title: UPEI-100, a conjugate of lipoic acid and apocynin, mediates neuroprotection in a rat model of ischemia/reperfusion.
abstract: Previous work in our laboratory has provided evidence that preadministration of apocynin and lipoic acid at subthreshold levels for neuroprotection enhanced the neuroprotective capacity when injected in combination. Therefore, the present investigation was designed to determine whether a co-drug consisting of lipoic acid and apocynin functional groups bound by a covalent bond, named UPEI-100, is capable of similar efficacy using a rodent model of stroke. Male rats were anesthetized with Inactin (100 mg/kg iv), and the middle cerebral artery was occluded for 6 h or allowed to reperfuse for 5.5 h following a 30-min occlusion (ischemia/reperfusion, I/R). Preadministration of UPEI-100 dose-dependently decreased infarct volume in the I/R model (P < 0.05), but not in the middle cerebral artery occlusion model of stroke. Using the optimal dose, we then injected UPEI-100 during the stroke or at several time points during reperfusion, and significant neuroprotection was observed when UPEI-100 was administered up to 90 min following the start of reperfusion (P < 0.05). A time course for this neuroprotective effect showed that UPEI-100 resulted in a decrease in infarct volume following 2 h of reperfusion compared with vehicle. The time course of this neuroprotective effect was also used to study several mediators along the antioxidant pathway and showed that UPEI-100 increased the level of mitochondrial superoxide dismutase and oxidized glutathione and decreased a marker of lipid peroxidation due to oxidative stress (HNE-His adduct formation). Taken together, the data suggest that UPEI-100 may utilize similar pathways to those observed for the two parent compounds; however, it may also act through a different mechanism of action.
authors.affiliation: Dept. of Biomedical Sciences, Atlantic Veterinary College, Univ. of Prince Edward Island, Charlottetown, P.E.I., Canada. tsaleh@upei.ca
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Connell
authors.forename: Monique C
authors.initials: MC
authors.lastname: Saleh
authors.forename: Bobby V
authors.initials: BV
authors.lastname: Khan
authors.forename: Desikan
authors.initials: D
authors.lastname: Rajagopal
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Saleh
mesh_terms: D000098:Acetophenones / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D019803:Glutathione Disulfide / Q000096:biosynthesis; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D013482:Superoxide Dismutase / Q000096:biosynthesis; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000098:Acetophenones; D015415:Biomarkers; D018696:Neuroprotective Agents; C572358:UPEI-100; D008063:Thioctic Acid; C056165:acetovanillone; D013482:Superoxide Dismutase; D019803:Glutathione Disulfide