Targeted delivery of erythropoietin by transcranial focused ultrasound for neuroprotection against ischemia/reperfusion-induced neuronal injury: a long-term and short-term study

Sheng-Kai Wu; Ming-Tao Yang; Kai-Hsiang Kang; Houng-Chi Liou; Dai-Hua Lu; Wen-Mei Fu; Win-Li Lin

doi:10.1371/journal.pone.0090107

Targeted delivery of erythropoietin by transcranial focused ultrasound for neuroprotection against ischemia/reperfusion-induced neuronal injury: a long-term and short-term study

PLoS One. 2014 Feb 28;9(2):e90107. doi: 10.1371/journal.pone.0090107. eCollection 2014.

Authors

Sheng-Kai Wu¹, Ming-Tao Yang², Kai-Hsiang Kang³, Houng-Chi Liou³, Dai-Hua Lu³, Wen-Mei Fu³, Win-Li Lin⁴

Affiliations

¹ Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan.
² Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan ; Department of Pediatrics, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
³ Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁴ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal / drug effects
Blood-Brain Barrier / metabolism
Brain Ischemia / drug therapy*
Brain Ischemia / pathology
Drug Delivery Systems / instrumentation
Drug Delivery Systems / methods*
Erythropoietin / administration & dosage*
Gait / drug effects
Infarction, Middle Cerebral Artery
Male
Microbubbles
Neurons / drug effects*
Neurons / pathology
Neuroprotective Agents / administration & dosage*
Rats
Rats, Wistar
Reperfusion Injury / drug therapy*
Reperfusion Injury / pathology
Sound

Substances

EPO protein, human
Neuroprotective Agents
Erythropoietin

Grants and funding

This work was supported by research grants from the National Science Council of Taiwan (NSC 99-2221-E-002-005-MY3) and National Health Research Institutes of Taiwan (NHRI ME-100-PP-13). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.