title: 2-Acetylcyclopentanone, an enolate-forming 1,3-dicarbonyl compound, is cytoprotective in warm ischemia-reperfusion injury of rat liver.
abstract: 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 minutes (ischemia phase), followed by recirculation for 180 minutes (reperfusion phase). This sequence was associated with substantial derangement of plasma liver enzyme activities, histopathological indices, and markers of oxidative stress. The 2-ACP (0.80-2.40 mmol/kg), administered by intraperitoneal injection 10 minutes prior to reperfusion, provided dose-dependent cytoprotection, as indicated by normalization of the IRI-altered liver histologic and biochemical parameters. The 2-ACP (2.40 mmol/kg) was also hepatoprotective when injected before clamping the circulation (ischemia phase). In contrast, an equimolar dose of N-acetylcysteine (2.40 mmol/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 most likely reflects the short duration of this experimental phase (45 minutes) and favorable pharmacokinetics that maintain effective 2-ACP liver concentrations during subsequent reperfusion. These results provide evidence that 2-ACP or an analog might be useful in treating IRI and other conditions that have oxidative stress as a common molecular etiology.
authors: Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.).
authors: Boleslav
authors: B
authors: Kosharskyy
authors: Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.).
authors: Amaresh
authors: A
authors: Vydyanathan
authors: Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.).
authors: Lihai
authors: L
authors: Zhang
authors: Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.).
authors: Naum
authors: N
authors: Shaparin
authors: Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.).
authors: Brian C
authors: BC
authors: Geohagen
authors: Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.).
authors: William
authors: W
authors: Bivin
authors: Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.).
authors: Qiang
authors: Q
authors: Liu
authors: Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.).
authors: Terrence
authors: T
authors: Gavin
authors: Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.) lopachin@einstein.yu.edu.
authors: Richard M
authors: RM
authors: LoPachin
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D019610:Cytoprotection; D006358:Hot Temperature; D007659:Ketones / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress; D011789:Quantum Theory; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: C583588:2-acetylcyclopentanone; D000447:Aldehydes; D007659:Ketones; D013385:Succinate Dehydrogenase; D000111:Acetylcysteine