A selective, non-peptide caspase-1 inhibitor, VRT-018858, markedly reduces brain damage induced by transient ischemia in the rat.
Neuropharmacology
; 53(5): 638-42, 2007 Oct.
Article
in En
| MEDLINE
| ID: mdl-17845807
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Azepines
/
Brain Damage, Chronic
/
Ischemic Attack, Transient
/
Enzyme Inhibitors
/
Caspase Inhibitors
/
Isoquinolines
Type of study:
Guideline
Limits:
Animals
Language:
En
Journal:
Neuropharmacology
Year:
2007
Document type:
Article
Affiliation country:
United kingdom