2-Acetylcyclopentanone, an enolate-forming 1,3-dicarbonyl compound, is cytoprotective in warm ischemia-reperfusion injury of rat liver

Boleslav Kosharskyy, Amaresh Vydyanathan, Lihai Zhang, Naum Shaparin, Brian C. Geohagen, William Bivin, Qiang Liu, Terrence Gavin, Richard M. LoPachin

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 mitochondrialbased 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.

Original languageEnglish (US)
Pages (from-to)150-158
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume353
Issue number1
DOIs
StatePublished - 2015

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Warm Ischemia
Reperfusion Injury
Liver
Reperfusion
Oxidative Stress
Ischemia
Constriction
Acrolein
Cytoprotection
2-acetylcyclopentanone
Acetylcysteine
Intraperitoneal Injections
Aldehydes
Free Radicals
Animal Models
Pharmacokinetics
Cell Culture Techniques
Metals
Ions
Wounds and Injuries

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Pharmacology

Cite this

2-Acetylcyclopentanone, an enolate-forming 1,3-dicarbonyl compound, is cytoprotective in warm ischemia-reperfusion injury of rat liver. / Kosharskyy, Boleslav; Vydyanathan, Amaresh; Zhang, Lihai; Shaparin, Naum; Geohagen, Brian C.; Bivin, William; Liu, Qiang; Gavin, Terrence; LoPachin, Richard M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 353, No. 1, 2015, p. 150-158.

Research output: Contribution to journalArticle

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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 mitochondrialbased 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.",
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