Neuregulin 1 protects against ischemic brain injury via ErbB4 receptors by increasing GABAergic transmission

Guan, Yiqing; Wu, Chengyuan; Fang, Yunxia; Zeng, Yuan-Ning; Luo, Zhiyong; Li, S.-J.; Li, Xifeng; Zhu, Xinhong; Mei, Lin; Gao, Tianming

doi:10.1016/j.neuroscience.2015.08.047

Cited by 36 publications

(33 citation statements)

References 39 publications

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“…In cancer cells and Schwann cells, NRG-1 signals through erbB2 and erbB3 receptors. Neuroprotection in stroke by NRG-1 is mediated by erbB4 which physically associates with NIK [46, 57]. Interestingly, NRG-1 alone has little effect on NF-kB in our in vitro studies.…”

Section: Discussionmentioning

confidence: 88%

Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway

Simmons

Surles-Zeigler

et al. 2016

J Neuroinflammation

114

110

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BackgroundWe previously demonstrated that neuregulin-1 (NRG-1) was neuroprotective in rats following ischemic stroke. Neuroprotection by NRG-1 was associated with the suppression of pro-inflammatory gene expression in brain tissues. Over-activation of brain microglia can induce pro-inflammatory gene expression by activation of transcriptional regulators following stroke. Here, we examined how NRG-1 transcriptionally regulates inflammatory gene expression by computational bioinformatics and in vitro using microglial cells.MethodsTo identify transcriptional regulators involved in ischemia-induced inflammatory gene expression, rats were sacrificed 24 h after middle cerebral artery occlusion (MCAO) and NRG-1 treatment. Gene expression profiles of brain tissues following ischemia and NRG-1 treatment were examined by microarray technology. The Conserved Transcription Factor-Binding Site Finder (CONFAC) bioinformatics software package was used to predict transcription factors associated with inflammatory genes induced following stroke and suppressed by NRG-1 treatment. NF-kappa B (NF-kB) was identified as a potential transcriptional regulator of NRG-1-suppressed genes following ischemia. The involvement of specific NF-kB subunits in NRG-1-mediated inflammatory responses was examined using N9 microglial cells pre-treated with NRG-1 (100 ng/ml) followed by lipopolysaccharide (LPS; 10 μg/ml) stimulation. The effects of NRG-1 on cytokine production were investigated using Luminex technology. The levels of the p65, p52, and RelB subunits of NF-kB and IkB-α were determined by western blot analysis and ELISA. Phosphorylation of IkB-α was investigated by ELISA.ResultsCONFAC identified 12 statistically over-represented transcription factor-binding sites (TFBS) in our dataset, including NF-kBP65. Using N9 microglial cells, we observed that NRG-1 significantly inhibited LPS-induced TNFα and IL-6 release. LPS increased the phosphorylation and degradation of IkB-α which was blocked by NRG-1. NRG-1 also prevented the nuclear translocation of the NF-kB p65 subunit following LPS administration. However, NRG-1 increased production of the neuroprotective cytokine granulocyte colony-stimulating factor (G-CSF) and the nuclear translocation of the NF-kB p52 subunit, which is associated with the induction of anti-apoptotic and suppression of pro-inflammatory gene expression.ConclusionsNeuroprotective and anti-inflammatory effects of NRG-1 are associated with the differential regulation of NF-kB signaling pathways in microglia. Taken together, these findings suggest that NRG-1 may be a potential therapeutic treatment for treating stroke and other neuroinflammatory disorders.

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Section: Discussionmentioning

confidence: 88%

Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway

Simmons

Surles-Zeigler

et al. 2016

J Neuroinflammation

114

110

View full text Add to dashboard Cite

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“…The knowledge concerning roles of NRG-1 in the peripheral nervous system is even more limited. It is known that NRG-1 influences Schwann cells, showing neuroprotective and regenerative effects [ 42 ], and may change the levels and activity of other neuronal active substances (mainly neuromediators and/or neuromodulators) and their receptors [ 43 ]. Some previous studies have shown the participation of NRG-1 in processes regulating the activity of ion channels within neuronal cells [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

The Influence of Bisphenol A (BPA) on Neuregulin 1-Like Immunoreactive Nerve Fibers in the Wall of Porcine Uterus

Rytel

2018

IJMS

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Bisphenol A (BPA), a substance commonly used in the manufacture of plastics, shows multidirectional negative effects on humans and animals. Due to similarities to estrogens, BPA initially leads to disorders in the reproductive system. On the other hand, it is known that neuregulin 1 (NRG-1) is an active substance which enhances the survivability of cells, inhibits apoptosis, and protects tissues against damaging factors. Because the influence of BPA on the nervous system has also been described, the aim of the present study was to investigate for the first time the influence of various doses of BPA on neuregulin 1-like immunoreactive (NRG-1-LI) nerves located in the porcine uterus using the routine single- and double-immunofluorescence technique. The obtained results have shown that BPA increases the number and affects the neurochemical characterization of NRG-1-LI in the uterus, and changes are visible even under the impact of small doses of this toxin. The character of observed changes depended on the dose of BPA and the part of the uterus studied. These observations suggest that NRG-1 in nerves supplying the uterus may play roles in adaptive and protective mechanisms under the impact of BPA.

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“…Interestingly, it has been reported that NRG reduced ROS levels in H 2 O 2 -treated PC12-ErbB-4 cells 38 . On the other hand, NRG protects against ischemic brain injury through an ErbB4-dependent manner 39 . Our results suggested that ErbB4 itself is related to a burst of excess oxygen radical production during early reperfusion.…”

Section: Discussionmentioning

confidence: 99%

Neuron-autonomous transcriptome changes upon ischemia/reperfusion injury

Shi

Xia

et al. 2017

Sci Rep

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Ischemic stroke and the following reperfusion, an acute therapeutic intervention, can cause irreversible brain damages. However, the underlying pathological mechanisms are still under investigation. To obtain a comprehensive, real-time view of the cell-autonomous mechanisms involved in ischemic stroke and reperfusion, we applied the next-generation sequencing (NGS) technology to characterize the temporal changes in gene expression profiles using primarily cultured hippocampal neurons under an oxygen-glucose deprivation/reperfusion (OGD/R) condition. We first identified the differentially expressed genes (DEGs) between normal cultured neurons, neurons with OGD, and neurons with OGD followed by reperfusion for 6 h, 12 h, and 18 h, respectively. We then performed bioinformatics analyses, including gene ontological (GO) and pathway analysis and co-expression network analysis to screen for novel key pathways and genes involved in the pathology of OGD/R. After we confirmed the changes of selected key genes in hippocampal cultures with OGD/R, we further validated their expression changes in an in vivo ischemic stroke model (MCAO). Finally, we demonstrated that prevention of the up-regulation of a key gene (Itga5) associated with OGD/R promoted hippocampal neuronal survival. Our research thereby provided novel insights into the molecular mechanisms in ischemic stroke pathophysiology and potential targets for therapeutic intervention after ischemic stroke.

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Neuregulin 1 protects against ischemic brain injury via ErbB4 receptors by increasing GABAergic transmission

Cited by 36 publications

References 39 publications

Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway

Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway

The Influence of Bisphenol A (BPA) on Neuregulin 1-Like Immunoreactive Nerve Fibers in the Wall of Porcine Uterus

Neuron-autonomous transcriptome changes upon ischemia/reperfusion injury

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