A selective, non-peptide caspase-1 inhibitor, VRT-018858, markedly reduces brain damage induced by transient ischemia in the rat.

Numerous preclinical studies have reported neuroprotective effects of new agents in animal studies. None of these agents has yet translated into a successful clinical trial and therefore to a new therapy. There are many possible reasons for this failure, including poor design of clinical trials, mismatch between preclinical and clinical protocols, and insufficient preclinical data. The enzyme caspase-1 has been implicated in neuronal death. Deletion of the caspase-1 gene, or administration of partially selective inhibitors, reduces neuronal injury induced by cerebral ischemia in rodents. We report here, for the first time, that VRT-018858, the non-peptide, active metabolite of the selective caspase-1 inhibitor pro-drug, pralnacasan, markedly reduced ischemic injury in rats. VRT-018858 was neuroprotective when delivered at 1 and 3h (42% and 58% neuroprotection, respectively) but not 6h after injury, and protection was sustained 7 days after the induction of ischemia (66% neuroprotection). These data confirm caspase-1 as an important target for intervention in acute CNS injury, and propose a new class of caspase-1 inhibitors as highly effective neuroprotective agents.

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.