scholarly journals A20 Establishes Negative Feedback With TRAF6/NF-κB and Attenuates Early Brain Injury After Experimental Subarachnoid Hemorrhage

2021 ◽  
Vol 12 ◽  
Author(s):  
Hong-Ji Deng ◽  
QuZhen Deji ◽  
WangDui Zhaba ◽  
Jia-Qiang Liu ◽  
Sheng-Qing Gao ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Negative Feedback ◽  
Inflammatory Cytokine ◽  
Neuroprotective Effect ◽  
Early Brain Injury ◽  
Brain Water Content ◽  
Nissl Staining ◽  
Cytokine Levels ◽  
Brain Water

Nuclear factor (NF)-κB–ty -50mediated neuroinflammation plays a crucial role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). As an important negative feedback regulator of NF-κB, A20 is essential for inflammatory homeostasis. Herein, we tested the hypothesis that A20 attenuates EBI by establishing NF-κB–associated negative feedback after experimental SAH. In vivo and in vitro models of SAH were established. TPCA-1 and lentivirus were used for NF-κB inhibition and A20 silencing/overexpression, respectively. Cellular localization of A20 in the brain was determined via immunofluorescence. Western blotting and enzyme-linked immunosorbent assays were applied to observe the expression of members of the A20/tumor necrosis factor receptor-associated factor 6 (TRAF6)/NF-κB pathway and inflammatory cytokines (IL-6, IL-1β, TNF-α). Evans blue staining, TUNEL staining, Nissl staining, brain water content, and modified Garcia score were performed to evaluate the neuroprotective effect of A20. A20 expression by astrocytes, microglia, and neurons was increased at 24 h after SAH. A20 and inflammatory cytokine levels were decreased while TRAF6 expression was elevated after NF-κB inhibition. TRAF6, NF-κB, and inflammatory cytokine levels were increased after A20 silencing but suppressed with A20 overexpression. Also, Bcl-2, Bax, MMP-9, ZO-1 protein levels; Evans blue, TUNEL, and Nissl staining; brain water content; and modified Garcia score showed that A20 exerted a neuroprotective effect after SAH. A20 expression was regulated by NF-κB. In turn, increased A20 expression inhibited TRAF6 and NF-κB to reduce the subsequent inflammatory response. Our data also suggest that negative feedback regulation mechanism of the A20/TRAF6/NF-κB pathway and the neuroprotective role of A20 to attenuate EBI after SAH.

scholarly journals Atorvastatin ameliorates early brain injury through inhibition of apoptosis and ER stress in a rat model of subarachnoid hemorrhage

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Wentao Qi ◽  
Demao Cao ◽  
Yucheng Li ◽  
Aijun Peng ◽  
Youwei Wang ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Water Content ◽  
Caspase 3 ◽  
Sham Group ◽  
Early Brain Injury ◽  
Brain Water Content ◽  
Atorvastatin Group ◽  
Related Proteins ◽  
Brain Water

Aneurysmal subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease with very poor prognosis. The aim of the present study was to evaluate the protective effects of atorvastatin on early brain injury (EBI) after SAH using a perforation SAH model. Male Sprague–Dawley rats were randomly divided into four groups: the sham group, the SAH group (model group), SAH + 10 mg.kg−1.day−1 atorvastatin (low atorvastatin group), and SAH + 20 mg.kg−1.day−1 atorvastatin (high atorvastatin group). Atorvastatin was administered orally by gastric gavage for 15 days before operation. At 24 h after SAH, we evaluated the effects of atorvastatin on brain water content, apoptosis by TUNEL assay and scanning electron microscope (SEM), and the expression of apoptosis-related proteins by immunofluorescence and Western blotting analysis. Compared with the sham group, we observed increased brain water content, significant apoptosis, and elevated levels of apoptosis-related proteins including caspase-3, CCAAT enhancer-binding protein homologous protein (CHOP), the 78-kDa glucose-regulated protein (GRP78), and aquaporin-4 (AQP4) in the SAH group. Atorvastatin administration under all doses could significantly reduce brain water content, apoptosis, and the expression levels of caspase-3, CHOP, GRP78, and AQP4 at 24 h after SAH. Our data show that early treatment with atorvastatin effectively ameliorates EBI after SAH through anti-apoptotic effects and the effects might be associated inhibition of caspase-3 and endoplasmic reticulum (ER) stress related proteins CHOP and GRP78.

scholarly journals Apelin-13 Attenuates Early Brain Injury Through Inhibiting Inflammation and Apoptosis in Rats After Experimental Subarachnoid Hemorrhage

2021 ◽  
Author(s):  
Xiaoyan Shen ◽  
Guiqiang Yuan ◽  
Bing Li ◽  
Cheng Cao ◽  
Demao Cao ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Neuronal Degeneration ◽  
Neuroprotective Effect ◽  
Temporal Cortex ◽  
Cortical Cell ◽  
Early Brain Injury ◽  
Neurological Dysfunction ◽  
Dependent Manner ◽  
Nissl Staining

Abstract Background: Early brain injury (EBI) has been considered as the major contributor to the neurological dysfunction and poor clinical outcomes of subarachnoid hemorrhage (SAH). Studies showed that apelin-13 exhibits a neuroprotective effect in brain damage induced by cerebral ischemia. However, it remains unclear whether apelin-13 could exhibit the protective functions following SAH. The present study aimed to validate the neuroprotective role of apelin-13 in SAH, and further investigated the underlying mechanisms. Methods and Results: We constructed SAH rat model and we found that apelin-13 significantly alleviated neurological disorder and brain edema, improved memory deficits in SAH rats. Apelin-13 treatment decreased contents of TNF-α and IL-1β in cerebral spinal fluid of SAH rat by using ELISA. Apelin-13 treatment promoted the expression of APJ and Bcl-2, and decreased the level of active caspase-3 and Bax in the temporal cortex after SAH by using western blot. Also, apelin-13 attenuated the cortical cell death and neuronal degeneration as shown by TUNEL, FJB and Nissl staining. However, ML221, an inhibitor of APJ, significantly reversed all the above neuroprotective effects of apelin-13. Moreover, a neuron-microglia co-culture system, which mimic SAH in vitro, confirmed the protective effect of apelin-13 on neurons and the inhibitory effect on inflammation through apoptosis-related proteins.Conclusions: These data demonstrated that apelin-13 exhibit a neuroprotective role after SAH through inhibition of apoptosis in an APJ dependent manner.

Abstract 2611: Inhibition Of Rho-kinase By Hydroxyfasudil Attenuates Early Brain Injury After Subarachnoid Hemorrhage In Rats

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Mutsumi Fujii ◽  
Kamil Duris ◽  
Orhan Altay ◽  
Yoshiteru Soejima ◽  
Prativa Sherchan ◽  
...  
Keyword(s):  
Brain Injury ◽  
Brain Edema ◽  
Rho Kinase ◽  
Early Brain Injury ◽  
Vehicle Group ◽  
Brain Water Content ◽  
Single Treatment ◽  
Ipsilateral Hemisphere ◽  
Neurological Score ◽  
Brain Water

Background: Early brain injury comprising of blood-brain barrier (BBB) disruption and brain edema is an important part of subarachnoid hemorrhage (SAH) pathophysiology. Although several reports have shown that inhibition of Rho-kinase (ROCK) plays an important role in suppressing barrier permeability, the effect of ROCK on the BBB in SAH is not well understood. Therefore, we assessed the hypothesis that (A) ROCK inhibitors, hydroxyfasudil (HF) and Y27632 attenuate early brain injury after SAH, and (B) HF decreases brain edema via preservation of the BBB. Methods: Adult male rats were randomly assigned to five groups; sham-operated, SAH with saline, SAH with HF (10mg/kg, i.p.) treatment at 0.5 hrs, SAH with HF (10mg/kg, i.p.) treatment at 0.5 and 6 hrs each , and SAH with Y27632 (10mg/kg, i.p.) treatment at 0.5 hrs. The endovascular perforation method was used to produce SAH. Neurological scores were evaluated before sacrifice at 24 and 72 hours after injury. Brain water content, Evans blue dye extravasation assay, Rho-kinase activity assay, and Western blotting analyses were performed. Results: Among 175 surgeries performed, 53 animals were excluded. Of those excluded, 26 died from severe SAH and 27 had only mild SAH. There were no differences between the SAH with saline group (Vehicle group), SAH with HF group, and SAH with Y27632 group in SAH grading and mortality. HF but not Y27632 significantly improved neurological outcomes. Both groups significantly attenuated brain water content (BWC) in the ipsilateral hemisphere compared with the Vehicle group at 24 hrs after SAH for single treatment. The BWC of the HF group was also significantly lower than that of the Vehicle group in the contralateral hemisphere and cerebellum. There was no difference in neurological score between the Vehicle and HF group with two treatments, however, HF significantly ameliorated BWC in the ipsilateral hemisphere compared with vehicle at 24 hrs after SAH. There was no difference in neurological score and BWC between the Vehicle and HF groups with single treatment at 72 hrs after SAH. Evans blue extravasation in the ipsilateral hemisphere in the Vehicle group was significantly higher than in the HF group for single treatment at 24 hours after SAH. Supernatants of the ipsilateral hemisphere of single treatment groups sacrificed at 24 hours showed significantly higher ROCK activity in the Vehicle group than the sham group, and the HF group showed significantly lower activity than the Vehicle group. As the tight junction (TJ) is one of the components of the endothelial junctional complex in the BBB, we evaluated TJ proteins, occludin and Zona occludens-1 (ZO-1) in Western blotting analyses. Occludin and ZO-1 levels were significantly lower in the Vehicle group than the HF group. Conclusion: The ROCK inhibitor, HF, attenuates early brain injury by decreasing brain edema after SAH via protection of tight junction proteins.

Dimethylfumarate alleviates early brain injury and secondary cognitive deficits after experimental subarachnoid hemorrhage via activation of Keap1-Nrf2-ARE system

2015 ◽  
Vol 123 (4) ◽  
pp. 915-923 ◽  
Author(s):  
Yizhi Liu ◽  
Jiaoxue Qiu ◽  
Zhong Wang ◽  
Wanchun You ◽  
Lingyun Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Neuroprotective Effect ◽  
Autologous Blood ◽  
Early Brain Injury ◽  
Related Factor ◽  
Learning Deficits

OBJECT Oxidative stress and the inflammatory response are thought to promote brain damage in the setting of subarachnoid hemorrhage (SAH). Previous reports have shown that dimethylfumarate (DMF) can activate the Kelch-like ECH-associated protein 1–nuclear factor erythroid 2-related factor 2–antioxidant-responsive element (Keap1-Nrf2-ARE) system in vivo and in vitro, which leads to the downregulation of oxidative stress and inflammation. The aim of this study was to evaluate the potential neuroprotective effect of DMF on SAH-induced brain injury in rats. METHODS Rats were subjected to SAH by the injection of 300 μl of autologous blood into the chiasmatic cistern. Rats in a DMF-treated group were given 15 mg/kg DMF twice daily by oral gavage for 2 days after the onset of SAH. Cortical apoptosis, neural necrosis, brain edema, blood-brain barrier impairment, learning deficits, and changes in the Keap1-Nrf2-ARE pathway were assessed. RESULTS Administration of DMF significantly ameliorated the early brain injury and learning deficits induced by SAH in this animal model. Treatment with DMF markedly upregulated the expressions of agents related to Keap1-Nrf2-ARE signaling after SAH. The inflammatory response and oxidative stress were downregulated by DMF therapy. CONCLUSIONS DMF administration resulted in abatement of the development of early brain injury and cognitive dysfunction in this prechiasmatic cistern SAH model. This result was probably mediated by the effect of DMF on the Keap1-Nrf2-ARE system.

scholarly journals Osteopontin-Enhanced Autophagy Attenuates Early Brain Injury via FAK–ERK Pathway and Improves Long-Term Outcome after Subarachnoid Hemorrhage in Rats

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 980 ◽  
Author(s):  
Chengmei Sun ◽  
Budbazar Enkhjargal ◽  
Cesar Reis ◽  
Tongyu Zhang ◽  
Qiquan Zhu ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Early Brain Injury ◽  
Potential Effect ◽  
Sprague Dawley ◽  
Early Administration ◽  
Nissl Staining ◽  
Term Outcome ◽  
Long Term Outcome

Osteopontin (OPN) enhances autophagy, reduces apoptosis, and attenuates early brain injury (EBI) after a subarachnoid hemorrhage (SAH). A total of 87 Sprague–Dawley rats were subjected to sham or SAH operations to further investigate the signaling pathway involved in osteopontin-enhanced autophagy during EBI, and the potential effect of recombinant OPN (rOPN) administration to improve long-term outcomes after SAH. Rats were randomly divided into five groups: Sham, SAH + Vehicle (PBS, phosphate-buffered saline), SAH + rOPN (5 μg/rat recombinant OPN), SAH + rOPN + Fib-14 (30 mg/kg of focal adhesion kinase (FAK) inhibitor-14), and SAH + rOPN + DMSO (dimethyl sulfoxide). Short-term and long-term neurobehavior tests were performed, followed by a collection of brain samples for assessment of autophagy markers in neurons, pathway proteins expression, and delayed hippocampal injury. Western blot, double immunofluorescence staining, Nissl staining, and Fluoro-Jade C staining assay were used. Results showed that rOPN administration increased autophagy in neurons and improved neurobehavior in a rat model of SAH. With the administration of FAK inhibitor-14 (Fib-14), neurobehavioral improvement and autophagy enhancement induced by rOPN were abolished, and there were consistent changes in the phosphorylation level of ERK1/2. In addition, early administration of rOPN in rat SAH models improved long-term neurobehavior results, possibly by alleviating hippocampal injury. These results suggest that FAK–ERK signaling may be involved in OPN-enhanced autophagy in the EBI phase after SAH. Early administration of rOPN may be a preventive and therapeutic strategy against delayed brain injury after SAH.

scholarly journals Ulinastatin alleviates traumatic brain injury by reducing endothelin-1

2020 ◽  
Vol 12 (1) ◽  
pp. 001-008
Author(s):  
Ting Liu ◽  
Xing-Zhi Liao ◽  
Mai-Tao Zhou
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Western Blot ◽  
Water Content ◽  
Brain Edema ◽  
Rat Model ◽  
Neurosurgical Procedures ◽  
Brain Water Content ◽  
The Brain ◽  
Brain Water

Abstract Background Brain edema is one of the major causes of fatality and disability associated with injury and neurosurgical procedures. The goal of this study was to evaluate the effect of ulinastatin (UTI), a protease inhibitor, on astrocytes in a rat model of traumatic brain injury (TBI). Methodology A rat model of TBI was established. Animals were randomly divided into 2 groups – one group was treated with normal saline and the second group was treated with UTI (50,000 U/kg). The brain water content and permeability of the blood–brain barrier were assessed in the two groups along with a sham group (no TBI). Expression of the glial fibrillary acidic protein, endthelin-1 (ET-1), vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) were measured by immunohistochemistry and western blot. Effect of UTI on ERK and PI3K/AKT signaling pathways was measured by western blot. Results UTI significantly decreased the brain water content and extravasation of the Evans blue dye. This attenuation was associated with decreased activation of the astrocytes and ET-1. UTI treatment decreased ERK and Akt activation and inhibited the expression of pro-inflammatory VEGF and MMP-9. Conclusion UTI can alleviate brain edema resulting from TBI by inhibiting astrocyte activation and ET-1 production.

scholarly journals TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yan Zhou ◽  
Tao Tao ◽  
Guangjie Liu ◽  
Xuan Gao ◽  
Yongyue Gao ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Therapeutic Target ◽  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Early Brain Injury ◽  
Neurological Deficits ◽  
Human Brain Tissue

AbstractNeuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.

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