INTERLEUKIN-1 AS A PATHOGENETIC MEDIATOR OF ISCHEMIC BRAIN-DAMAGE IN RATS

Background and Purpose It has been suggested that interleukin-1 (IL-1) is a potent inflammatory mediator and that it is synthesized and secr eted into the brain parenchyma. The aim of the present study is to eva luate the contribution of IL-1 to brain edema formation after focal br ain ischemia. Methods The brain water content was measured to evaluate postischemic brain injury in rats after 60 minutes of middle cerebral artery occlusion and reperfusion. The effects of exogenous applicatio n of recombinant human interleukin-1 beta (rhIL-1 beta), anti-interleu kin-1 beta neutralizing antibodies (anti-IL-1 beta), and the IL-1 bloc ker zinc protoporphyrin (ZnPP) on brain water content were observed, a nd histological technique was used to measure the infarction size and number of inflammatory cells infiltrated into the brain. Results Trans ient ischemia induced marked increase of brain water content, necrosis , and neutrophilic infiltration in the cortex perfused by the middle c erebral artery and the dorsal and ventral areas of the caudate putamen . Injection of rhIL-1 beta into the left lateral ventricle immediately after reperfusion markedly enhanced ischemic brain edema formation in these three areas in a dose-dependent manner (85.4+/-0.7% and 86.6+/- 0.4% in the dorsal and ventral parts of the caudate putamen, respectiv ely, in rats treated with 10 ng rhIL-1 beta; P<.01). rhIL-1 beta also increased the size of the brain infarction, and it tended to increase the number of infiltrating neutrophils in ischemic areas and the numbe r of neutrophils adherent to the endothelium. In contrast, administrat ion of anti-IL-1 beta and ZnPP into the left cerebral ventricle attenu ated the postischemic increase of brain water content and decreased th e size of brain infarction (83.5+/-2.0% and 79.9+/-2.0% in the dorsal and ventral parts of the caudate putamen, respectively, in rats treate d with 10 mu g anti-IL-1 beta; P<.01). The number of neutrophils that infiltrated into ischemic areas also tended to decrease with anti-IL-1 beta or ZnPP treatment. Conclusions Application of rhIL-1 beta augmen ted the increase of brain water content, and application of anti-IL-1 beta depressed the increase of water content. These results tended to correlate with the neutrophilic infiltration into the parenchyma. It t hus appears that IL-1 beta may play an important role in ischemic brai n damage after reperfusion.