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 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.

Phloretin cytoprotection and toxicity

“…In contrast, the 1,3-dicarbonyl enols (e.g., 2-ACP) and polyphenols (e.g., THA) are stable, non-toxic and relatively water soluble compounds (Ballantyne and Cawley, 2001; LoPachin et al, 2011; Zhang et al, 2013). Our present findings and recent studies demonstrating the ability of enolate-forming compounds to inhibit liver ischemia/reperfusion injury (Kosharskyy et al, 2015) suggest that 2-ACP, THA, PG and other enolate-forming derivatives might be viable platforms for development of new pharmacotherapeutic approaches to diseases, injury states or drug-induced toxicities that involve electrophile-mediated cellular damage.…”

Albumin Cys34 adducted by acrolein as a marker of oxidative stress in ischemia-reperfusion injury during hepatectomy

“…These compounds ionize in aqueous solutions to form nucleophilic enolate anions, which can form 1,4-Michael adducts with ACR, HNE and other electrophilic unsaturated aldehydes involved in the oxidative stress-induced injury. Recently, it has been found that 2-ACP reduces the liver I/R damage in dosedependent manner by sequestering electrophilic species and in particular ACR, as indicated by the normalization of the I/R-altered liver histologic and biochemical parameters [40]. Hence, our results demonstrate that ACR is produced also in the liver I/R damage and, although partially neutralized by albumin and endogenous detoxificants, it can induce a damaging action.…”

Therapeutic potential of N-acetylcysteine in acrylamide acute neurotoxicity in adult zebrafish

“…Acrylamide (ACR), a water-soluble type-2 alkene, is used in different processes in the paper, textile, and cosmetics industry, as soil conditioner in mineral processing and mining, and as chemical sewer in grouting operations 1 . ACR induces neurotoxicity by depleting cellular glutathione (GSx) levels and by forming Michael type adducts with functionally critical nucleophilic sulfhydryl thiolate groups on cysteine residues of proteins in the synaptic terminals 2,3 . The loss of function of some relevant proteins directly involved in the synaptic vesicles recycling finally results in an altered synaptic function 3 .…”