title: UPEI-400, a conjugate of lipoic acid and scopoletin, mediates neuroprotection in a rat model of ischemia/reperfusion.
abstract: Previously, our laboratory provided evidence that lipoic acid (LA) covalently bonded to various antioxidants, resulted in enhanced neuroprotection compared to LA on its own. The naturally occurring compound scopoletin, a coumarin derivative, has been shown in various in vitro studies to have both antioxidant and anti-inflammatory mechanism of actions. The present investigation was designed to determine if scopoletin on its own, or a co-drug consisting of LA and scopoletin covalently bonded together, named UPEI-400, would be capable of demonstrating a similar neuroprotective efficacy. Using a rat stroke model, male rats were anesthetized (Inactin®; 100 mg/kg, iv), the middle cerebral artery was permanently occluded for 6 h (pMCAO), or in separate animals, occluded for 30 min followed by 5.5 h of reperfusion (ischemia/reperfusion; I/R). Pre-administration of either scopoletin or UPEI-400 significantly decreased infarct volume in the I/R model (p < 0.05), but not in the pMCAO model of stroke. UPEI-400 was ∼1000 times more potent compared to scopoletin alone. Since UPEI-400 was only effective in a model of I/R, it is possible that it may act to enhance neuronal antioxidant capacity and/or upregulate anti-inflammatory pathways to prevent the neuronal cell death.
authors.affiliation: Department of Biomedical Science, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, Canada.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Connell
authors.affiliation: Department of Biomedical Science, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, Canada.
authors.forename: Monique C
authors.initials: MC
authors.lastname: Saleh
authors.affiliation: Department of Chemistry & Pharmaceutical Chemistry, School of Advanced Sciences, VIT University, Vellore, India.
authors.forename: Desikan
authors.initials: D
authors.lastname: Rajagopal
authors.affiliation: Department of Biomedical Science, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, Canada; Department of Biomedical Science, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada. Electronic address: tsaleh@uoguelph.ca.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Saleh
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D012603:Scopoletin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020521:Stroke / Q000517:prevention & control*; D008063:Thioctic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; C000616633:UPEI-400; D008063:Thioctic Acid; D012603:Scopoletin
keywords: Animal model; Antioxidant; Co-drug; Reperfusion-injury; Stroke