Intranasal administration of recombinant Netrin-1 attenuates neuronal apoptosis by activating DCC/APPL-1/AKT signaling pathway after subarachnoid hemorrhage in rats

Xie, Zongyi; Huang, Lei; Enkhjargal, Budbazar; Reis, Cesar; Wan, Weifeng; Tang, Jiping; Yuan, Chao; Zhang, Junyi

doi:10.1016/j.neuropharm.2017.03.025

Cited by 45 publications

(30 citation statements)

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“…Innate immune responses and inflammation contribute to the pathophysiology of EBI following SAH (Xie et al, 2017 ). In this study, we investigated the role of PP2A and TTP in EBI after SAH and found that silencing PP2A or TTP exacerbated brain edema and reduced neurological scores following SAH.…”

Section: Discussionmentioning

confidence: 99%

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RETRACTED: Neuroprotective Effect of Protein Phosphatase 2A/Tristetraprolin Following Subarachnoid Hemorrhage in Rats

Yin

et al. 2018

Front. Neurosci.

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Early brain injury (EBI) following subarachnoid hemorrhage (SAH) can lead to inflammation and neuronal dysfunction. There is a need for effective strategies to mitigate these effects and improve the outcome of patients who experience SAH. The mRNA-destabilizing protein tristetraprolin (TTP) is an anti-inflammatory factor that induces the decay of cytokine transcripts and has been implicated in diseases such as glioma. However, the mechanism of action of TTP in EBI after SAH is unclear. The present study investigated the effects of TTP regulation via phosphorylation in a rat model of SAH by protein phosphatase (PP)2A, which is a pleiotropic enzyme complex with multiple substrate phospho-proteins. We hypothesized that inhibitory phosphorylation of TTP by PP2A would reduce neuroinflammation and apoptosis. To evaluate the function of each factor, the PP2A agonist FTY720, short interfering (si)RNAs targeting TTP and PP2A were administered to rats by intracerebroventricular injection 24 h before SAH. Rats were evaluated with SAH grade, neurological score, brain water content and by western blotting, and terminal deoxynucleotidyltransferase dUTP nick-end labeling. We found that endogenous PP2A and TTP levels were increased after SAH. FTY720 induced PP2A activation would lead to dephosphorylation and activation of TTP and decreased production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8. SiRNA-mediated TTP knockdown abolished anti-inflammatory effects of FTY720 treatment, indicating that PP2A was associated with TTP activation in vivo. Decreased TNF-α, IL-6, and IL-8 levels were associated with improvement of neurological function, reduction of brain edema, suppression of caspase-3, and up-regulation of B cell lymphoma-2. These results demonstrated that PP2A activation could enhance the anti-inflammatory and anti-apoptotic effects of TTP, by which it might shed light on the development of an effective therapeutic strategy against EBI following SAH.

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Section: Discussionmentioning

confidence: 99%

“…The rat model of SAH was generated as previously described (Xie et al, 2017 ), with some modifications. Briefly, animals were anesthetized with 3% isoflurane in 60/40% medical air/oxygen.…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: Neuroprotective Effect of Protein Phosphatase 2A/Tristetraprolin Following Subarachnoid Hemorrhage in Rats

Yin

et al. 2018

Front. Neurosci.

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“…Double fluorescence staining was conducted as described previously [ 27 ]. The rats were deeply anesthetized at 24 h post-SAH and were transcardially perfused with 60-ml ice-cold PBS followed by 60 ml of 10% paraformaldehyde.…”

Section: Methodsmentioning

confidence: 99%

Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-κB pathway after subarachnoid hemorrhage in rats

Zhu

Enkhjargal

Huang

et al. 2018

J Neuroinflammation

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127

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BackgroundNeuroinflammation and blood-brain barrier (BBB) disruption are two critical mechanisms of subarachnoid hemorrhage (SAH)-induced brain injury, which are closely related to patient prognosis. Recently, angiogenic factor with G-patch and FHA domain 1 (Aggf1) was shown to inhibit inflammatory effect and preserve vascular integrity in non-nervous system diseases. This study aimed to determine whether Aggf1 could attenuate neuroinflammation and preserve BBB integrity after experimental SAH, as well as the underlying mechanisms of its protective roles.MethodsTwo hundred forty-nine male Sprague-Dawley rats were subjected to the endovascular perforation model of SAH. Recombinant human Aggf1 (rh-Aggf1) was administered intravenously via tail vein injection at 1 h after SAH induction. To investigate the underlying neuroprotection mechanism, Aggf1 small interfering RNA (Aggf1 siRNA) and PI3K-specific inhibitor LY294002 were administered through intracerebroventricular (i.c.v.) before SAH induction. SAH grade, neurological score, brain water content, BBB permeability, Western blot, and immunohistochemistry were performed.ResultsExpression of endogenous Aggf1 was markedly increased after SAH. Aggf1 was primarily expressed in endothelial cells and astrocytes, as well as microglia after SAH. Administration of rh-Aggf1 significantly reduced brain water content and BBB permeability, decreased the numbers of infiltrating neutrophils, and activated microglia in the ipsilateral cerebral cortex following SAH. Furthermore, rh-Aggf1 treatment improved both short- and long-term neurological functions after SAH. Meanwhile, exogenous rh-Aggf1 significantly increased the expression of PI3K, p-Akt, VE-cadherin, Occludin, and Claudin-5, as well as decreased the expression of p-NF-κB p65, albumin, myeloperoxidase (MPO), TNF-α, and IL-1β. Conversely, knockdown of endogenous Aggf1 aggravated BBB breakdown, inflammatory response and neurological impairments at 24 h after SAH. Additionally, the protective roles of rh-Aggf1 were abolished by LY294002.ConclusionsTaken together, exogenous Aggf1 treatment attenuated neuroinflammation and BBB disruption, improved neurological deficits after SAH in rats, at least in part through the PI3K/Akt/NF-κB pathway.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1211-8) contains supplementary material, which is available to authorized users.

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“…In addition, NT-1 phosphorylated AMP-activated protein kinase (AMPK) and reduced the phosphorylation of mammalian target of rapamycin (mTOR) and P70S6K in a spinal cord injury model [ 36 ]. NT-1 also activated APPL1-AKT signing pathway via combining with DCC receptor to reduce apoptosis after subarachnoid hemorrhage in rats [ 37 ]. When introducing to astrocytes, AKT signing pathway was reported to protect astrocytes from activation [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Netrin-1 attenuates brain injury after middle cerebral artery occlusion via downregulation of astrocyte activation in mice

Liu

Lin

et al. 2018

J Neuroinflammation

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BackgroundNetrin-1 functions largely via combined receptors and downstream effectors. Evidence has shown that astrocytes express netrin-1 receptors, including DCC and UNC5H2. However, whether netrin-1 influences the function of astrocytes was previously unknown.MethodsLipopolysaccharide was used to stimulate the primary cultured astrocytes; interleukin release was used to track astrocyte activation. In vivo, shRNA and netrin-1 protein were injected in the mouse brain. Infarct volume, astrocyte activation, and interleukin release were used to observe the function of netrin-1 in neuroinflammation and brain injury after middle cerebral artery occlusion.ResultsOur results demonstrated that netrin-1 reduced lipopolysaccharide-induced interleukin-1β and interleukin-12β release in cultured astrocytes, and blockade of the UNC5H2 receptor with an antibody reversed this effect. Additionally, netrin-1 increased p-AKT and PPAR-γ expression in primary cultured astrocytes. In vivo studies showed that knockdown of netrin-1 increased astrocyte activation in the mouse brain after middle cerebral artery occlusion (p < 0.05). Moreover, injection of netrin-1 attenuated GFAP expression (netrin-1 0.27 ± 0.06 vs. BSA 0.62 ± 0.04, p < 0.001) and the release of interleukins and reduced infarct volume after brain ischemia (netrin-1 0.27 ± 0.06 vs. BSA 0.62 ± 0.04 mm3, p < 0.05).ConclusionOur results indicate that netrin-1 is an important molecule in regulating astrocyte activation and neuroinflammation in cerebral ischemia and provides a potential target for ischemic stroke therapy.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1291-5) contains supplementary material, which is available to authorized users.

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Intranasal administration of recombinant Netrin-1 attenuates neuronal apoptosis by activating DCC/APPL-1/AKT signaling pathway after subarachnoid hemorrhage in rats

Cited by 45 publications

References 39 publications

RETRACTED: Neuroprotective Effect of Protein Phosphatase 2A/Tristetraprolin Following Subarachnoid Hemorrhage in Rats

RETRACTED: Neuroprotective Effect of Protein Phosphatase 2A/Tristetraprolin Following Subarachnoid Hemorrhage in Rats

Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-κB pathway after subarachnoid hemorrhage in rats

Netrin-1 attenuates brain injury after middle cerebral artery occlusion via downregulation of astrocyte activation in mice

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