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).
journal_name
Neuropharmacologyjournal_title
Neuropharmacologyauthors
Gamdzyk M,Doycheva DM,Malaguit J,Enkhjargal B,Tang J,Zhang JHdoi
10.1016/j.neuropharm.2018.08.003subject
Has Abstractpub_date
2018-09-15 00:00:00pages
150-161eissn
0028-3908issn
1873-7064pii
S0028-3908(18)30470-2journal_volume
140pub_type
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