title: Effect of Oxygen Affinity of Liposome-Encapsulated Hemoglobin on Cerebral Ischemia and Reperfusion as Detected by Positron Emission Tomography in Nonhuman Primates.
abstract: We tested a hypothesis that liposome-encapsulated hemoglobin (LEH) with high oxygen (O2) affinity (h-LEH, P50O2= 10 mm Hg) may work better than LEH with low O2affinity (l-LEH, P50O2= 40 mm Hg) in cerebral ischemia and reperfusion injury using positron emission tomography (PET) in primates undergoing middle cerebral artery (MCA) occlusion and reperfusion. Cerebral blood flow (CBF), O2extract fraction (OEF), and cerebral metabolic rate of O2(CMRO2) were successively determined by PET before ischemia, at 2 h of ischemia, immediately after reperfusion, and 3 h after reperfusion. Five minutes after MCA occlusion, 10 mL/kg of h-LEH (n = 6) was intravenously infused and compared with the results from previous data of monkeys treated with l-LEH (n = 6), empty liposome (n = 4), or saline (n = 8) as control. After the series of PET studies, the integrated area of cerebral infarction was determined histologically in 12 coronal brain slices. There was no significant difference in CBF, OEF, or CMRO2up to 2 h of ischemia. A high CBF with a low OEF tended to be suppressed after reperfusion in LEH-treated monkeys. Three hours after reperfusion, the area of mild CMRO2reduction (down to -30%) decreased (P < 0.05) and the area of mild CMRO2increase (up to 30%) expanded in LEH-treated monkeys (P < 0.05) regardless of O2affinity with no difference in the area of moderate-to-severe reduction (<-30%) or increase (<+30%) in CMRO2compared to animals treated with empty liposome or saline. Distribution of CMRO2reduction and histological damages showed that LEH mainly protected the cerebral cortex rather than basal ganglia where neuronal dendritic processes were severely lost. There was little difference between the animals treated with l-LEH or h-LEH both at 10 mL/kg or between treatment with empty liposome or saline. In conclusion, LEH was effective regardless of O2affinity in preserving CMRO2and in reducing the area of histological damage in the cerebral cortex, but not in basal ganglia, shortly after occlusion/reperfusion of MCA in monkey.
authors.affiliation: Tokai University School of Medicine, Kanagawa.
authors.forename: Akira T
authors.initials: AT
authors.lastname: Kawaguchi
authors.affiliation: Osaka Prefecture University, Osaka.
authors.forename: Mariko
authors.initials: M
authors.lastname: Yamano
authors.affiliation: Tokai University Junior College of Nursing and Medical Technologies, Hiratsuka.
authors.forename: Munetaka
authors.initials: M
authors.lastname: Haida
authors.affiliation: Hamamatsu Photonics Co. Ltd., Shizuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohba
authors.affiliation: Hamamatsu Photonics Co. Ltd., Shizuoka, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Kakiuchi
authors.affiliation: Hamamatsu Photonics Co. Ltd., Shizuoka, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
mesh_terms: D000818:Animals; D001802:Blood Substitutes / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002544:Cerebral Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D006454:Hemoglobins / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008081:Liposomes; D008252:Macaca fascicularis; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D049268:Positron-Emission Tomography; D015424:Reperfusion; D015427:Reperfusion Injury / Q000188:drug therapy*
chemical_list: D001802:Blood Substitutes; D006454:Hemoglobins; D008081:Liposomes; D010100:Oxygen
keywords: -Cerebral blood flow; -Encapsulated Hemoglobin; -Ischemia; -Oxygen affinity; -Reperfusion; Liposome