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.

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 L-3-n-butylphthalide protect the neuro by reducing inflammation and brain edema in rat intracerebral hemorrhage model

2019 ◽  
Author(s):  
Zhou Zeng ◽  
Xiyu Gong ◽  
Zhiping Hu
Keyword(s):  
Ischemic Stroke ◽  
Intracerebral Hemorrhage ◽  
Water Content ◽  
Brain Edema ◽  
Blood Brain Barrier ◽  
Vehicle Group ◽  
Brain Water Content ◽  
Tnf Α ◽  
Brain Barrier Permeability ◽  
Brain Water

Abstract Background：Previous studies have shown that L-3-n-butylphthalide(NBP), which is a compound found in Apium graveolens Linn seed extracts, could have neuroprotective effects on acute ischemic stroke through anti-inflammation and by reducing brain edema. The pathological inflammatory pathways and consequent brain edema in intracerebral hemorrhage (ICH) share some characteristics with ischemic stroke. Methods：We hypothesized that NBP has anti-inflammatory and therapeutic effects on rats with ICH. ICH was induced by an infusion of bacterial collagenase type IV into the unilateral striatum of anesthetized rats. The therapeutic effect of NBP was measured by assessing neurological function, brain water content, blood-brain barrier permeability, and expression of tumor necrosis factor-alpha (TNF-α) and matrix metalloproteinase-9 (MMP-9) around the hematoma 48 hours after surgery. Magnetic resonance imaging (MRI) was performed 4 and 48 hours after ICH induction, and ICH-induced injured area volumes were measured using T2-weighted images. Results： The NBP treatment group performed better in the neurological function test than the vehicle group. Moreover, in comparison with the vehicle group, NBP group showed a lower expanded hematoma volume, brain water content, blood-brain barrier permeability, and TNF-α/ MMP-9 expression level. Conclusions：Our results suggested that NBP have a neuroprotective effect by reducing inflammation and brain edema in rat ICH model. Therefore, our findings also show the potential for clinical application of NBP in the treatment of ICH.

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 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.

Abstract WP256: Pretreatment of Rosuvastatin Ameliorates Early Brain Injury after Subarachnoid Hemorrhage through the Inhibition of Microglial Activation in Rats.

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Ken Uekawa ◽  
Yu Hasekawa ◽  
Mingjie Ma ◽  
Takashi Nakagawa ◽  
Tetsuji Katayama ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Brain Edema ◽  
Microglial Activation ◽  
Inflammatory Responses ◽  
Early Brain Injury ◽  
Water Soluble ◽  
Vehicle Group ◽  
Protective Effects ◽  
Anti Inflammatory

BACKGROUND AND PURPOSE: We investigated the protective effects of pretreatment of oral-administered rosuvastatin, a water soluble HMG-CoA reductase inhibitor, on early brain injury (EBI) after subarachnoid hemorrhage (SAH). METHOD: Male Sprague-Dawley rats were operated on with endovascular perforation model and randomly divided into 4 groups: sham-operated, SAH+vehicle, SAH+1mg/kg, or 10mg/kg rosuvastatin. The animals in treatment groups were administered with daily oral rosuvastatin from 7 days before to 1 day after operation. All rats were evaluated regarding neurofunction, brain edema, and blood-brain barrier (BBB) disruption at 24 hours after SAH. Anti-inflammatory responses were also conducted using Western blot and immunohistochemistry at 24 hours after SAH. RESULTS: Compared with the vehicle group, rosuvastatin significantly improved the neurofunction score (modified Garcia score/ 22: 13.0±1.6 vs 17.0±1.0, P <0.05) , brain edema (brain water content: 79.11±0.15% vs 78.68±0.09%, P <0.05) , and BBB disruption (IgG extravasation); data are showed as a mean±SEM. Rosuvastatin reduced number of activated microglial cells , activation of nuclear factor-kappa B(NF-kB), and expression of tumor necrosis factor-alpha (TNF-α) , which were considered as markers of inflammatory response from microglia, and downregulated the expression of neuronal cyclooxygenase-2 (COX-2) and endothelial matrix metalloproteinase-9 (MMP-9). CONCLUSION: The current study showed that pretreatment of rosuvastatin induced anti-inflammatory processes through inhibition of microglial activation and thereby attenuated early brain injury. Rosuvastatin seems to be a promising agent for treatment of SAH.

FGF10 Attenuates Experimental Traumatic Brain Injury through TLR4/MyD88/NF-κB Pathway

2021 ◽  
pp. 1-9
Author(s):  
Qinhan Hou ◽  
Hongmou Chen ◽  
Quan Liu ◽  
Xianlei Yan
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Protein Expression ◽  
Water Content ◽  
Neurological Deficit ◽  
Neuronal Apoptosis ◽  
Neuronal Damage ◽  
Intraventricular Injection ◽  
Brain Water Content ◽  
Brain Water

Traumatic brain injury (TBI) can induce neuronal apoptosis and neuroinflammation, resulting in substantial neuronal damage and behavioral disorders. Fibroblast growth factors (FGFs) have been shown to be critical mediators in tissue repair. However, the role of FGF10 in experimental TBI remains unknown. In this study, mice with TBI were established via weight-loss model and validated by increase of modified neurological severity scores (mNSS) and brain water content. Secondly, FGF10 levels were elevated in mice after TBI, whereas intraventricular injection of Ad-FGF10 decreased mNSS score and brain water content, indicating the remittance of neurological deficit and cerebral edema in TBI mice. In addition, neuronal damage could also be ameliorated by stereotactic injection of Ad-FGF10. Overexpression of FGF10 increased protein expression of Bcl-2, while it decreased Bax and cleaved caspase-3/PARP, and improved neuronal apoptosis in TBI mice. In addition, Ad-FGF10 relieved neuroinflammation induced by TBI and significantly reduced the level of interleukin 1β/6, tumor necrosis factor α, and monocyte chemoattractant protein-1. Moreover, Ad-FGF10 injection decreased the protein expression level of Toll-like receptor 4 (TLR4), MyD88, and phosphorylation of NF-κB (p-NF-κB), suggesting the inactivation of the TLR4/MyD88/NF-κB pathway. In conclusion, overexpression of FGF10 could ameliorate neurological deficit, neuronal apoptosis, and neuroinflammation through inhibition of the TLR4/MyD88/NF-κB pathway, providing a potential therapeutic strategy for brain injury in the future.

scholarly journals Expression of IL-1β, IL-6 and TNF-α in rats with thioacetamide-induced acute liver failure and encephalopathy: correlation with brain edema

2011 ◽  
Vol 5 (2) ◽  
pp. 205-215 ◽  
Author(s):  
Li-Qing Wang ◽  
Heng-Jun Zhou ◽  
Cai-Fei Pan ◽  
Sheng-Mei Zhu ◽  
Lin-Mei Xu
Keyword(s):  
Hepatic Encephalopathy ◽  
Motor Activity ◽  
Water Content ◽  
Brain Edema ◽  
Proinflammatory Cytokines ◽  
Enzyme Linked Immunosorbent Assay ◽  
Brain Water Content ◽  
Tnf Α ◽  
The Relationship ◽  
Brain Water

Abstract Background: Secondary brain edema is a serious complication of hepatic encephalopathy (HE). Recently, it has been reported that proinflammatory cytokines are involved in the pathogenesis of brain edema during HE. Objectives: Observe the dynamic expressions of brain and plasma proinflammatory cytokines in encephalopathy rats, and evaluate the relationship between proinflammatory cytokines and brain edema. Methods: Acute HE rats were induced by intraperitoneal injection of thioacetamide (TAA) in 24 hours intervals for two consecutive days. Then, clinical symptom and stages of hepatic encephalopathy, motor activity counts, index of liver function, and brain water content were observed. The dynamic expressions of IL-1β, IL-6, and TNF-α in plasma and brain tissues were measured with enzyme-linked immunosorbent assay. Results: Typical clinical performances of hepatic encephalopathy were occurred in all TAA-administrated rats. The TAA rats showed lower motor activity counts and higher the index of alanine aminotransferase, aspartate aminotransferase, total bilirubin and ammonia than those in control rats. Brain water content was significantly enhanced in TAA rats compared with the control. The expressions of IL-1β, IL-6, and TNF- α in plasma and brain significantly increased in TAA rats. In addition, the expressions of cerebral proinflammatory cytokines were positively correlated with brain water content but negatively correlated with motor activity counts.Conclusion: Inflammation was involved in the pathogenesis of brain edema during TAA-induced HE.

Brain edema after intracerebral hemorrhage in rats: the role of iron overload and aquaporin 4

2009 ◽  
Vol 110 (3) ◽  
pp. 462-468 ◽  
Author(s):  
Wang Gai Qing ◽  
Yang Qi Dong ◽  
Tang Qing Ping ◽  
Li Guang Lai ◽  
Li Dong Fang ◽  
...  
Keyword(s):  
Iron Overload ◽  
Water Content ◽  
Brain Edema ◽  
Time Course ◽  
Iron Chelator ◽  
Brain Water Content ◽  
Edema Formation ◽  
Aqp4 Expression ◽  
The Right ◽  
Brain Water

Object Brain edema formation following intracerebral hemorrhage (ICH) appears to be partly related to erythrocyte lysis and hemoglobin release. An increase of brain water content was associated with an increase of brain iron, which is an erythrocyte degradation product. Expression of AQP4 is highly modified in several brain disorders, and it can play a key role in cerebral edema formation. However, the question whether AQP4 is regulated by drugs lacks reliable evidence, and the interacting roles of iron overload and AQP4 in brain edema after ICH are unknown. The goal of this study was to clarify the relationship between iron overload and AQP4 expression and to characterize the effects of the iron chelator deferoxamine (DFO) on delayed brain edema after experimental ICH. Methods A total of 144 Sprague-Dawley rats weighing between 250 and 300 g were used in this work. The animals were randomly divided into 4 groups. The ICH models (Group C) were generated by injecting 100 μl autologous blood stereotactically into the right caudate nucleus; surgical control rats (Group B) were generated in a similar fashion, by injecting 100 μl saline into the right caudate nucleus. Intervention models (Group D) were established by intraperitoneal injection of DFO into rats in the ICH group. Healthy rats (Group A) were used for normal control models. Brain water content, iron deposition, and AQP4 in perihematomal brain tissue were evaluated over the time course of the study (1, 3, 7, and 14 days) in each group. Results Iron deposition was found in the perihematomal zone as early as the 1st day after ICH, reaching a peak after 7 days and remaining at a high level thereafter for at least 14 days following ICH. Rat brain water content around the hematoma increased progressively over the time course, reached its peak at Day 3, and still was evident at Day 7 post-ICH. Immunohistochemical analysis showed that AQP4 was richly expressed over glial cell processes surrounding microvessels in the rat brain; there was upregulation of the AQP4 expression in perihematomal brain during the observation period, and it reached maximum at 3 to 7 days after ICH. The changes of brain water content were accompanied by an alteration of AQP4. The application of the iron chelator DFO significantly reduced iron overload, brain water content, and AQP4 level in the perihematomal area compared with the control group. Conclusions Iron overload and AQP4 may play a critical role in the formation of brain edema after ICH. In addition, AQP4 expression was affected by iron concentration. Importantly, treatment with DFO significantly reduced brain edema in rats and inhibited the AQP4 upregulation after ICH. Deferoxamine may be a potential therapeutic agent for treating ICH.

Effect of sex steroid hormones on brain edema, intracranial pressure, and neurologic outcomes after traumatic brain injury

2010 ◽  
Vol 88 (4) ◽  
pp. 414-421 ◽  
Author(s):  
Nader Shahrokhi ◽  
Mohammad Khaksari ◽  
Zahra Soltani ◽  
Mehdi Mahmoodi ◽  
Nouzar Nakhaee
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Intracranial Pressure ◽  
Steroid Hormones ◽  
Brain Edema ◽  
Sex Steroid Hormones ◽  
Female Rats ◽  
Sex Steroid ◽  
Vehicle Group ◽  
Ovx Rats

Recent studies have reported that estrogen and progesterone have a neuroprotective effect after traumatic brain injury (TBI); however, the mechanism(s) for this effect have not yet been elucidated. The aim of the present study was to investigate the role of sex steroid hormones on changes in brain edema, intracranial pressure (ICP), and cerebral perfusion pressure (CPP) after TBI in ovariectomized (OVX) rats. In this study, 50 female rats were divided into 5 groups: control (intact), sham, and 3 TBI groups consisting of vehicle, estrogen (1 mg/kg), and progesterone (8 mg/kg). TBI was induced by the Marmarou method, and the hormones were injected i.p. 30 min after TBI. ICP was measured in the spinal cord, and CPP was calculated by subtracting the mean arterial pressure (MAP) from ICP. The results revealed that brain water content after TBI was lower (p < 0.001) in the estrogen and progesterone groups than in the vehicle group. After trauma, ICP was significantly higher in TBI rats (p < 0.001). The ICP in the estrogen and progesterone groups decreased at 4 and 24 h after TBI compared with vehicle (p < 0.001 and p < 0.05, respectively). The CPP in the estrogen and progesterone groups increased after 24 h compared with vehicle (p < 0.001). Also after TBI, the neurological score (veterinary coma scale) was significantly higher than vehicle at 1 h (p < 0.01) and 24 h (p < 0.001) in the group treated with estrogen. In conclusion, pharmacological doses of estrogen and progesterone improved ICP, CPP, and neurological scores after TBI in OVX rats, which implies that these hormones play a neuroprotective role in TBI.

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