title: A selective, non-peptide caspase-1 inhibitor, VRT-018858, markedly reduces brain damage induced by transient ischemia in the rat.
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 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.
authors.affiliation: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Jerard
authors.initials: J
authors.lastname: Ross
authors.forename: David
authors.initials: D
authors.lastname: Brough
authors.forename: Rosemary M
authors.initials: RM
authors.lastname: Gibson
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Loddick
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Rothwell
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001784:Blood Gas Analysis; D001925:Brain Damage, Chronic / Q000473:pathology* / Q000517:prevention & control*; D061945:Caspase Inhibitors; D003627:Data Interpretation, Statistical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001381:Azepines; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D018696:Neuroprotective Agents; C525665:VRT 018858