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.
Ross
Jerard
J
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
Brough
David
D
Gibson
Rosemary M
RM
Loddick
Sarah A
SA
Rothwell
Nancy J
NJ
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
D001381:Azepines; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D018696:Neuroprotective Agents; C525665:VRT 018858