title: UPEI-300, a conjugate of lipoic acid and edaravone, mediates neuroprotection in ischemia/reperfusion.
abstract: Edaravone, an electron spin trapper with radical scavenging activity, has been shown to be effective in reducing infarct volume in humans following ischemic stroke. However, concerns of edaravone-induced renal toxicity have limited its clinical adoption. Previous work has demonstrated that edaravone produced significant neuroprotection when injected prior to a period of ischemia and/or reperfusion. The current investigation was designed to determine if a newly synthesized co-drug consisting of lipoic acid and edaravone, named UPEI-300, could produce neuroprotection in in vitro and/or an in vivo rodent model of stroke. UPEI-300 produced dose-dependent neuroprotection in vitro and was subsequently tested in vivo. Male rats were anaesthetized and the middle cerebral artery was occluded for 30 min followed by 5.5 h of reperfusion (ischemia/reperfusion; I/R). Pre-administration of UPEI-300 dose-dependently decreased infarct volume. Significant neuroprotection was also observed when UPEI-300 (1.0 mg/kg) was injected during the 30 min period of ischemia as well as up to 60 min following the start of reperfusion. These results indicate that a co-drug consisting of edaravone and lipoic acid is a potent neuroprotectant, and clinically, the use of such a novel co-drug following an ischemic stroke might maintain neuroprotection while potentially decreasing edaravone associated renal toxicity.
authors.affiliation: Dept. of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Connell
authors.affiliation: Dept. of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3.
authors.forename: Monique C
authors.initials: MC
authors.lastname: Saleh
authors.affiliation: Department of Chemistry, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3.
authors.forename: Inan
authors.initials: I
authors.lastname: Kucukkaya
authors.affiliation: Department of Chemistry, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3.
authors.forename: Alaa S
authors.initials: AS
authors.lastname: Abd-El-Aziz
authors.affiliation: Dept. of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3; Carmel BioSciences, 5673 Peachtree Dunwoody Road, Atlanta, GA 30342, USA.
authors.forename: Bobby V
authors.initials: BV
authors.lastname: Khan
authors.affiliation: Dept. of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3. Electronic address: tsaleh@upei.ca.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Saleh
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004338:Drug Combinations; D008297:Male; D019579:Neocortex / Q000166:cytology; D009457:Neuroglia / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D020521:Stroke / Q000473:pathology / Q000517:prevention & control*; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D004338:Drug Combinations; D018696:Neuroprotective Agents; C000592133:UPEI-300; D008063:Thioctic Acid; D000983:Antipyrine
keywords: Antioxidant; Co-drug; Middle cerebral artery occlusion; Oxidative stress; Reperfusion injury; Stroke