rats (81.3 +/- 0.4% compared with 83.2 +/- 0.4 % and 82.5 +/- 0.4% in control rats). The reduction in thrombin-induced ede ma was associated with a reduction in PMNL infiltration into the basal gang lia, as assessed by MPO assay (49% reduction) and histological examination. Conclusions. Overexpression of IL-1ra by using an adenovirus vector attenua ted brain edema formation and thrombin-induced intracerebral inflammation f ollowing ICH. The reduction in ICH-induced edema with IL-1ra may result fro m reduction of thrombin-induced brain inflammation.