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

Jerard Ross, David Brough, Rosemary M. Gibson, Sarah A. Loddick, Nancy J. Rothwell

Research output: Contribution to journalArticlepeer-review

Abstract

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 3 h (42% and 58% neuroprotection, respectively) but not 6 h 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. © 2007 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)638-642
Number of pages4
JournalNeuropharmacology
Volume53
Issue number5
DOIs
Publication statusPublished - Oct 2007

Keywords

  • Brain
  • Caspase-1
  • Cerebral ischemia
  • IL-1

Research Beacons, Institutes and Platforms

  • Dementia@Manchester

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