Therapeutic Potentials of an Artificial Oxygen-Carrier, Liposome-Encapsulated Hemoglobin, for Ischemia/Reperfusion-Induced Cerebral Dysfunction in Rats

Abstract

Abstract. We performed this study to elucidate whether a newly developed liposome-encapsulated hemoglobin, TRM-645 (TRM), can prevent cerebral dysfunction resulting from acute ischemic stroke when used as an oxygen carrier. Hippocampal long-term potentiation (LTP) in the perforant path-dentate gyrus synapses and anxiety-related behaviors in the elevated plus-maze test were evaluated as indices of cerebral functional outcomes in the rat with two-vessel occlusion (2VO), which was induced by 10-min clamping of bilateral common carotid arteries. Saline or TRM (hemoglobin concentration of 6 g/dl: 2.5 or 5 ml/kg) was administered via the tail vein immediately after ischemic insult. Hippocampal LTP formation was markedly impaired and the open arm durations in the elevated plus-maze decreased significantly 4 days after 2VO, compared to those of sham-operated (control) rats, suggesting the hippocampal synaptic dysfunction and anxiogenic properties in 2VO rats. TRM (5 ml/kg) restored the hippocampal LTP formation and normalized the anxiety-related behavior. TRM also improved the decreased tissue oxygen partial pressure in the 2VO rat hippocampus, possibly due to oxygen delivery to ischemic regions. Liposomeencapsulated hemoglobin TRM might have therapeutic potentials for protecting the brain from neurological complications associated with acute ischemic stroke, as a promising blood substitute for oxygen therapy.

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.…”

Nanovesicular liposome-encapsulated hemoglobin (LEH) prevents multi-organ injuries in a rat model of hemorrhagic shock

“…We recently reported that resuscitation with LEH was able to restore the brain metabolism in the rats with hemorrhagic shock (Rao et al, 2015). Others have also reported similar recovery of cerebral function by LEH infusion (Kakehata et al, 2010; Kaneda et al, 2014; Tiwari et al, 2010). However, the brain is protected, to a certain extent, against hypoxia and hypoperfusion by virtue of a physiologic diversion of blood flow from peripheral vascular network into the cerebral supply.…”

Efficacy of Liposome-Encapsulated Hemoglobin in a Rat Model of Cerebral Ischemia

“…Given its physicochemical properties such as a small diameter and low viscosity, LEH has been studied not only as a blood substitute but also as a pharmacological agent for treating ischemic diseases. Several reports have demonstrated the efficacy of LEH in rat models of cerebral ischemia and in nonhuman primates . Furthermore, results of studies using imaging techniques in cerebral ischemia models indicated that LEH could distribute and deliver oxygen to ischemic tissues ; taken together, these results encourage the development of LEH for the treatment of ischemic stroke.…”