We have previously shown that 2-acetylcyclopentanone (2-ACP), an enolate-forming 1,3-dicarbonyl compound, provides protection in cell culture and animal models of oxidative stress. The pathophysiology of ischemia-reperfusion injury (IRI) involves oxidative stress and, therefore, we determined the ability of 2-ACP to prevent this injury in a rat liver model. IRI was induced by clamping the portal vasculature for 45 min (ischemia phase) followed by re-circulation for 180 min (reperfusion phase). This sequence was associated with substantial derangement of plasma liver enzyme activities, histopathological indices and markers of oxidative stress. 2-ACP (0.80-2.40mmol/kg), administered by intraperitoneal (i.p.) injection 10 min prior to reperfusion, provided dose-dependent cytoprotection as indicated by normalization of the IRI-altered liver histological and biochemical parameters. 2-ACP (2.40mmol/kg) was also hepatoprotective when injected before clamping the circulation (ischemia phase). In contrast, an equimolar dose of N-acetyl cysteine (NAC; 2.40mmol/kg) was not hepatoprotective when administered prior to reperfusion. Our studies to date suggest that during reperfusion the enolate nucleophile of 2-ACP limits the consequences of mitochondrial-based oxidative stress through scavenging unsaturated aldehyde electrophiles (e.g., acrolein) and chelation of metal ions that catalyze the free radical generating Fenton reaction. The ability of 2-ACP to reduce IRI when injected prior to ischemia likely reflects the short duration of this experimental phase (45 min) and favorable pharmacokinetics that maintain effective 2-ACP liver concentrations during subsequent reperfusion. These results provide evidence that 2-ACP or an analogue might be useful in treating IRI and other conditions that have oxidative stress as a common molecular etiology.
- covalent drug binding
- drug discovery
- ischemia / reperfusion injury
- liver injury
- oxidative stress
- The American Society for Pharmacology and Experimental Therapeutics