Delayed administration of interleukin-1 receptor antagonist protects against transient cerebral ischaemia in the rat

The cytokine interleukin-1 (IL-1) has been implicated in ischaemic, excitotoxic and traumatic brain damage in rodents. The naturally occurring IL-1 receptor antagonist (IL-1ra) markedly reduces neuronal injury in these conditions. However, the effects of IL-1ra on focal, transient cerebral ischaemia in the rat, which is of major clinical relevance, have not been reported. The objectives of this study were to test the effects of IL-1ra on cell death after temporary cerebral ischaemia, and to investigate the therapeutic time window for IL-1ra treatment. Ischaemia was induced by temporary (60 min) occlusion of the middle cerebral artery (MCAO) in rats, via surgical insertion (and subsequent removal) of a thread into the internal carotid artery. Damage was quantified at various times after MCAO to investigate the temporal progression of damage and establish an appropriate time to assess the effects of IL-1ra on cell death. Cell death was complete 18-24 h after temporary MCAO. Intracerebroventricular injection of IL-1ra (10 microg) at the time of MCAO and 60 min later reduced the lesion volume measured 24 h (57% reduction) or 48 h (52% reduction) after MCAO. Cell death was also significantly reduced when IL-1ra (20 microg) was administered as a single injection, 1 h (47%), 2 h (57%) or 3 h (46%) after MCAO, when compared to vehicle. These data show that IL-1ra markedly reduces cell death even when administration is delayed until 3 h after induction of reversible, focal cerebral ischaemia in the rat, and support our proposal that IL-1ra may be of therapeutic benefit in stroke.