scholarly journals Rehmannia and Rhubarb Decoction Exerts Neuroprotective Effects on the Blood-brain barrier during Acute Intracerebral Hemorrhage by Downregulating the HMGB1/TLR4/MMP9 signaling pathway

2020 ◽  
Author(s):  
Shan Jiang ◽  
Chun-Mei Li ◽  
Ding-Fang Cai ◽  
Jing-Si Zhang ◽  
Xiao-Fei Yu
Keyword(s):  
Intracerebral Hemorrhage ◽  
Protective Effect ◽  
Water Content ◽  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Evans Blue ◽  
Brain Barrier ◽  
Brain Water Content ◽  
Acute Intracerebral Hemorrhage ◽  
Brain Water

Abstract Background Blood-brain barrier (BBB) is a gate-keeping system with selective permeability that serves to protect the central nervous system. The underlying neuroprotective mechanism of the BBB during acute intracerebral hemorrhage (ICH) remains poorly understood. Rehmannia and rhubarb decoction (RRD) is a classic traditional Chinese medicine formula that has been extensively applied for hemorrhagic diseases in China. In the present study, the potential protective effects of RRD on the BBB during acute ICH and the underlying mechanism were investigated. Methods The ICH model was established by injection of autologous blood (100 µl) into spontaneously hypertensive rats, which were randomly divided into the following groups: i) Sham; ii) ICH; iii) RRD; iv) TAK-242; v) TAK-242 + RRD; vi) high mobility group box 1 protein (HMGB1) inhibitor ethyl pyruvate (EP); and vii) EP + RRD. Neurological deficits, pathological examination, brain water content, Evans blue(EB) extravasation, immunofluorescence staining and the expression levels of HMGB1, toll-like receptor 4 (TLR4), matrix metalloproteinase 9 (MMP-9), Claudin-5, Occludin and zona occludens − 1 (Zo-1) were subsequently examined in each group on day 3 following operation. In addition, MRI and transmission electron microscopy were also performed to observe the BBB structure. Results RRD treatment markedly improved neurological functions, reduced brain water content and Evans blue extravasation, ameliorated the disruption of BBB and downregulated HMGB1, TLR4 and MMP-9 expression whilst upregulating the expression of Claudin-5, Occludin and Zo-1. Conclusion These results demonstrate that RRD has a protective effect on the BBB in rats during ICH and this protective effect is related to the down-regulation of HMGB1/TLR4/MMP9 signaling pathway.

scholarly journals Sheng-Di-Da-Huang Decoction Inhibited Inflammation Expressed in Microglia after Intracerebral Hemorrhage in Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Min Cai ◽  
Zhonghai Yu ◽  
Wen Zhang ◽  
Li Yang ◽  
Jun Xiang ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Water Content ◽  
Evans Blue ◽  
Microglial Activation ◽  
Critical Role ◽  
Neurological Deficits ◽  
Secondary Brain Injury ◽  
Brain Water Content ◽  
Evans Blue Extravasation ◽  
Brain Water

Objects. Sheng-Di-Da-Huang Decoction was used as an effective hemostatic agent in ancient China. However, its therapeutic mechanism is still not clear. Inflammatory injury plays a critical role in ICH-induced secondary brain injury. After hemolysis, hematoma components are released, inducing microglial activation via TLR4, which initiates the activation of transcription factors (such as NF-κB) to regulate expression of proinflammatory cytokine genes. This study aimed to verify the anti-inflammatory effects of Sheng-Di-Da-Huang Decoction on ICH rats. Materials and Methods. Intracerebral hemorrhage was induced by injection of bacterial collagenase (0.2 U) in rats. Neurological deficits, brain water content, Evans blue extravasation, expression of TLR4, NF-κB, Iba-1 positive cells (activated microglia), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were examined 1, 3, 7, and 14 days after collagenase injection. MR images were also studied. Results. Sheng-Di-Da-Huang Decoction remarkably improved neurological function, reduced brain water content as well as Evans blue extravasation, downregulated expression of TLR4, NF-κB, TNF-α, and IL-1β, and inhibited microglial activation. Conclusions. Sheng-Di-Da-Huang Decoction reduced inflammation reaction after ICH through inhibited inflammation expressed in microglia.

scholarly journals GOLGA2/GM130 is a novel target of neuroprotection therapy in intracerebral hemorrhage

2021 ◽  
Author(s):  
shu wen deng ◽  
Qing Hu ◽  
Qiang He ◽  
Xi qian Chen ◽  
Qiang Lei ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Water Content ◽  
Autophagy Flux ◽  
Blood Brain ◽  
Brain Water

Abstract Background Impairment of the blood-brain barrier after intracerebral hemorrhage (ICH) can lead to secondary brain injury and aggravate neurological deficits. Owing in part to our lack of understanding of the mechanism of ICH injury to the blood-brain barrier, there are currently no effective methods to prevent or treat it. Here, we explored the effects of Golgi apparatus protein GM130 overexpression or silencing on the blood-brain barrier and neurological function after ICH, to better understand the mechanism involved and facilitate the development of new therapeutic methods. Results Levels of the tight junction-associated proteins ZO-1 and occludin decreased, while those of LC3-II, a marker for autophagosomes, increased in hemin-treated Bend.3 cells (p < 0.05). The levels of ZO-1 and occludin increased, while those of LC3-II decreased with GM130 overexpression (p < 0.05). ZO-1 and occludin expression decreased and LC3-II increased after siGM130 transfection, mimicking the effect of hemin (p < 0.05). Tight junctions were disconnected after hemin or siGM130 treatment and repaired with GM130 overexpression. siGM130 transfection in Bend.3 cells increased autophagy flux, whereas GM130 overexpression downregulated autophagy flux. Similar results were verified in an in vivo ICH model. Perihematomal ZO-1 and occludin expression increased, while LC3-II expression decreased in ICH rats (p < 0.05). ZO-1 and occluding expression further decreased and LC3-II expression increased in siGM130-treated ICH rats (p < 0.05), whereas a reverse effect was observed in AAV-GM130-treated ICH rats (p < 0.05). Perihematomal Evans blue and brain water content were much higher in siGM130-treated ICH rats than in the control ICH rats. AAV-GM130-treated ICH rats showed a lower perihematomal Evans blue and brain water content than the control ICH rats. Conclusions GM130 overexpression can protect the integrity of the blood-brain barrier from brain injury, inhibit excessive autophagy flux in an ICH in vivo model, and further improve the neurobehavioral prognosis. GM130 overexpression may mediate tight junction protein repair by directly reducing autophagy flux in an ICH in vitro model. GM130 may be a therapeutic target for acute brain injury after ICH.

Abstract TP350: Escin Attenuates the Impairment of Neurological Function by Ameliorating Systemic Inflammation in Intracerebral Hemorrhagic Mice

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Fenghua Fu ◽  
Tian Wang
Keyword(s):  
Water Content ◽  
Signaling Pathway ◽  
Systemic Inflammation ◽  
Evans Blue ◽  
Test Scores ◽  
Neurological Function ◽  
Brain Water Content ◽  
Evans Blue Extravasation ◽  
Brain Water ◽  
Water Contents

Background and Purpose: Escin could attenuate cerebral ischemia-induced brain injury. The present study aimed to investigate whether Escin may attenuate the impairment of neurological function by ameliorating systemic inflammation in ICH mice. Methods: The ICH model was prepared by intrastriatal injection of collagenase. At 0.5 h, 2 h, 6 h and 12 h after Escin injection, the concentration of Escin in the serum and brain were detected. The effects of Escin on the Garcia test were evaluated. Brain water content was observed via a wet/dry weight method. Evans blue extravasation in the cerebrums were also assayed. The serum IL-1β level was detected with the ELISA kit. The ICH mice were further treated with Escin plus IL-1β. At 24 h of the ICH, Garcia test, and brain water content, the Evans blue extravasation and serum IL-1β levels were evaluated. Additionally, the expression of RhoA, ROCK1, IκBα, nuclear NF-κB, cytosolic NF-κB, Occludin and Claudin-5 in mice brain tissue were investigated with the Western blot. Results: Escin was detected in the serum of the Control group and ICH group at 0.5 h, 2 h, 6 h and 12 h after Escin administration. Escin was not detected in brain tissues at any time points in the animals. At 24 h and 72 h of ICH, the Garcia test scores in the Escin groups were significantly increased ( P < 0.05 or P < 0.01). Brain water contents and Evans blue extravasation of the right basal ganglia in the Escin groups were significantly reduced ( P < 0.05 or P < 0.01). Escin abated the increase of IL-1β induced by ICH ( P < 0.05 or P < 0.01). IL-1β administration reversed the effect of Escin on Garcia test scores, the brain water contents, and the Evans blue extravasation ( P < 0.01). In the ICH group, the levels of RhoA, ROCK1, nuclear NF-κB were increased while the expression of IκBα, cytosolic NF-κB, Occludin, Claudin-5 were reduced ( P < 0.05 or P < 0.01). However, Escin abated RhoA, ROCK1, nuclear NF-κB and augmented IκBα, cytosolic NF-κB, Occludin, and Claudin-5. IL-1β administration partially blocked the Escin-mediated regulation of IL-1β/RhoA/NF-κB signaling pathway. Conclusion: Escin cannot penetrate the blood brain barrier (BBB). Escin improves neurological function and by inhibiting systemic inflammation, and then regulating IL-1β/RhoA/NF-κB signaling pathway in BBB.

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 Meprin β: A novel regulator of blood–brain barrier integrity

2020 ◽  
Vol 41 (1) ◽  
pp. 31-44
Author(s):  
Markus Gindorf ◽  
Steffen E Storck ◽  
Anke Ohler ◽  
Franka Scharfenberg ◽  
Christoph Becker-Pauly ◽  
...  
Keyword(s):  
Water Content ◽  
Blood Brain Barrier ◽  
Mouse Brain ◽  
Brain Barrier ◽  
Brain Water Content ◽  
Cerebral Microvessels ◽  
Knock Out ◽  
Blood Brain ◽  
Primary Mouse ◽  
Brain Water

The metalloprotease meprin β (Mep1b) is capable of cleaving cell-adhesion molecules in different tissues (e.g. skin, kidney and intestine) and is dysregulated in several diseases associated with barrier breakdown (Alzheimer´s disease, kidney disruption, inflammatory bowel disease). In this study, we demonstrate that Mep1b is a novel regulator of tight junction (TJ) composition and blood–brain barrier (BBB) integrity in brain endothelium. In Mep1b-transfected mouse brain endothelial cells (bEnd.3), we observed a reduction of the TJ protein claudin-5, decreased transendothelial electrical resistance (TEER) and an elevated permeability to paracellular diffusion marker [14C]-inulin. Analysis of global Mep1b knock-out (Mep1b−/−) mice showed increased TJ protein expression (claudin-5, occludin, ZO-1) in cerebral microvessels and increased TEER in cultivated primary mouse brain endothelial compared to wild-type (wt) mice. Furthermore, we investigated the IgG levels in cerebrospinal fluid (CSF) and the brain water content as additional permeability markers and detected lower IgG levels and reduced brain water content in Mep1b−/− mice compared to wt mice. Showing opposing features in overexpression and knock-out, we conclude that Mep1b plays a role in regulating brain endothelial TJ-proteins and therefore affecting BBB tightness in vitro and in vivo.

Effects of postnatal dexamethasone on blood-brain barrier permeability and brain water content in newborn lambs

2001 ◽  
Vol 280 (2) ◽  
pp. R547-R553 ◽  
Author(s):  
Gregory D. Sysyn ◽  
Katherine H. Petersson ◽  
Clifford S. Patlak ◽  
Grazyna B. Sadowska ◽  
Barbara S. Stonestreet
Keyword(s):  
Water Content ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Water Content ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Postnatal Treatment ◽  
Brain Water

We showed that antenatal corticosteroids reduced blood-brain barrier permeability in fetuses at 60 and 80%, but not 90% of gestation, and decreased brain water content in fetuses. Our objective was to examine the effects of postnatal corticosteroids on regional blood-brain barrier permeability and brain water content in newborn lambs. Three dexamethasone treatment groups were studied in 3- to 5-day-old lambs. A 0.01 mg/kg dose was selected to estimate the amount of dexamethasone that might have reached fetuses via antenatal treatment of ewes in our previous studies. The other doses (0.25 and 0.5 mg/kg) were chosen to approximate those used clinically to treat infants with bronchopulmonary dysplasia. Lambs were randomly assigned to receive four intramuscular injections of dexamethasone or placebo given 12 h apart on days 3 and 4 of age. Blood-brain barrier function was measured with the blood-to-brain transfer constant ( K i) to α-aminoisobutyric acid, brain plasma volume was measured with polyethylene glycol for the calculation of K i, and brain water was measured by wet-to-dry tissue weights. Postnatal treatment with corticosteroids did not reduce barrier permeability in newborn lambs. Brain blood volume was higher in the 0.25 and 0.5 mg/kg dose dexamethasone groups than in the placebo group. Brain water content did not differ among the groups. We conclude that postnatal treatment with corticosteroids did not reduce regional blood-brain barrier permeability or brain water content but increased the brain plasma volume in newborn lambs. These findings are consistent with our previous work indicating that barrier permeability is responsive to corticosteroids at 60 and 80% of gestation and brain water regulation at 60% of gestation, but not in near-term fetuses or newborn lambs.

scholarly journals Metabolic Insight Into the Neuroprotective Effect of Tao-He-Cheng-Qi (THCQ) Decoction on ICH Rats Using Untargeted Metabolomics

2021 ◽  
Vol 12 ◽  
Author(s):  
Rui-Pei Yang ◽  
Da-Ke Cai ◽  
Yu-Xing Chen ◽  
Hai-Ning Gang ◽  
Mei Wei ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Amino Acid ◽  
Intracerebral Hemorrhage ◽  
Water Content ◽  
Sham Group ◽  
Neuroprotective Effect ◽  
Treated Group ◽  
Brain Water Content ◽  
Model Group ◽  
Brain Water

Tao-He-Cheng-Qi decoction (THCQ) is an effective traditional Chinese medicine used to treat intracerebral hemorrhage (ICH). This study was performed to investigate the possible neuroprotective effect of THCQ decoction on secondary brain damage in rats with intracerebral hemorrhage and to elucidate the potential mechanism based on a metabolomics approach. Sprague-Dawley (SD) rats were randomly divided into five groups: the sham group, collagenase-induced ICH model group, THCQ low-dose (THCQ-L)-treated group, THCQ moderate-dose (THCQ-M)-treated group and THCQ high-dose (THCQ-H)-treated group. Following 3 days of treatment, behavioral changes and histopathological lesions in the brain were estimated. Untargeted metabolomics analysis with multivariate statistics was performed by using ultrahigh-performance liquid chromatography–mass spectrometry (UPLC-Q-Exactive Orbitrap MS). THCQ treatment at two dosages (5.64 and 11.27 g/kg·d) remarkably improved behavior (p &lt; 0.05), brain water content (BMC) and hemorheology (p &lt; 0.05) and improved brain nerve tissue pathology and inflammatory infiltration in ICH rats. Moreover, a metabolomic analysis demonstrated that the serum metabolic profiles of ICH patients were significantly different between the sham group and the ICH-induced model group. Twenty-seven biomarkers were identified that potentially predict the clinical benefits of THCQ decoction. Of these, 4 biomarkers were found to be THCQ-H group-specific, while others were shared between two clusters. These metabolites are mainly involved in amino acid metabolism and glutamate-mediated cell excitotoxicity, lipid metabolism-mediated oxidative stress, and mitochondrial dysfunction caused by energy metabolism disorders. In addition, a correlation analysis showed that the behavioral scores, brain water content and hemorheology were correlated with levels of serum metabolites derived from amino acid and lipid metabolism. In conclusion, the results indicate that THCQ decoction significantly attenuates ICH-induced secondary brain injury, which could be mediated by improving metabolic disorders in cerebral hemorrhage rats.

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