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

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).

Gamdzyk M ，Doycheva DM ，Malaguit J ，Enkhjargal B ，Tang J ，Zhang JH ... -  《-》

IRE1α inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17-5p after neonatal hypoxic-ischemic brain injury in rats.

Chen D ，Dixon BJ ，Doycheva DM ，Li B ，Zhang Y ，Hu Q ，He Y ，Guo Z ，Nowrangi D ，Flores J ，Filippov V ，Zhang JH ，Tang J ... -  《Journal of Neuroinflammation》

GW0742 activates miR-17-5p and inhibits TXNIP/NLRP3-mediated inflammation after hypoxic-ischaemic injury in rats and in PC12 cells.

This study aimed to investigate the effects of PPAR-β/δ receptor agonist GW0742 on neuroinflammation in a rat model of hypoxia-ischaemia (HI) and in PC12 cells in OGD model. HI was induced by ligating the common carotid artery and inducing hypoxia for 150 minutes. Immunofluorescence was used for quantification of microglia activation and for determining cellular localization of PPAR-β/δ. Expression of proteins was measured by Western blot. Activation of miR-17-5p by GW0742 was assessed in PC12 cells by Dual-Luciferase Reporter Gene Assay. The endogenous expression of TXNIP, NLRP3, cleaved caspase-1 and IL-1β was increased after HI. GW0742 treatment significantly reduced the number of activated pro-inflammatory microglia in ipsilateral hemisphere after HI. Mechanistically, GW0742 significantly decreased the expression of TXNIP, NLRP3, IL-6 and TNF-α. Either PPAR-β/δ antagonist GSK3787, miR-17-5p inhibitor, or TXNIP CRISPR activation abolished the anti-inflammatory effects of GW0742. Activation of PPAR-β/δ by GW0742 activated miR-17-5p expression in PC12 cells and increased cell viability after OGD, which was accompanied by decreased expression of TXNIP and reduced secretion of IL-1β and TNF-α. In conclusion, GW0742 may be a promising neurotherapeutic for the management of HI patients.

Gamdzyk M ，Doycheva DM ，Kang R ，Tang H ，Travis ZD ，Tang J ，Zhang JH ... -  《-》

Evidence for the role of peroxisome proliferator-activated receptor-beta/delta in the development of spinal cord injury.

Paterniti I ，Esposito E ，Mazzon E ，Galuppo M ，Di Paola R ，Bramanti P ，Kapoor A ，Thiemermann C ，Cuzzocrea S ... -  《-》

IRE1α inhibition attenuates neuronal pyroptosis via miR-125/NLRP1 pathway in a neonatal hypoxic-ischemic encephalopathy rat model.

Huang J ，Lu W ，Doycheva DM ，Gamdzyk M ，Hu X ，Liu R ，Zhang JH ，Tang J ... -  《Journal of Neuroinflammation》