Overexpression of interleukin-1 receptor antagonist in the mouse brain reduces ischemic brain injury

It has been reported that middle cerebral artery occlusion in rats causes overexpression of interleukin-l, and that administration of the interleukin-l receptor antagonist protein (IL-1ra) reduces ischemic brain injury. The aim of the present study is to determine whether a recombinant adenovirus vector carrying human interleukin-l receptor antagonist cDNA (Ad.RSVIL-1ra) could be used to overexpress IL-1ra in mouse brain and to evaluate its effect on brain edema formation and infarction after permanent focal ischemia in mice. Ad.RSVIL-1ra, control adenovirus containing the lacZ gene (Ad.RSVlacZ), or saline was injected into the right cerebral ventricle in mice. Brain IL-1ra concentrations were measured I to 13 days later. On the fifth day after virus injection, the middle cerebral artery was occluded for 24 h. Brain water content was determined and a histological technique was used to measure the infarction size. Overexpression of human IL-1ra protein in whole brain was confirmed by immunoassay in the Ad.RSVIL-1ra injected mice. It began on the first day, peaked at 5-7 days, and was sustained for 13 days. Brain edema and cerebral infarct volume were significantly reduced following 24 h of permanent middle cerebral artery occlusion in mice transfected with Ad.RSVIL-1ra compared to Ad.RSVlacZ or saline 5 days earlier. These studies demonstrate that adenoviral vectors can be used to deliver genes to small animals such as mice and also suggest the feasibility of gene therapy for stroke and other neurological diseases. Overexpression of human IL-1ra attenuated ischemic brain injury, suggesting that IL-1 may play an important role in cerebral ischemia.