title: Targeted delivery of erythropoietin by transcranial focused ultrasound for neuroprotection against ischemia/reperfusion-induced neuronal injury: a long-term and short-term study.
abstract: Erythropoietin (EPO) is a neuroprotective agent against cerebral ischemia/reperfusion (I/R)-induced brain injury. However, its crossing of blood-brain barrier is limited. Focused ultrasound (FUS) sonication with microbubbles (MBs) can effectively open blood-brain barrier to boost the vascular permeability. In this study, we investigated the effects of MBs/FUS on extending the therapeutic time window of EPO and its neuroprotective effects in both acute and chronic phases. Male Wistar rats were firstly subjected to two common carotid arteries and right middle cerebral artery occlusion (three vessels occlusion, 3VO) for 50 min, and then the rats were treated with hEPO (human recombinant EPO, 5000 IU/kg) with or without MBs/FUS at 5 h after occlusion/reperfusion. Acute phase investigation (I/R, I/R+MBs/FUS, I/R+hEPO, and I/R+hEPO+MBs/FUS) was performed 24 h after I/R; chronic tests including cylinder test and gait analysis were performed one month after I/R. The experimental results showed that MBs/FUS significantly increased the cerebral content of EPO by bettering vascular permeability. In acute phase, both significant improvement of neurological score and reduction of infarct volume were found in the I/R+hEPO+MBs/FUS group, as compared with I/R and I/R+hEPO groups. In chronic phase, long-term behavioral recovery and neuronal loss in brain cortex after I/R injury was significantly improved in the I/R+hEPO+MBs/FUS group. This study indicates that hEPO administration with MBs/FUS sonication even at 5 h after occlusion/reperfusion can produce a significant neuroprotection.
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Sheng-Kai
authors.initials: SK
authors.lastname: Wu
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan ; Department of Pediatrics, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Ming-Tao
authors.initials: MT
authors.lastname: Yang
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Kai-Hsiang
authors.initials: KH
authors.lastname: Kang
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Houng-Chi
authors.initials: HC
authors.lastname: Liou
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Dai-Hua
authors.initials: DH
authors.lastname: Lu
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Fu
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan ; Division of Medical Engineering Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Win-Li
authors.initials: WL
authors.lastname: Lin
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D004921:Erythropoietin / Q000008:administration & dosage*; D005684:Gait / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D045423:Microbubbles; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D013016:Sound
chemical_list: C554270:EPO protein, human; D018696:Neuroprotective Agents; D004921:Erythropoietin