Netrin‐1 Preserves Blood‐Brain Barrier Integrity Through Deleted in Colorectal Cancer/Focal Adhesion Kinase/RhoA Signaling Pathway Following Subarachnoid Hemorrhage in Rats

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

doi:10.1161/jaha.116.005198

Cited by 37 publications

(32 citation statements)

References 43 publications

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“…In our study, we found that the Mas expression in left hemisphere of brain was decreased and reached to the lowest level at 24 h after SAH. According to previous studies [47] , [48] , [49] , the EBI was much worse at 24 h when compared with other time points after experimental SAH, of which the damaging factors may include neuronal apoptosis, brain edema, and inflammation. As Mas is primarily produced in neurons, the expression of Mas was the lowest at 24 h after SAH, corresponding to the severity of EBI.…”

Section: Discussionmentioning

confidence: 63%

AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats

et al. 2019

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Oxidative stress and neuronal apoptosis have been demonstrated to be key features in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have indicated that Mas receptor activation initiates an anti-oxidative and anti-apoptotic role in the brain. However, whether Mas activation can attenuate oxidative stress and neuronal apoptosis after SAH remains unknown. To investigate the beneficial effect of Mas on oxidative stress injury and neuronal apoptosis induced by SAH, a total of 196 rats were subjected to an endovascular perforation model of SAH. AVE 0991 (AVE), a selective agonist of Mas, was administered intranasally 1 h after SAH induction. A779, a selective inhibitor of Mas, and small interfering ribonucleic acid (siRNA) for UCP-2 were administered by intracerebroventricular (i.c.v) injection at 1 h and 48 h before SAH induction respectively. Neurological tests, immunofluorescence, TUNEL, Fluoro-Jade C, DHE staining, and Western blot experiments were performed. We found that Mas activation with AVE significantly improved neurobehavioral scores and reduced oxidative stress and neuronal apoptosis in SAH+AVE group compared with SAH+vehicle group. Moreover, AVE treatment significantly promoted phosphorylation of CREB and the expression UCP-2, as well as upregulated expression of Bcl-2 and downregulation of Romo-1 and Bax. The protective effects of AVE were reversed by i.c.v injection of A779 and UCP-2 siRNA in SAH+AVE+A779 and SAH+AVE+UCP-2 siRNA groups, respectively. In conclusion, our data provides evidence that Mas activation with AVE reduces oxidative stress injury and neuronal apoptosis through Mas/PKA/p-CREB/UCP-2 pathway after SAH. Furthermore, our study indicates that Mas may be a novel therapeutic treatment target in early brain injury of SAH.

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Section: Discussionmentioning

confidence: 63%

AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats

et al. 2019

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“…Netrin-1 (R&D Systems, 6419-N1-025) was given at 45 µg/kg in phosphate-buffered saline (PBS), and administered through tail vain with a total volume of 200 µL at 1 hour after surgery, while the equal volume of PBS was given in control group and surgery group. The dose of netrin-1 was based on the researches using other models of acute in ammation with slight modi cation [21]. 3 POD mouse model A simple laparotomy was performed under iso urane anesthesia using the methods described in our previous studies [22].…”

Section: Experimental Protocolmentioning

confidence: 99%

“…Overexpression of NTN-1 promoted angiogenesis and improved long-term neurological functions following ischemic stroke. Recent studies indicated that NTN-1 preserved BBB integrity in model of traumatic brain injury and experimental autoimmune encephalomyelitis [20,21].…”

Section: Introductionmentioning

confidence: 99%

Netrin-1 Ameliorates Postoperative Delirium-like Behavior in Aged Mice by Suppressing Neuroinflammation and Restoring Impaired Blood Brain Barrier Permeability

Li¹,

Wang²,

Chen³

et al. 2020

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Background Postoperative delirium (POD) is a common and serious postoperative complication in elderly patients, of which the underlying mechanism is elusive and without effective therapy at present. In recent years, the neuroinflammatory hypothesis has been developed in the pathogenesis of POD. Netrin-1, an axonal guidance molecule, has been reported to have strong inflammatory regulatory and neuroprotective effects.Methods We applied treatment with Netrin-1(45 µg/kg) in aged mice by using the POD model with a simple laparotomy to assess systemic inflammatory, neuroinflammation by detecting interleukin-6 (IL-6), interleukin-10 (IL-10), high mobility group box chromosomal protein-1(HMGB-1) and assessing the reactive states of microglia, permeability of blood-brain barrier (BBB) by detecting cell junction proteins and leakage of dextran, and behavior of the aged mice.Results We found that a single dose of Netrin-1 prophylaxis decreased the expression of IL-6 and HMGB-1, and upregulated the expression of IL-10 in peripheral blood, hippocampus and prefrontal cortex. Nerin-1 reduced activation of microglia cells in the hippocampus and prefrontal cortex and improved the POD-like behavior. Besides, Netrin-1 also attenuated the anesthesia/surgery-induced increase in BBB permeability by up-regulating the expression of tight junction-associated proteins such as ZO-1, claudin-5, and occludin.Conclusions These findings confirm the anti-inflammatory and BBB protective effects of Netrin-1 in an inflammatory environment in vivo and provide better insights into the pathophysiology and potential treatment of POD.

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“…Perivascular astrocytes have been found to engage in promoting brain neovascularization, vessel differentiation, and stabilization [ 52 , 54 ], suggesting that angiogenesis induced by netrin-1 may be mediated partly through the DCC-expressing perivascular astrocytes. Moreover, as perivascular astrocytes have a supportive role in the maintenance of the brain–blood barrier [ 55 ], and netrin-1 has been found to support blood–brain barrier integrity and protect the central nervous system against injury [ 56 , 57 ], we speculate that netrin-1 and DCC may also play a positive role in the restoration of the brain–blood barrier after cerebral ischemia, which also needs further clarification.…”

Section: Discussionmentioning

confidence: 99%

Effects of intra-arterial transplantation of adipose-derived stem cells on the expression of netrin-1 and its receptor DCC in the peri-infarct cortex after experimental stroke

et al. 2017

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BackgroundStem cell transplantation has been documented to promote functional recovery in animal models of stroke; however, the underlying mechanisms are not yet fully understood. As netrin-1 and its receptor deleted in colorectal cancer (DCC) are important regulators in neuronal and vascular activities, the present study attempted to explore whether netrin-1 and DCC are involved in the neuroprotection of stem cell-based therapies in a rat ischemic stroke model.MethodsAdult male Sprague–Dawley rats were subjected to a transient middle cerebral artery occlusion (MCAO) and subsequently received an intra-arterial injection of 2 × 106 PKH26-labeled adipose-derived stem cells (ADSCs) or saline 24 h later. Neurological function was evaluated by behavioral tests before the rats were sacrificed at days 7 and 14 after MCAO. The migration of ADSCs and regeneration of neuronal fibers and blood vessels were determined by immunofluorescence staining. The expression of netrin-1 and DCC was analyzed by Western blot and immunofluorescence staining.ResultsADSC transplantation significantly improved the neurological recovery at days 7 and 14, and noticeably promoted the regeneration of neuronal fibers and blood vessels in the peri-infarct cortex at day 14. PKH26-labeled ADSCs located mainly in the peri-infarct area at days 7 and 14. In ADSC-treated rats, the expression of netrin-1 and DCC significantly increased in the peri-infarct cortex at days 7 and 14. Immunofluorescence staining showed that netrin-1 was mainly expressed by neuronal perikaryal in the peri-infarct cortex, and DCC was mainly expressed by neuronal fibers and was present around the blood vessels in the peri-infarct cortex.ConclusionsThese findings suggest that ADSC transplantation facilitates the regeneration of neuronal fibers and blood vessels in the peri-infarct cortex and improves neurological functions, which may be attributed, at least in part, to the involvement of upregulated netrin-1 and DCC in the remodeling of neuronal and vascular networks in the peri-infarct cortex.

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Netrin‐1 Preserves Blood‐Brain Barrier Integrity Through Deleted in Colorectal Cancer/Focal Adhesion Kinase/RhoA Signaling Pathway Following Subarachnoid Hemorrhage in Rats

Cited by 37 publications

References 43 publications

AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats

AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats

Netrin-1 Ameliorates Postoperative Delirium-like Behavior in Aged Mice by Suppressing Neuroinflammation and Restoring Impaired Blood Brain Barrier Permeability

Effects of intra-arterial transplantation of adipose-derived stem cells on the expression of netrin-1 and its receptor DCC in the peri-infarct cortex after experimental stroke

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