Netrin‐1 overexpression improves neurobehavioral outcomes and reduces infarct size via inhibition of the notch1 pathway following experimental stroke

Yang, Xiaosheng; Li, Shiting; Li, Bin; Wang, Xiaoqiang; Sun, Chongran; Qin, Haiqiang; Sun, Hui

doi:10.1002/jnr.24018

Cited by 16 publications

(14 citation statements)

References 23 publications

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“…Netrin-1 binding with its receptor DCC can regulate synaptic plasticity and promote axonal outgrowth in both developmental and mature CNS ( Horn et al, 2013 ). Previous studies demonstrate that Netrin-1 facilitates angiogenesis and long-term neurological recovery ( Lu et al, 2011 , 2012 ), decreases the infarct size ( Ding et al, 2014 ; Yang et al, 2017 ), improves spatial memory and synaptic plasticity ( Bayat et al, 2012 ), and promotes anti-apoptosis after stroke. Above all, Netrin-1 can facilitate neural functional recovery after hypoxic ischemic injury in versatile ways.…”

Section: Discussionmentioning

confidence: 99%

Netrin-1 Promotes Synaptic Formation and Axonal Regeneration via JNK1/c-Jun Pathway after the Middle Cerebral Artery Occlusion

Zheng

Chen

et al. 2018

Front. Cell. Neurosci.

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As a secreted axon guidance molecule, Netrin-1 has been documented to be a neuroprotective factor, which can reduce infarct volume, promote angiogenesis and anti-apoptosis after stroke in rodents. However, its role in axonal regeneration and synaptic formation after cerebral ischemic injury, and the related underlying mechanisms remain blurred. In this study, we used Adeno-associated vectors carrying Netrin-1 gene (AAV-NT-1) to up-regulate the expression level of Netrin-1 in rats’ brain after middle cerebral artery occlusion (MCAO). We found that the up-regulated level of Netrin-1 and its receptor DCC promoted axonal regeneration and synaptic formation; the overexpression of Netrin-1 activated the JNK1 signaling pathway; these effects were partially reduced when JNK1 signaling pathway was inhibited by SP600125 (JNK specific inhibitor). Taken together, these findings suggest that Netrin-1 can facilitate the synaptic formation and axonal regeneration via the JNK1 signaling pathway after cerebral ischemia, thus promoting the recovery of neural functions.

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Section: Discussionmentioning

confidence: 99%

Netrin-1 Promotes Synaptic Formation and Axonal Regeneration via JNK1/c-Jun Pathway after the Middle Cerebral Artery Occlusion

Zheng

Chen

et al. 2018

Front. Cell. Neurosci.

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“…Overexpression of Netrin-1 remarkably reduced infarct areas and improved motor function. 10,11 In addition, Netrin-1 mediates the proliferation of newly generated vessels in the ischemic penumbra, thus playing a cerebral protective role. 12 However, it is not clear what kind of direct influence Netrin-1 has on ischemic neurons.…”

Section: Introductionmentioning

confidence: 99%

Exogenous Netrin-1 Inhibits Autophagy of Ischemic Brain Tissues and Hypoxic Neurons via PI3K/mTOR Pathway in Ischemic Stroke

Tang

Gao

Yang

et al. 2019

Journal of Stroke and Cerebrovascular Diseases

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Background and Objective: Ischemic stroke is a serious disease that endangers human health. How to reduce the damage of neurons in ischemic regions is an urgent problem to be explored. Autophagy is an important pathophysiological process in cerebral ischemia and Netrin-1 is an effective neuroprotective protein. This study aims to investigate the effect of Netrin-1 on autophagy of ischemic brain tissues and hypoxic neurons. Methods: We constructed rat persistent middle cerebral artery occlusion model in vivo and constructed the Oxygen Glucose-Deprivation model in vitro. Rats and cells were treated with or without Netrin-1. Western blot analysis was performed to detect autophagy related proteins LC3B, P62 and pathway related proteins PI3K, p-PI3K, mTOR, p-mTOR. CCK-8 assay was performed to detect the viability of hypoxic neurons. We also performed western-blot analysis and qRT-PCR test to detect levels of Netrin-1 protein and mRNA. Results: Autophagy enhanced both in ischemic brain tissues and hypoxic neurons. Netrin-1 inhibited autophagy through PI3K/mTOR pathway both in vivo and in vitro. At the same time, we found that exogenous Netrin-1 can promote the secretion of Netrin-1 protein by neurons themselves, which indicated that Netrin-1 can further amplify the neuroprotective effect through the positive feedback mechanism. Conclusions: Exogenous Netrin-1 alleviates damage of ischemic brain tissues and enhances viability of hypoxic neurons by inhibiting autophagy via PI3K/mTOR pathway. This effect can be amplified by positive feedback mechanism.

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“…This is similar to the conclusion obtained in TBI17. Notably, in both ischemic stroke [22] and subarachnoid hemorrhage [23] models, up-regulation of Netrin-1 and its receptors was observed around the injury site, which was opposite to the changes in peripheral blood. A possible explanation is that Netrin-1 is involved in the inflammatory response process and inhibits the progression of inflammation, which leads to the depletion of peripheral blood Netrin-1 [15].…”

Section: Discussionmentioning

confidence: 90%

The Prognostic Value of Deleted in Colorectal Cancer (DCC) Receptor and Serum Netrin-1 in Severe Traumatic Brain Injury

Zhang

Sun

et al. 2022

JCM

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Traumatic brain injury (TBI) is a common neurological disease. Netrin-1 and deleted in colorectal cancer (DCC) receptor are potential biomarkers associated with nerve regeneration and immune regulation. We aimed to investigate the ability of the DCC receptor and Netrin-1 to predict a high ICP level after operation in severe traumatic brain injury and their prognostic significance. This study is a prospective observational study. We selected 23 patients with traumatic brain injury who had undergone surgical operations as subjects. Immunohistochemical staining was performed on the contusion tissue that was removed by the operation to determine the expression of DCC receptor. At the same time, enzyme-linked immunosorbent assay (ELISA) kits were used to detect the serum Netrin-1 content. Determination of intracranial pressure (ICP) value was measured by intraventricular catheter. The Glasgow Outcome Scale (GOS) score at six months after trauma was defined as the main study endpoint. The results showed that serum Netrin-1 concentrations of patients in the critical TBI group (GCS 3–5 points) was significantly lower than that in the severe TBI group (GCS 6–8 points). The ICP peak and average mannitol consumption in the high Netrin-1 group were significantly lower than those in the low Netrin-1 group. DCC receptor-positive patients had a significantly lower ICP peak. There was no significant difference in six month-GOS scores between patients in the high and low Netrin-1 groups, while DCC receptor concentrations below 3.82 ng/mL predicted poor prognosis (GOS 1–3 points). In conclusion, the expression level of the DCC receptor can better evaluate the postoperative high ICP level and prognosis than the level of serum Netrin-1 in severe traumatic brain injury.

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Netrin‐1 overexpression improves neurobehavioral outcomes and reduces infarct size via inhibition of the notch1 pathway following experimental stroke

Cited by 16 publications

References 23 publications

Netrin-1 Promotes Synaptic Formation and Axonal Regeneration via JNK1/c-Jun Pathway after the Middle Cerebral Artery Occlusion

Netrin-1 Promotes Synaptic Formation and Axonal Regeneration via JNK1/c-Jun Pathway after the Middle Cerebral Artery Occlusion

Exogenous Netrin-1 Inhibits Autophagy of Ischemic Brain Tissues and Hypoxic Neurons via PI3K/mTOR Pathway in Ischemic Stroke

The Prognostic Value of Deleted in Colorectal Cancer (DCC) Receptor and Serum Netrin-1 in Severe Traumatic Brain Injury

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