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

Abstract

Abstract. Liposome-encapsulated hemoglobin (LEH) has been developed as a blood substitute. In spite of its size (1/30 -1/40 of erythrocytes), LEH has an oxygen-carrying capacity comparable to erythrocytes. Thus, LEH is expected to carry oxygen into vital organs via collateral routes during ischemia induced by vascular embolism. In the present study, we examined the therapeutic effects of LEH on behavioral impairments in rats after four-vessel occlusion (4VO) for 30 min. In the open-field test, locomotor activity in 4VO rats did not alter 7 days after ischemia. However, in the contextual fear conditioning (CFC) test, the freezing rate was significantly decreased in 4VO rats, although no behavioral changes in the Y-maze test and elevated plus-maze test were observed. Phosphorylation of the cyclic AMP response element-binding protein (CREB) in the hippocampal CA1 region after the CFC test was attenuated. These 4VO-induced impairments were significantly alleviated by the administration of LEH (5 ml/kg, i.v.) during occlusion. Moreover, LEH did not alter hippocampal blood flow and tissue oxygen pressure during 4VO, but it did suppress hyperoxia after ischemia-reperfusion. These findings suggest that LEH, an artificial oxygen carrier, could be a novel therapeutic agent for brain dysfunction after acute cerebral ischemia.

Effects of Liposome-Encapsulated Hemoglobin on Learning Ability in Tokai High-Avoider Rat After Total Brain Ischemia and Reperfusion

“…Although these observations may appear contradictory, they might be compatible with our previous observations on focal brain ischemia, where LEH was protective largely in the cortex but not as much in the basal ganglia . Such observation may also be compatible with the results of Hamadate , who demonstrated the benefits of l ‐LEH treatment in a four‐vessel occlusion model in the rat. The traditional model , however, is not the same as the current model in that the occluded vertebral arteries might have reperfused by the time of carotid artery occlusion 7 days later when newly developed collaterals might have prevented whole‐brain ischemia, but rather created a situation similar to partial ischemia.…”

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.…”

Estradiol protects against hippocampal damage and impairments in fear conditioning resulting from transient global ischemia in mice

“…For example, performance on the hippocampally-dependent water maze task is impaired in ischemic rats (Block and Schwarz, 1997; Block and Schwarz, 1998; Hagan and Beaughard, 1990; Jaspers et al, 1990; Nelson et al, 1997; Netto et al, 1993; Nunn et al, 1994; Olsen et al, 1994a; Olsen et al, 1994b; Wright et al, 1996). Likewise, rats subjected to transient global ischemia via four-vessel occlusion exhibit impairments in contextual fear conditioning (Hamadate et al, 2010; Mori et al, 2001). …”