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

Abstract

Object. Adenovirus-mediated overexpression of interleukin-1 receptor antagonist (IL-1ra) attenuates the inflammatory reaction and brain injury that follows focal cerebral ischemia. Recently, an inflammatory reaction after intracerebral hemorrhage (ICH) was identified. In this study the authors examine the hypothesis that overexpression of IL-1ra reduces brain injury (specifically edema formation) after ICH. Methods. Adenoviruses expressing IL-1ra (Ad.RSVIL-1ra) or LacZ, a control protein (Ad.RSVlacZ), or saline were injected into the left lateral cerebral ventricle in rats. On the 5th day after virus injection, 100 µl of autologous blood or 5 U thrombin was infused into the right basal ganglia. Rats with 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 measurements and an assessment of polymorphonuclear leukocyte (PMNL) infiltration by myeloperoxidase (MPO) assay, as well as histological evaluation. Compared with saline-treated and Ad.RSVlacZ—transduced controls, Ad.RSVIL-1ra-transduced rats had significantly attenuated edema in the ipsilateral basal ganglia 3 days after ICH (81.5 ± 0.3% compared with 83.4 ± 0.4% and 83.3 ± 0.5% in control animals). Thrombin-induced brain edema was also reduced 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 edema was associated with a reduction in PMNL infiltration into the basal ganglia, as assessed by MPO assay (49% reduction) and histological examination. Conclusions. Overexpression of IL-1ra by using an adenovirus vector attenuated brain edema formation and thrombin-induced intracerebral inflammation following ICH. The reduction in ICH-induced edema with IL-1ra may result from reduction of thrombin-induced brain inflammation.