Role of PPAR-β/δ/miR-17/TXNIP pathway in neuronal apoptosis after neonatal hypoxic-ischemic injury in rats

Marcin Gamdzyk, Desislava Met Doycheva, Jay Malaguit, Budbazar Enkhjargal, Jiping Tang, John H. Zhang

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)150-161
Number of pages12
JournalNeuropharmacology
Volume140
DOIs
StatePublished - 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

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