Intranasal delivery of an antisense oligonucleotide to the RNA-binding protein HuR relieves nerve injury-induced neuropathic pain

神经病理性疼痛 小胶质细胞 基因敲除 鼻腔给药 医学 促炎细胞因子 脊髓 p38丝裂原活化蛋白激酶 基因沉默 MAPK/ERK通路 分子生物学 癌症研究 化学 信号转导 药理学 免疫学 细胞生物学 生物 炎症 细胞凋亡 基因 生物化学 精神科
作者
Vittoria Borgonetti,Nicoletta Galeotti
出处
期刊:Pain [Lippincott Williams & Wilkins]
卷期号:162 (5): 1500-1510 被引量:43
标识
DOI:10.1097/j.pain.0000000000002154
摘要

Abstract Neuropathic pain remains an undertreated condition and there is a medical need to develop effective treatments. Accumulating evidence indicates that posttranscriptional regulation of gene expression is involved in neuropathic pain; however, RNA processing is not clearly investigated. Our study investigated the role of HuR, an RNA binding protein, in promoting neuropathic pain and trauma-induced microglia activation in the spared nerve injury mouse model. To this aim, an antisense oligonucleotide (ASO) knockdown of HuR gene expression was used. Antisense oligonucleotides poorly cross the blood–brain barrier and an intranasal (i.n.) administration was used to achieve central nervous system penetration through a noninvasive delivery. The efficacy of i.n. ASO administration was compared to an intrathecal (i.t.) delivery. I.n. administered ASO reduced spinal HuR protein and relieved pain hypersensitivity with a similar efficacy to i.t. administration. Immunofluorescence studies showed that HuR was expressed in activated microglia, colocalized with p38 and, partially, with extracellular signal-regulated kinase (ERK)1/2 within the spinal cord dorsal horn. An anti-HuR ASO inhibited the activation of spinal microglia by reducing the levels of proinflammatory cytokines, inducible nitric oxide synthase, the activation of nuclear factor-κB (NF-κB), and suppressed the spared nerve injury–induced overphosphorylation of spinal p38, ERK1/2 and c-Jun-N-terminal kinase (JNK)-1. In addition, HuR silencing increased the expression of the anti-inflammatory cytokine IL-10, promoting the shift of microglial M1 to M2 phenotype. Targeting HuR by i.n. anti-HuR ASO might represent a noninvasive promising perspective for neuropathic pain management by its powerful inhibition of microglia-mediated spinal neuroinflammation and promotion of an anti-inflammatory and neuroprotectant response.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
李健的小迷弟应助xifan采纳,获得10
刚刚
科研通AI5应助饱满小兔子采纳,获得10
刚刚
追寻的筝发布了新的文献求助10
刚刚
离夜发布了新的文献求助10
3秒前
1s发布了新的文献求助10
4秒前
4秒前
香蕉君达完成签到,获得积分10
4秒前
舒心的寻琴完成签到,获得积分10
5秒前
科研通AI5应助唾沫星子采纳,获得30
5秒前
斯文傲芙完成签到,获得积分10
6秒前
万能图书馆应助含蓄尔竹采纳,获得10
6秒前
6秒前
小蘑菇应助TTT采纳,获得10
7秒前
Hnuy完成签到,获得积分10
8秒前
8秒前
每天睡不醒完成签到,获得积分10
10秒前
11秒前
12秒前
充电宝应助结实的导师采纳,获得10
12秒前
12秒前
科研通AI5应助echo采纳,获得30
13秒前
13秒前
14秒前
fangfang完成签到,获得积分10
14秒前
sdd完成签到,获得积分10
14秒前
15秒前
15秒前
搜集达人应助insane采纳,获得10
16秒前
和谐代灵完成签到,获得积分10
16秒前
17秒前
橙树发布了新的文献求助10
17秒前
17秒前
含蓄尔竹发布了新的文献求助10
17秒前
嘟~完成签到,获得积分10
17秒前
加拿大一枝黄花完成签到,获得积分10
17秒前
丁真先生完成签到,获得积分10
17秒前
17秒前
18秒前
CipherSage应助kmoonkkk采纳,获得10
18秒前
爱在西元前完成签到,获得积分10
18秒前
高分求助中
【此为提示信息,请勿应助】请按要求发布求助,避免被关 20000
All the Birds of the World 4000
Production Logging: Theoretical and Interpretive Elements 3000
Musculoskeletal Pain - Market Insight, Epidemiology And Market Forecast - 2034 2000
Animal Physiology 2000
Am Rande der Geschichte : mein Leben in China / Ruth Weiss 1500
CENTRAL BOOKS: A BRIEF HISTORY 1939 TO 1999 by Dave Cope 1000
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 物理 生物化学 纳米技术 计算机科学 化学工程 内科学 复合材料 物理化学 电极 遗传学 量子力学 基因 冶金 催化作用
热门帖子
关注 科研通微信公众号,转发送积分 3747963
求助须知:如何正确求助?哪些是违规求助? 3290830
关于积分的说明 10071227
捐赠科研通 3006723
什么是DOI,文献DOI怎么找? 1651273
邀请新用户注册赠送积分活动 786287
科研通“疑难数据库(出版商)”最低求助积分说明 751630