Abstract
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 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 PPAR-β/δ/miR-17/TXNIP pathway. GW0742 could represent a therapeutic target for treatment of neonatal hypoxic ischemic encephalopathy (HIE).
Original language | English |
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Pages (from-to) | 150-161 |
Number of pages | 12 |
Journal | Neuropharmacology |
Volume | 140 |
DOIs | |
State | Published - Sep 15 2018 |
ASJC Scopus Subject Areas
- Pharmacology
- Cellular and Molecular Neuroscience
Keywords
- Apoptosis
- GW0742
- HI
- PPAR-β/δ
- TXNIP
- miR-17
- MAP Kinase Kinase Kinase 5/antagonists & inhibitors
- Thiazoles/pharmacology
- Neurons/pathology
- Apoptosis/drug effects
- Rats
- Male
- Benzamides/pharmacology
- PPAR-beta/agonists
- Sulfones/pharmacology
- Cerebral Infarction/drug therapy
- Carrier Proteins/antagonists & inhibitors
- Signal Transduction/physiology
- MAP Kinase Signaling System/drug effects
- PPAR delta/agonists
- Animals
- Hypoxia-Ischemia, Brain/metabolism
- Cell Cycle Proteins
- MicroRNAs/antagonists & inhibitors