Attenuation of temporary focal cerebral ischemic injury in the mouse following transfection with interleukin-1 receptor antagonist

The proinflammatory cytokine interleukin-1 beta (IL-1 beta) is thought to p lay an important role in the stimulation of the inflammatory response follo wing ischemia and reperfusion, This study investigated the inflammatory eff ect of IL-1 beta during transient focal cerebral ischemia and reperfusion i n the mouse transduced with the interleukin-l receptor antagonist (IL-1ra) gene. An adenoviral vector encoding, either the human IL-1ra gene (AdRSVIL- 1ra) or the LacZ gene (AdRSVlacZ) or normal saline, were injected into the right lateral ventricles of adult CD-1 mice (n = 96). Five days later, the mice received 1 h temporary middle cerebral artery occlusion (tMACAO) follo wed by 23 h reperfusion. Cerebral blood flow (CBF), infarct volume, blood-b rain barrier (BBB) permeability, and the number of intracellular adhesion m olecule-1 positive vessels were measured to determine the effect of IL-1 be ta during postischemic reperfusion, Infarct volume in the AdRSVIL-1ra-trans duced mice was markedly reduced compared to the AdRSVlacZ-transduced and sa line-injected mice (36.0 +/- 5.3 mm(3) vs. 60.0 +/- 6.2 mm(3), 69.5 +/- 6.3 mm(3), after 23 h of reperfusion, n = 6-8 per group, p < 0.05). BBB disrup tion and intracellular adhesion molecule-1 expression (135 +/- 23 vs. 311 /- 40 and 357 +/- 51, n = 6-8 per group, p < 0.05) in the AdRSVIL-1ra-trans duced mice were also less than that of the AdRSVlacZ-transduced and saline- injected mice. Our studies demonstrated that overexpression of IL-1ra in th e mouse brain can downregulate intracellular adhesion molecule-1 expression both in the cortex and basal ganglia, which suggests that IL-1 beta may pl ay an important role in the activation of the inflammatory response during focal cerebral ischemia by promoting leukocyte adhesion to endothelial cell s. The decrease of BBB disruption in AdRSVIL-1ra-transduced mice suggests t hat the endothelial cells may be a target for IL-1 beta during postischemic reperfusion. (C) 1999 Elsevier Science B.V. All rights reserved.