Abstract
Nurr1 is a member of the nuclear receptor 4 family of orphan nuclear receptors that is decreased in inflammatory responses and leads to neurons death in Parkinson’s disease. Abnormal expression of Nurr1 have been attributed to various signaling pathways, but little is known about microRNAs (miRNAs) regulation of Nurr1 in ischemia/reperfusion injury. To investigate the post transcriptional regulatory networks of Nurr1, we used a miRNA screening approach and identified miR-145-5p as a putative regulator of Nurr1. By using computer predictions, we identified and confirmed a miRNA recognition element in the 3′UTR of Nurr1 that was responsible for miR-145-5p-mediated suppression. We next demonstrated that overexpression of Nurr1 inhibited TNF-α expression in microglia by trans-repression and finally attenuated ischemia/reperfusion-induced inflammatory and cytotoxic response of neurons. Results of further in vivo study revealed that anti-miR-145-5p administration brought about increasing expression of Nurr1 and reduction of infarct volume in acute cerebral ischemia. Administration of anti-miR-145-5p promotes neurological outcome of rats post MCAO/R. It might be an effective therapeutic strategy to relieve neurons injury upon ischemia/reperfusion of rats through interrupting the axis signaling of miR-145-5p- Nurr1-TNF-α in acute phase.
Highlights
Cerebral ischemia/reperfusion (I/R) injury-induced neuronal cell death is the most difficult problem to solve in clinical stroke (Al-Mufti et al, 2017)
Both mRNA and protein levels of Nurr1 decreased from the start of ischemic stroke, reached a minimum at 12 h, and increased until 48 h (Figures 1A,B)
Clear reductions in both Nurr1 mRNA and protein expression were detected in microglia post OGD/R 2 h and accompanied by a substantial elevation in tumor necrosis factor-α (TNF-α) gene expression (Figures 4A,C)
Summary
Cerebral ischemia/reperfusion (I/R) injury-induced neuronal cell death is the most difficult problem to solve in clinical stroke (Al-Mufti et al, 2017). Nurr has been shown to inhibit expression of proinflammatory neurotoxic mediators by docking to NF-κB-p65 on target inflammatory gene promoters in microglia (Saijo et al, 2009; Kim et al, 2015). Cystatin C induces VEGF expression and attenuates PC12 cell degeneration by regulating p-PKC-α/p-ERK1/2-NURR1 signaling and inducing autophagy in Parkinson’s disease (Zou et al, 2017). Taken together, these findings indicate that Nurr could be a promising therapeutic target in neuronal diseases. The specific functions and/or mechanisms of Nurr in I/R injury are still unknown
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