Post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin can reduce ischemia reperfusion injury.
Despite successful revascularization, reperfusion after prolonged ischemia causes ischemia reperfusion (I/R) injury. Recruitment and activation of neutrophils is thought to be a key event causing I/R injury. We examined whether post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin (LEH), an artificial oxygen carrier without neutrophils, could reduce I/R injury in a rat transient middle cerebral artery occlusion (MCAO) model. Male Sprague-Dawley rats were subjected to 2-h MCAO and then were divided into three groups: (1) LEH group (n=7) infused with LEH (Hb concentration of 6g/dl, 10ml/kg/h) through the recanalized internal carotid artery for 2h, (2) vehicle group (n=8) infused with saline (10ml/kg/h) in the same manner as the LEH group, and (3) control group (n=9) subjected to recanalization only. After 24-h reperfusion, all rats were tested for neurological score and then sacrificed to examine infarct and edema volumes, myeloperoxidase (MPO) expression, matrix metalloproteinase-9 (MMP-9) expression and activity, and reactive oxygen species (ROS) production. Compared with the control group and the vehicle group, the LEH group showed a significantly better neurological score and significantly smaller infarct and edema volumes. MPO expression, MMP-9 expression and activity, and ROS production in the LEH group were also significantly lower than those in the control and vehicle groups. The results in the present study suggest that post-ischemic intra-arterial infusion of LEH can reduce I/R injury through reducing the effect of MMP-9, most likely produced by neutrophils. This therapeutic strategy may be a promising candidate to prevent I/R injury after thrombolysis and/or thromboectomy.
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Daisuke
D
Shimbo
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. Electronic address: abumiya@med.hokudai.ac.jp.
Takeo
T
Abumiya
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Hideo
H
Shichinohe
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Naoki
N
Nakayama
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Ken
K
Kazumata
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Kiyohiro
K
Houkin
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002343:Carotid Artery, Internal; D004487:Edema / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006454:Hemoglobins / Q000627:therapeutic use*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D007261:Infusions, Intra-Arterial; D008081:Liposomes / Q000627:therapeutic use*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D012720:Severity of Illness Index
D000447:Aldehydes; D006454:Hemoglobins; D008081:Liposomes; D017382:Reactive Oxygen Species; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; C027576:4-hydroxy-2-nonenal
Artificial oxygen carrier; Ischemia reperfusion injury; MMP-9; Neutrophil