Therapeutic potentials of an artificial oxygen-carrier, liposome-encapsulated hemoglobin, for ischemia/reperfusion-induced cerebral dysfunction in rats.
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. Liposome-encapsulated 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.
Kakehata
Jin
J
Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Japan.
Yamaguchi
Taku
T
Togashi
Hiroko
H
Sakuma
Ichiro
I
Otani
Hiroshi
H
Morimoto
Yuji
Y
Yoshioka
Mitsuhiro
M
D000818:Animals; D001802:Blood Substitutes / Q000494:pharmacology; D002545:Brain Ischemia / Q000628:therapy*; D017536:Carotid Artery, Common / Q000503:physiopathology; D018891:Dentate Gyrus / Q000098:blood supply / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006454:Hemoglobins / Q000494:pharmacology*; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D008081:Liposomes; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D010100:Oxygen / Q000494:pharmacology*; D010102:Oxygen Inhalation Therapy; D019580:Perforant Pathway / Q000098:blood supply / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000503:physiopathology / Q000628:therapy*; D020521:Stroke / Q000503:physiopathology; D013569:Synapses / Q000502:physiology
D001802:Blood Substitutes; D006454:Hemoglobins; D008081:Liposomes; D010100:Oxygen