Role of PPAR-β/δ/miR-17/TXNIP pathway in neuronal apoptosis after neonatal hypoxic-ischemic injury in rats.
Role of PPAR-β/δ/miR-17/TXNIP pathway in neuronal apoptosis after neonatal hypoxic-ischemic injury in rats.
复制标题
DOI：
10.1016/j.neuropharm.2018.08.003
复制
发表时间：
2018-09-15
影响因子：
4.7
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Gamdzyk M;Doycheva DM;Malaguit J;Enkhjargal B;Tang J;Zhang JH
过氧化物酶体增殖物激活受体β/δ（PPAR - β/δ）是一种作为转录因子的核受体，在多种神经疾病模型中被证明具有保护作用。然而，关于PPAR - β/δ在新生儿缺氧缺血（HI）中的作用及其分子机制尚无相关信息。在本研究中，我们假设PPAR - β/δ激动剂GW0742能够激活miR - 17 - 5p，进而抑制TXNIP和ASK1/p38通路，从而减轻细胞凋亡。10日龄的大鼠幼崽接受右侧颈总动脉结扎，随后缺氧2.5小时。在HI后1小时和24小时经鼻给予GW0742。在HI前1小时和HI后24小时经鼻给予PPAR - β/δ受体拮抗剂GSK3787，在HI前24小时和48小时分别经脑室给予抗miR - 17 - 5p和TXNIP CRISPR激活质粒。进行了脑梗死面积测量、神经功能测试、蛋白质印迹、逆转录定量实时聚合酶链反应（RT - qPCR）、荧光玉红C和免疫荧光染色。GW0742在HI后72小时和4周减少了脑梗死面积、脑萎缩和细胞凋亡，并改善了神经功能。此外，GW0742治疗在HI后增加了同侧大脑半球中PPAR - β/δ的核表达和miR - 17 - 5p水平，并降低了TXNIP，从而抑制了ASK1/p38通路并减轻了细胞凋亡。抑制PPAR - β/δ受体和miR - 17 - 5p以及激活TXNIP逆转了保护作用。我们首次提供证据表明，经鼻给予PPAR - β/δ激动剂GW0742至少部分通过PPAR - β/δ/miR - 17/TXNIP通路减轻神经元细胞凋亡。GW0742可能成为治疗新生儿缺氧缺血性脑病（HIE）的一个治疗靶点。
Activation of peroxisome proliferator-activated receptor beta/delta (PPAR-β/δ), a nuclear receptor acting as a transcription factor, was shown to be protective in various models of neurological diseases. However, there is no information about the role of PPAR-β/δ as well as its molecular mechanisms in neonatal hypoxia-ischemia (HI). In the present study, we hypothesized that PPAR-β/δ agonist GW0742 can activate miR-17-5p, consequently inhibiting TXNIP and ASK1/p38 pathway leading to attenuation of apoptosis. Ten-day-old rat pups were subjected to right common carotid artery ligation followed by 2.5 h hypoxia. GW0742 was administered intranasally 1 and 24 h post HI. PPAR-β/δ receptor antagonist GSK3787 was administered intranasally 1 h before and 24 h after HI, antimir-17-5p and TXNIP CRISPR activation plasmid were administered intracerebroventricularly 24 and 48 h before HI, respectively. Brain infarct area measurement, neurological function tests, western blot, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Fluoro-Jade C and immunofluorescence staining were conducted. GW0742 reduced brain infarct area, brain atrophy, apoptosis, and improved neurological function at 72 hours(h) and 4 weeks post HI. Furthermore, GW0742 treatment increased PPAR-β/δ nuclear expression and miR-17-5p level and reduced TXNIP in ipsilateral hemisphere after HI, resulting in inhibition of ASK1/p38 pathway and attenuation of apoptosis. Inhibition of PPAR-β/δ receptor and miR-17-5p and activation of TXNIP reversed the protective effects. For the first time, we provide evidence that intranasal administration of PPAR-β/δ agonist GW0742 attenuated neuronal apoptosis at least in part via PPARyg-β/δ/miR-17/TXNIP pathway. GW0742 could represent a therapeutic target for treatment of neonatal hypoxic ischemic encephalopathy (HIE).
登录
查看更多内容
影响因子：
4.7
作者：
Dharap A;Pokrzywa C;Murali S;Kaimal B;Vemuganti R
通讯作者：
Vemuganti R
DOI：
10.1124/jpet.106.115758
发表时间：
2007-03-01
影响因子：
3.5
作者：
Iwashita, Akinori;Muramatsu, Yuko;Matsuoka, Nobuya
通讯作者：
Matsuoka, Nobuya
影响因子：
6.7
作者：
Haskova, Z.;Hoang, B.;Kilgore, K. S.
通讯作者：
Kilgore, K. S.
影响因子：
4.8
作者：
Hong, Kyunghee;Xu, Guanlan;Shalev, Anath
通讯作者：
Shalev, Anath
影响因子：
2.3
作者：
Ibabe, A;Bilbao, E;Cajaraville, MP
通讯作者：
Cajaraville, MP