Liposome-Encapsulated Hemoglobin Reduces the Size of Cerebral Infarction in the Rat

Abstract

Background and Purpose-Liposome-encapsulated hemoglobin (LEH; TRM-645) is a novel oxygen (O 2 ) carrier with a lower O 2 affinity (P 50 O 2 ϭ40 mm Hg) than red blood cells. In contrast to cell-free hemoglobin, encapsulation prevents hemoglobin extravasation, whereas its subcellular size (230 nm) may improve O 2 delivery and limit the severity of cerebral infarction. Methods-The extent of cerebral infarction was determined 24 hours after photochemically induced thrombosis of the middle cerebral artery from the integrated area of infarction detected by triphenyltetrazolium chloride staining in rats receiving no treatment, 10 mL/kg of LEH, homologous blood, empty liposomes, or saline. To develop a dose-response relationship, LEH dose was reduced from 10 mL/kg to 2 mL/kg, 0.4 mL/kg, and 0.08 mL/kg. Results-Infarction extent was significantly suppressed in rats receiving LEH as compared with animals receiving no infusion, saline, empty liposome, or transfusion in the cortex but not in the basal ganglia, where all had similar degrees of damage. The dose-response relationship revealed that as little as 2 mL/kg of LEH was protective, whereas the total blood O 2 content, hemoglobin level, and transfusion and/or infusion of empty liposomes or saline were not effective. Conclusions-Our results suggest that LEH significantly reduces the area of infarction in the cortex but not in basal ganglia after photochemically induced thrombosis of the middle cerebral artery in the rat.

Post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin can reduce ischemia reperfusion injury

“…Since LEH can deliver oxygen more efficiently to peripheral tissues because of its smaller diameter (200-250 nm; 1/40th the size of RBC), several studies have attempted to assess the therapeutic effects of LEH on brain ischemia. Intravenous administration of LEH reduced the extent of infarction in the cortex of a rat thrombotic MCAO model (Kawaguchi et al, 2007;Fukumoto et al, 2009) and in a nonhuman primate transient MCAO model (Kawaguchi et al, 2010). Another therapeutic effect of LEH on cognitive impairment was revealed in the analysis of hippocampal dysfunction after transient two-vessel or four-vessel occlusion (Kakehata et al, 2007;Hamadate et al, 2009).…”

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

“…Several studies reported in the literature suggest the efficacy of Hb liposomes in the treatment of stroke by enhancing the biodistribution of Hb liposomes within the ischemic area in the brain. 144,145,147,[160][161][162][163][164]167,171,191,193,194 In the same way, liposomes for the delivery of angiogenic peptides 140 and VEGF 157 to promote angiogenesis in ischemic tissue were developed, and both formulations effectively promoted vascular regeneration. 140,157 Over the years, many liposomal formulations have been developed for the treatment of stroke.…”

Liposome-Encapsulated Hemoglobin Ameliorates Impairment of Fear Memory and Hippocampal Dysfunction After Cerebral Ischemia in Rats

“…LEH reduced the size of cerebral infarction in rats subjected to photochemically induced thrombosis (PIT) of the middle cerebral artery (MCA) (6,7) and also in primates treated with MCA occlusion (MCAO) (8). Transfusion of LEH rescued lethal progressive hemodilution and improved hemodilution-induced metabolic acidosis in rats (9).…”