Protecting neurons from cerebral ischemia/reperfusion injury via nanoparticle-mediated delivery of an siRNA to inhibit microglial neurotoxicity

Ye Wang; Shi-Yong Li; Song Shen; Jun Wang

doi:10.1016/j.biomaterials.2018.01.039

Protecting neurons from cerebral ischemia/reperfusion injury via nanoparticle-mediated delivery of an siRNA to inhibit microglial neurotoxicity

Biomaterials. 2018 Apr:161:95-105. doi: 10.1016/j.biomaterials.2018.01.039. Epub 2018 Feb 6.

Authors

Ye Wang¹, Shi-Yong Li², Song Shen³, Jun Wang⁴

Affiliations

¹ Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, PR China.
² Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, PR China; Department of Cardiology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, PR China. Electronic address: sylicg@ustc.edu.cn.
³ Institutes for Life Sciences, School of Biomedical Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510006, PR China; National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou, Guangdong 510006, PR China.
⁴ Institutes for Life Sciences, School of Biomedical Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510006, PR China; National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou, Guangdong 510006, PR China; Research Institute for Food Nutrition and Human Health, Guangzhou, Guangdong 510006, PR China. Electronic address: mcjwang@scut.edu.cn.

PMID: 29421566
DOI: 10.1016/j.biomaterials.2018.01.039

Abstract

Complement component C3 (C3) plays a central role in microglial neurotoxicity following cerebral ischemia/reperfusion (I/R) injury. In this study, we focused on the role of nanoparticles loaded with C3 siRNA (NP_siC3) in inhibiting microglial neurotoxicity after brain (I/R) injury. NP_siC3 inhibited the hypoxia/re-oxygenation-induced increase in C3 expression in microglia in vitro. Importantly, treatment with NP_siC3 decreased C3b deposition on neurons and reduced microglia-mediated neuronal damage under hypoxia/re-oxygen conditions. Nanoparticles could effectively deliver C3-siRNA from the blood into ischemic penumbra across the blood-brain barrier (BBB) and significantly decrease C3 expression in microglia and ischemic brain tissue, while reducing the number of infiltrating inflammatory cells and the concentration of pro-inflammatory factors in the penumbra. Furthermore, NP_siC3 also prevented neuronal apoptosis, reduced the volume of the ischemic zone, and substantially improved functional recovery after I/R injury. Therefore, the NP_siC3-induced inhibition of microglial neurotoxicity represents a novel therapeutic strategy for treating brain I/R injury.

Keywords: Cerebral ischemia/reperfusion injury; Complement component 3; Microglia; Nanoparticles.

Publication types

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

MeSH terms

Animals
Cells, Cultured
Coculture Techniques
Complement C3 / antagonists & inhibitors
Immunohistochemistry
Leukocytes / metabolism
Male
Mice
Mice, Inbred C57BL
Microglia / drug effects
Nanoparticles / administration & dosage*
Nanoparticles / chemistry*
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / therapeutic use*
Reperfusion Injury / drug therapy*

Substances

Complement C3
RNA, Small Interfering