AIM:To study the blood-brain barrier integrity,brain edema, animal behavior and ammonia plasma levels in prehepatic portal hypertensive rats with and without acute liver intoxication. METHODS:Adults male Wistar rats w...AIM:To study the blood-brain barrier integrity,brain edema, animal behavior and ammonia plasma levels in prehepatic portal hypertensive rats with and without acute liver intoxication. METHODS:Adults male Wistar rats were divided into four groups.Group Ⅰ:sham operation;Ⅱ:Prehepatic portal hypertension,produced by partial portal vein ligation;Ⅲ: Acetaminophen intoxication and Ⅳ:Prehepatic portal hypertension plus acetaminophen.Acetaminophen was administered to produce acute hepatic injury.Portal pressure,liver serum enzymes and ammonia plasma levels were determined.Brain cortex water content was registered and trypan blue was utilized to study blood brain barrier integrity.Reflexes and behavioral tests were recorded. RESULTS:Portal hypertension was significantly elevated in groups Ⅱ and Ⅳ.Uver enzymes and ammonia plasma levels were increased in groups Ⅱ,Ⅲ and Ⅳ.Prehepatic portal hypertension (group Ⅱ),acetaminophen intoxication (group Ⅲ) and both (group Ⅳ) had changes in the blood brain-barrier integrity (trypan blue) and hyperammonemia.Cortical edema was present in rats with acute hepatic injury in groups Ⅲ and Ⅳ.Behavioral test (rota rod) was altered in group Ⅳ. CONCLUSION:These results suggest the possibility of another pathway for cortical edema production because blood brain barrier was altered (vasogenic) and hyperammonemia was registered (oltotoxic).Group Ⅳ,with behavioral altered test,can be considered as a model for study at an early stage of portal-systemic encephalopathy.展开更多
Purpose: The purpose of this study was to investigate the effects of obesity and high-intensity acute exercise on oxidant-antioxidant status,neurotrophic factor expression, and blood-brain barrier(BBB) disruption.Meth...Purpose: The purpose of this study was to investigate the effects of obesity and high-intensity acute exercise on oxidant-antioxidant status,neurotrophic factor expression, and blood-brain barrier(BBB) disruption.Methods: Twenty-four healthy, untrained men(12 non-obese(mean 14.9% body fat) and 12 obese subjects(mean 29.8% body fat)) performed20 min of continuous submaximal aerobic exercise at 85% maximal oxygen consumption. Blood sampling was performed to examine the oxidant-antioxidant status(reactive oxygen species(ROS) and superoxide dismutase(SOD)), neurotrophic factors(brain-derived neurotrophic factor(BDNF) and nerve growth factor(NGF)), and BBB disruption(S100β and neuron-specific enolase) before and after acute exercise.Results: The obese group showed significantly higher pre-exercise serum ROS levels and significantly lower pre-exercise serum SOD levels than the non-obese group(p < 0.05). Serum ROS, SOD, BDNF, NGF, and S100β levels were significantly increased post-exercise compared with pre-exercise levels in both the non-obese and the obese groups(p < 0.05). The obese group showed significantly higher serum ROS, BDNF, NGF,and S100β levels post-exercise compared to the non-obese group(p < 0.05).Conclusion: Our study suggests that episodic vigorous exercise can increase oxidative stress and blood neurotrophic factor levels and induce disruption of the BBB. Moreover, high levels of neurotrophic factor in the blood after exercise in the obese group may be due to BBB disruption,and it is assumed that oxidative stress was the main cause of this BBB disruption.展开更多
AIM： To study the blood-brain barrier integrity in prehepatic portal hypertensive rats induced by partial portal vein ligation, at 14 and 40 dafer ligation when portal pressure is spontaneously normalized. METHODS： ...AIM： To study the blood-brain barrier integrity in prehepatic portal hypertensive rats induced by partial portal vein ligation, at 14 and 40 dafer ligation when portal pressure is spontaneously normalized. METHODS： Adult male Wistar rats were divided into four groups： Group Ⅰ： Sham14d, sham operated; Group Ⅱ： PHil, portal vein stenosis, （both groups were used 14 days after surgery）; Group Ⅲ： Sham4od, Sham operated and Group Ⅳ： PH4od Portal vein stenosis （Groups Ⅱ and Ⅳ used 40 d afer surgery）. Plasma ammonia, plasma and cerebrospinal fluid protein and liver enzymes concentrations were determined. Trypan and Evans blue dyes, systemically injected, were investigated in hippocampus to study blood-brain barrier integrity. Portal pressure was periodically recorded. RESULTS： Forty days afer stricture, portal pressure was normalized, plasma ammonia was moderately high, and both dyes were absent in central nervous system parenchyma. All other parameters were reestablished. When portal pressure was normalized and ammonia level was lowered, but not normal, the altered integrity of blood-brain barrier becomes reestablished. CONCLUSION： The impairment of blood-brain barrier and subsequent normalization could be a mechanism involved in hepatic encephalopathy reversibility. Hemodynamic changes and ammonia could trigger blood-brain barrier alterations and its reestablishment.展开更多
Cromakalim,an adenosine triphosphate-sensitive potassium channel opener,exhibits protective effects on cerebral ischemia/reperfusion injury.However,there is controversy as to whether this effect is associated with aqu...Cromakalim,an adenosine triphosphate-sensitive potassium channel opener,exhibits protective effects on cerebral ischemia/reperfusion injury.However,there is controversy as to whether this effect is associated with aquaporin-4 and blood-brain barrier permeability.Immunohistochemistry results show that preventive administration of cromakalim decreased aquaporin-4 and IgG protein expression in rats with ischemia/reperfusion injury;it also reduced blood-brain barrier permeability,and alleviated brain edema,ultimately providing neuroprotection.展开更多
Brain metastases are common intracranial tumors, and their occurrence not only represents a high degree of malignancy, but also often is the major factor in treatment failure and poor prognosis. Primary site of brain ...Brain metastases are common intracranial tumors, and their occurrence not only represents a high degree of malignancy, but also often is the major factor in treatment failure and poor prognosis. Primary site of brain metastases often occur in lung. P-glycoprotein is a member of the （ATP binding cassette） transporter superfamily,which is closely related to the development of lung metastases. It is the main reason for influencing the drug through the blood_brain barrier into the brain tissue, and it also is an important factor affecting the treatment of brain metastases. According to the theory of traditional chinese mddicine, the pathogenesis of brain metastases is due to phlegm, poison, stasis, virtual and so on. The principle of treatment is to promote blood circulation, remove phlegm turbidity. In recent years, the impact of Chinese herbal medicine on P-glycoprotein is increasing. This paper analyzes the mechanism and components of the relevant Chinese medicine on P-glycoprotein. It provides a reference for clinical rational drug use.展开更多
EAE （experimental autoimmune encephalomyelitis） is an established, inducible animal model employed in the study of MS （multiple sclerosis） characterized by inflammation, BBB （blood brain barrier） malfunction, de...EAE （experimental autoimmune encephalomyelitis） is an established, inducible animal model employed in the study of MS （multiple sclerosis） characterized by inflammation, BBB （blood brain barrier） malfunction, demyelination and neuronal disruption. CRF （corticotropin releasing factor） is a neuropeptide critically associated with immune function, BBB permeability, and the hypothalamic-pituitary-adrenal axis. Potential CRF targets in the brain include astrocytes, as well as endothelial cells of cerebral microvessels, since they have been reported to express CRFR （CRF receptors）. Further, both of these cell types function critically in regulating BBB permeability. CRF-BP （CRF binding protein） is also expressed in both neurons and glial cells. Changes in the cortical CRF system could be a contributing factor to the BBB disruption associated with MS/EAE and has been suggested to play a protective role against cytokine-induced inflammation. The current study assessed alterations associated with the C57BL/6 mouse model of EAE in the cortical CRF system and correlated these events with changes to the microvascular unit. Immunohistochemical confocal microscopy was used to analyze the distribution of CRF, CRF-BP, and CRFR in the mouse cerebral cortex. The authors observed a reduction in detectable CRF immunofluorescence in the EAE motor cortex, an increase in CRFBP immunoreactivity in EAE astrocytes and a concurrent reduction in astrocytic CRFR immunofluorescence. Staining techniques were used to visualize astrocytes/microvessels to document alterations in BBB integrity. Changes in the CRF system were associated with a modification of the blood brain barrier as manifested by a poorly defined astrocytic barrier in EAE microvessels. Evidence suggests that manipulation of CRF signaling pathways offers an intriguing target for interventional therapies designed to modify BBB permeability that may be beneficial for treating disease states such as MS.展开更多
OBJECTIVE: To study whether recombinant adeno-associated virus (rAAV) mediated foreign gene, LacZ, could pass the blood brain barrier by intra-carotid artery delivery and express in vivo in ischemic brain of the foc...OBJECTIVE: To study whether recombinant adeno-associated virus (rAAV) mediated foreign gene, LacZ, could pass the blood brain barrier by intra-carotid artery delivery and express in vivo in ischemic brain of the focal embolic stroke rats to investigate a possibility of delivering foreign gene through carotid artery to treat acute ischemic stroke. METHODS: The carotid artery territory in 41 rats was embolized with or without arterial-like fibrin rich clots to make a model of focal embolic stroke rat. rAAV containing LacZ gene (rAAV-LacZ) was constructed in 293 cells by calcium phosphate cotransfection. The rats were assigned to one of the following treatments: 1 control (without embolism) groups, including PBS treated (n = 6), pLacZ treated (n = 6 ) and rAAV-LacZ treated (n = 6): 2 embolic groups, including embolism + PBS (n =7),embolism + pLacZ (n = 8) and embolism + rAAV-LacZ (n = 8). Brains were cryosectioned and kappa-Gal stain was performed at 2, 4, and 8 weeks, respectively, after transfection, and then infarct volume was measured and the percentage of LacZ staining-positive cells was calculated. RESULTS: In all the control groups and embolism + PBS treated animal, no kappa-Gal staining-positive cells were found, but in embolism + pLacZ (n = 8) and embolism+rAAV-LacZ groups a lot of kappa-Gal staining-positive cells were found. The expression cells were in the tissues around the infarction. The gene expression persisted only nearly four weeks in embolic group with pLacZ. In the embolic group with rAAV-LacZ the expression was very stable during the experiment course (eight weeks) and the percentage of the expressed cells was significantly higher than that of its contralateral areas at the same time points, respectively. CONCLUSIONS: The plasmid vector and rAAV could enter the brain through the ischemia-damaged blood barrier and foreign gene can be expressed in brain. The positive gene expression is mainly in the peripheral areas of the infarction. rAAV as a permanent expression vector may ultimately be used for gene therapy of human ischemia cerebravascular diseases.展开更多
We investigated the effects of glucosamine(GS) on blood-brain barrier(BBB) function and matrix metalloproteinase-9 (MMP-9) expression in rats with experimental autoimmune encephalomyelitis(EAE).Animals were randomly d...We investigated the effects of glucosamine(GS) on blood-brain barrier(BBB) function and matrix metalloproteinase-9 (MMP-9) expression in rats with experimental autoimmune encephalomyelitis(EAE).Animals were randomly divided into three groups,among which the EAE and GS groups were immunized with complete antigen and pertussis toxin,and the adjuvant group was immunized with complete Freund's adjuvant and pertussis toxin.Rats were treated by peritoneal injection of GS 180 mg/(kg·d) in the GS group and peritoneal injection of phosphate-buffered saline 4.5 mL/(kg·d) in the EAE and adjuvant groups.We proposed to assess the integrity of BBB by calculating cerebrospinal fluid to serum albumin quotient(QA) on days 6,8,10,12,14,16 and 18 post-immunization.At the same time,the brains and spinal cords were removed for MMP-9 immunohistochemical staining. Experiments demonstrated that in the EAE group,QA value and MMP-9 expression were highly elevated and up-regulated and correlated to disease severity.Moreover,there was statistically significantly positive correlation between QA value and MMP-9 expression.In the GS group,we observed that the mean disease onset date was delayed,the incidence and mean score of symptom were suppressed at the peak phase of disease(P<0.05).Furthermore,QA value and MMP-9 expression in the GS group showed stronger inhibition when compared with those of the EAE group(P<0.05).Our study showed that GS would reduce the BBB breakdown and leukocyte trafficking by inhibiting the production of MMP-9 and mitigate EAE.展开更多
Objective To investigate the underlying mechanism for the selective modulation of the permeability of blood-tumor barrier(BTB) by small dose of bradykinin(BK). Methods C6 glioma cells were treated with BK,and changes ...Objective To investigate the underlying mechanism for the selective modulation of the permeability of blood-tumor barrier(BTB) by small dose of bradykinin(BK). Methods C6 glioma cells were treated with BK,and changes of intracellular nitric oxide(NO) and intracellular calcium level were measured with fluorescent spectrophotometer. Results The initial application of BK easily triggered extracellular calcium influx,which resulted in intracellular calcium store release in C6 glioma cells. The above mechanism w...展开更多
Small vessel disease （SVD） is responsible for brain chronic circular disorder,and accounts for 20%–30%cases of ischemic stroke as well as cerebral hemorrhage,and to a great extent,encephalopathy.Binswanger’s disea...Small vessel disease （SVD） is responsible for brain chronic circular disorder,and accounts for 20%–30%cases of ischemic stroke as well as cerebral hemorrhage,and to a great extent,encephalopathy.Binswanger’s disease and multiple small strokes,which are common in older people,are also closely associated with SVD.These disorders often cause decline in cognition,vascular dementia,impairment in gait and balance,mood depression,and urinary incontinence,and often brings great social and economic burdens.SVD-related encephalopathy increases the incidences of fall,disability and death in elderly people.With the aging of the society,more attention should be paid to the importance of early diagnosis and prophylactic treatment of SVD.Here the clinical manifestations and pathophysiology of SVD are reviewed.展开更多
4-Acylated or 3,4-diacylated caffeic acid phenethyl ester （CAPE） was prepared as prodrug to improve its stability and lipid solubility. Their neuroprotective activities were assessed by H202 model and 6-OHDA model. ...4-Acylated or 3,4-diacylated caffeic acid phenethyl ester （CAPE） was prepared as prodrug to improve its stability and lipid solubility. Their neuroprotective activities were assessed by H202 model and 6-OHDA model. The results showed that target compounds displayed positive abilities to protect PC 12 nerve cells from oxidative stress injury, superior to that of CAPE. Additionally, target compounds showed high blood-brain barrier permeability.展开更多
Objective：To explore the effects of Xingnaojing injection on cerebral edema and blood-brain barrier （BBB） in rats following traumatic brain injury （TBI）.Methods： A total of 108 adult male Sprague-Dawley rats wer...Objective：To explore the effects of Xingnaojing injection on cerebral edema and blood-brain barrier （BBB） in rats following traumatic brain injury （TBI）.Methods： A total of 108 adult male Sprague-Dawley rats were used as subjects and randomly assigned to three groups：sham-operation,TBI and Xingnaojing injection was set up by the improved device of Feeney＇s weightcontent and BBB permeability expressed as Evans blue content were measured at 1, 3, 5 and 7 days after surgery.Results： In sham-operation group, brain water content and Evans blue content in brain tissue were 78.97%±1.22%and 5.13μg±0.71μg. Following TBI, water content in brain tissue was increased significantly at 1, 3, 5 and 7 days （83.49%±0.54%, 82.74%±0.72%, 80.22%±0.68%, 79.21%±0.60%）, being significantly higher than that in sham operation group （P〈0.05）. Evans blue content was increased in TBI group （16.54 μg±0.60 μg, 14.92μg±0.71μg, 12.44 μg ±0.92μg, 10.14μg±0.52 μg） as compared with sham-operation group（P〈0.05）. After treatment with Xingnaojing injection, brain water content decreased as compared with TBI group （81.91%±1.04%, 80.38%±0.72%, 79.54%±0.58%,78.60%±0.77%, P〈0.05）. Xingnaojing injection also reduced the leakage of BBB as compared with TBI group （15.11 μg± 0.63 μg, 13.62 μg±0.85μg, 10.06 μg±0.67 μg, 9.54 μg±0.41 μg,P〈0.05）.Conclusion： Xingnaojing injection could alleviate cerebral edema following TBI via reducing permeability ofBBB.展开更多
Ischemic stroke seriously threatens human health and quality of life.Xiao-Xu-Ming(XXM)decoction has been a classical prescription for stroke therapy.In our previous studies,we have found that XXM exerts neuroprotectiv...Ischemic stroke seriously threatens human health and quality of life.Xiao-Xu-Ming(XXM)decoction has been a classical prescription for stroke therapy.In our previous studies,we have found that XXM exerts neuroprotective effects,improves brain injury,and attenuates neuroinflammation in cerebral ischemia rats.In this study,we investigated the effects and possible mechanism of XXM on thrombotic focal cerebral ischemia.After treatment with XXM,the neurological function and motor abilities were improved,and cerebral infarction volume was significantly decreased compared with rats of thrombotic focal cerebral ischemia.Besides,the results of BBB integrity detected by EB leakage and tight junction(TJ)protein expression showed that XXM could maintain BBB integrity and improve the expressions of TJ proteins,including claudin-1,occluding,and ZO-1,in the ischemic ipsilateral cortex disrupted by thrombotic cerebral ischemia.Furthermore,proteomic techniques were used to identify the differentially expressed proteins(DEPs)in the ischemic cerebral cortex,and the results showed that 132 DEPs regulated by XXM were detected in the ischemic cerebral cortex.Bioinformatic analysis showed that these regulated proteins by XXM were mainly involved in complement and coagulation cascade,and lysosome,etc.Furthermore,there was an interaction among DEPs,including Lgals3,Ctsz,Capg,C1qa,S100a4,Grn,Hspb1,Aif1,and Anxa1,etc.In conclusion,XXM ameliorated brain injury of thrombotic focal ischemic stroke,and Lgals3,Ctsz,Capg,C1qa,S100a4,Grn,Hspb1,Aif1,and Anxa1 could help provide possible therapeutic targets of XXM for ischemic stroke and offer research direction for further research.展开更多
Objective： To evaluate plasma arginine vasopressin （AVP） level in patients with traumatic brain injury and investigate the role of AVP in the process of brain edema. Methods ： A total of 30 patients with traumatic...Objective： To evaluate plasma arginine vasopressin （AVP） level in patients with traumatic brain injury and investigate the role of AVP in the process of brain edema. Methods ： A total of 30 patients with traumatic brain injury were involved in our study. They were divided into two groups by Glasgow Coma Scale： severe tranmatic brain injury group （ STBI, GCS ≤ 8 ） and moderate traumatic brain injury group （ MTBI, GCS 〉 8 ）. Samples of venous blood were collected in the morning at rest from 15 healthy volunteers （control group）and within 24 h after traumatic brain injury from these patients for AVP determinations by radioimmunoassay. The severity and duration of the brain edema were estimated by head CT scan. Results： plasma AVP levels （ng/L） were （mean± SD） control, 3.06 ± 1.49; MTBI, 38. 12 ± 7. 25; andSTBI, 66. 61 ± 17. 10. The plasma level of AVP was significantly increased within 24 h after traumatic brain injury and followed by the reduction of GCS, suggesting the deterioration of cerebral injury （ P 〈 0.01 ）. And the AVP level was correlated with the severity （ STBI r = 0. 919, P 〈 0.01 ; MTBI r = 0. 724, P 〈 0.01 ） and the duration of brain edema （STBI r =0.790, P 〈0.01; MTBI r =0.712, P〈0.01）. Conclusions. The plasma AVP level is dosely associated with the severity of traumatic brain injury. AVP may play an important role in pathogenesis of brain edema after traumatic brain injury.展开更多
Focused ultrasound(FUS)-induced blood–brain barrier(BBB) opening is crucial for enhancing glioblastoma(GBM) therapies. However, an in vivo imaging approach with a high spatial–temporal resolution to monitor the BBB ...Focused ultrasound(FUS)-induced blood–brain barrier(BBB) opening is crucial for enhancing glioblastoma(GBM) therapies. However, an in vivo imaging approach with a high spatial–temporal resolution to monitor the BBB opening process in situ and synchronously is still lacking. Herein, we report the use of indocyanine green(ICG)-dopped microbubbles(MBs-ICG) for visualizing the FUS-induced BBB opening and enhancing the photothermal therapy(PTT) against GBM. The MBs-ICG show bright fluorescence in the second near-infrared window(NIR-II), ultrasound contrast, and ultrasound-induced size transformation properties. By virtue of complementary contrast properties, MBs-ICG can be successfully applied for cerebral vascular imaging with NIR-II fluorescence resolution of ~168.9 lm and ultrasound penetration depth of ~7 mm. We further demonstrate that MBs-ICG can be combined with FUS for in situ and synchronous visualization of the BBB opening with a NIR-II fluorescence signal-tobackground ratio of 6.2 ± 1.2. Finally, our data show that the MBs-ICG transform into lipid-ICG nanoparticles under FUS irradiation, which then rapidly penetrate the tumor tissues within 10 min and enhance PTT in orthotopic GBM-bearing mice. The multifunctional MBs-ICG approach provides a novel paradigm for monitoring BBB opening and enhancing GBM therapy.展开更多
In the present study,novel ester derivatives of CAPE were designed and synthesized as neuroprotective agents.The anti-inflammatory and antioxidant activities of these compounds were evaluated at the cellular level,whi...In the present study,novel ester derivatives of CAPE were designed and synthesized as neuroprotective agents.The anti-inflammatory and antioxidant activities of these compounds were evaluated at the cellular level,while the blood-brain barrier(BBB)permeability was predicted by parallel artificial membrane permeability assay(PAMPA).The results revealed that phenolic hydroxyl groups and double bonds in the structure of CAPE had important effects on neuroprotective activities.Accordingly,a preliminary structure-activity relationship was summarized in this paper.In addition,we observed a significant improvement on BBB permeability.These results provided important references for the structural modification and optimization of CAPE in the future.展开更多
The blood-brain barrier permeability of 20（S） and 20（R）-protopanaxatriol epimers and dammar-20（22）E,24-diene- 313,6α,12β-triol were investigated using the MDCK-pHaMDR cell monolayer model. The bidirectional pe...The blood-brain barrier permeability of 20（S） and 20（R）-protopanaxatriol epimers and dammar-20（22）E,24-diene- 313,6α,12β-triol were investigated using the MDCK-pHaMDR cell monolayer model. The bidirectional permeability tests were carried out, and the apparent permeability coefficients （Papp） were calculated. The two protopanaxatriol epimers showed good permeability with Papp values of-10^-5 cm/s, whereas dammar-20（22）E,24-diene-3β,6α, 12β-triol showed poor permeability with Papp of 〈1 × 10^-7 cm/s. The three compounds showed differences in intracellular accumulations due to their different structures. Inhibition of P-gp with verapamil showed that the transport mechanisms in MDCK-pHaMDR cell monolayer for compounds 1 and 2 epimers were not only simple passive diffusion but also involving an effiux way mediated by P-gp. These findings provided new basis for the further study of compounds 1 and 2 acting on the brain.展开更多
In recent years, injuries induced by explosive blast have got more and more attention owing to weapon development and frequent terrorist activities. Tear, bleeding and edema of tissues and organs are the main manifest...In recent years, injuries induced by explosive blast have got more and more attention owing to weapon development and frequent terrorist activities. Tear, bleeding and edema of tissues and organs are the main manifestations of blast shock wave damage. Vascular endothelial barrier is the main defense of tissues and organs＇ integrity. This article aims to discuss possible mechanisms of endothelial barrier damage induced by explosive blast and main manifestations of blood brain barrier, blood-air barrier, and intestinal vascular barrier impairments. In addition, the main regulatory factors of vascular permeability are also summarized so as to provide theoretical basis for prevention and cure of vascular endothelial barrier damaue resultinu from exolosive blast.展开更多
基金Supported by Grant #TB 56 from the University of Buenos Aires,Argentina
文摘AIM:To study the blood-brain barrier integrity,brain edema, animal behavior and ammonia plasma levels in prehepatic portal hypertensive rats with and without acute liver intoxication. METHODS:Adults male Wistar rats were divided into four groups.Group Ⅰ:sham operation;Ⅱ:Prehepatic portal hypertension,produced by partial portal vein ligation;Ⅲ: Acetaminophen intoxication and Ⅳ:Prehepatic portal hypertension plus acetaminophen.Acetaminophen was administered to produce acute hepatic injury.Portal pressure,liver serum enzymes and ammonia plasma levels were determined.Brain cortex water content was registered and trypan blue was utilized to study blood brain barrier integrity.Reflexes and behavioral tests were recorded. RESULTS:Portal hypertension was significantly elevated in groups Ⅱ and Ⅳ.Uver enzymes and ammonia plasma levels were increased in groups Ⅱ,Ⅲ and Ⅳ.Prehepatic portal hypertension (group Ⅱ),acetaminophen intoxication (group Ⅲ) and both (group Ⅳ) had changes in the blood brain-barrier integrity (trypan blue) and hyperammonemia.Cortical edema was present in rats with acute hepatic injury in groups Ⅲ and Ⅳ.Behavioral test (rota rod) was altered in group Ⅳ. CONCLUSION:These results suggest the possibility of another pathway for cortical edema production because blood brain barrier was altered (vasogenic) and hyperammonemia was registered (oltotoxic).Group Ⅳ,with behavioral altered test,can be considered as a model for study at an early stage of portal-systemic encephalopathy.
基金supported by the Dong-A University (Busan, Korea) research fund
文摘Purpose: The purpose of this study was to investigate the effects of obesity and high-intensity acute exercise on oxidant-antioxidant status,neurotrophic factor expression, and blood-brain barrier(BBB) disruption.Methods: Twenty-four healthy, untrained men(12 non-obese(mean 14.9% body fat) and 12 obese subjects(mean 29.8% body fat)) performed20 min of continuous submaximal aerobic exercise at 85% maximal oxygen consumption. Blood sampling was performed to examine the oxidant-antioxidant status(reactive oxygen species(ROS) and superoxide dismutase(SOD)), neurotrophic factors(brain-derived neurotrophic factor(BDNF) and nerve growth factor(NGF)), and BBB disruption(S100β and neuron-specific enolase) before and after acute exercise.Results: The obese group showed significantly higher pre-exercise serum ROS levels and significantly lower pre-exercise serum SOD levels than the non-obese group(p < 0.05). Serum ROS, SOD, BDNF, NGF, and S100β levels were significantly increased post-exercise compared with pre-exercise levels in both the non-obese and the obese groups(p < 0.05). The obese group showed significantly higher serum ROS, BDNF, NGF,and S100β levels post-exercise compared to the non-obese group(p < 0.05).Conclusion: Our study suggests that episodic vigorous exercise can increase oxidative stress and blood neurotrophic factor levels and induce disruption of the BBB. Moreover, high levels of neurotrophic factor in the blood after exercise in the obese group may be due to BBB disruption,and it is assumed that oxidative stress was the main cause of this BBB disruption.
基金Supported by Grant TB 56 from the University of Buenos Aires, Buenos Aires, Argentina
文摘AIM： To study the blood-brain barrier integrity in prehepatic portal hypertensive rats induced by partial portal vein ligation, at 14 and 40 dafer ligation when portal pressure is spontaneously normalized. METHODS： Adult male Wistar rats were divided into four groups： Group Ⅰ： Sham14d, sham operated; Group Ⅱ： PHil, portal vein stenosis, （both groups were used 14 days after surgery）; Group Ⅲ： Sham4od, Sham operated and Group Ⅳ： PH4od Portal vein stenosis （Groups Ⅱ and Ⅳ used 40 d afer surgery）. Plasma ammonia, plasma and cerebrospinal fluid protein and liver enzymes concentrations were determined. Trypan and Evans blue dyes, systemically injected, were investigated in hippocampus to study blood-brain barrier integrity. Portal pressure was periodically recorded. RESULTS： Forty days afer stricture, portal pressure was normalized, plasma ammonia was moderately high, and both dyes were absent in central nervous system parenchyma. All other parameters were reestablished. When portal pressure was normalized and ammonia level was lowered, but not normal, the altered integrity of blood-brain barrier becomes reestablished. CONCLUSION： The impairment of blood-brain barrier and subsequent normalization could be a mechanism involved in hepatic encephalopathy reversibility. Hemodynamic changes and ammonia could trigger blood-brain barrier alterations and its reestablishment.
基金the Shandong Provincial Science and Technology Program,No. 2006GG202004
文摘Cromakalim,an adenosine triphosphate-sensitive potassium channel opener,exhibits protective effects on cerebral ischemia/reperfusion injury.However,there is controversy as to whether this effect is associated with aquaporin-4 and blood-brain barrier permeability.Immunohistochemistry results show that preventive administration of cromakalim decreased aquaporin-4 and IgG protein expression in rats with ischemia/reperfusion injury;it also reduced blood-brain barrier permeability,and alleviated brain edema,ultimately providing neuroprotection.
文摘Brain metastases are common intracranial tumors, and their occurrence not only represents a high degree of malignancy, but also often is the major factor in treatment failure and poor prognosis. Primary site of brain metastases often occur in lung. P-glycoprotein is a member of the （ATP binding cassette） transporter superfamily,which is closely related to the development of lung metastases. It is the main reason for influencing the drug through the blood_brain barrier into the brain tissue, and it also is an important factor affecting the treatment of brain metastases. According to the theory of traditional chinese mddicine, the pathogenesis of brain metastases is due to phlegm, poison, stasis, virtual and so on. The principle of treatment is to promote blood circulation, remove phlegm turbidity. In recent years, the impact of Chinese herbal medicine on P-glycoprotein is increasing. This paper analyzes the mechanism and components of the relevant Chinese medicine on P-glycoprotein. It provides a reference for clinical rational drug use.
文摘EAE （experimental autoimmune encephalomyelitis） is an established, inducible animal model employed in the study of MS （multiple sclerosis） characterized by inflammation, BBB （blood brain barrier） malfunction, demyelination and neuronal disruption. CRF （corticotropin releasing factor） is a neuropeptide critically associated with immune function, BBB permeability, and the hypothalamic-pituitary-adrenal axis. Potential CRF targets in the brain include astrocytes, as well as endothelial cells of cerebral microvessels, since they have been reported to express CRFR （CRF receptors）. Further, both of these cell types function critically in regulating BBB permeability. CRF-BP （CRF binding protein） is also expressed in both neurons and glial cells. Changes in the cortical CRF system could be a contributing factor to the BBB disruption associated with MS/EAE and has been suggested to play a protective role against cytokine-induced inflammation. The current study assessed alterations associated with the C57BL/6 mouse model of EAE in the cortical CRF system and correlated these events with changes to the microvascular unit. Immunohistochemical confocal microscopy was used to analyze the distribution of CRF, CRF-BP, and CRFR in the mouse cerebral cortex. The authors observed a reduction in detectable CRF immunofluorescence in the EAE motor cortex, an increase in CRFBP immunoreactivity in EAE astrocytes and a concurrent reduction in astrocytic CRFR immunofluorescence. Staining techniques were used to visualize astrocytes/microvessels to document alterations in BBB integrity. Changes in the CRF system were associated with a modification of the blood brain barrier as manifested by a poorly defined astrocytic barrier in EAE microvessels. Evidence suggests that manipulation of CRF signaling pathways offers an intriguing target for interventional therapies designed to modify BBB permeability that may be beneficial for treating disease states such as MS.
基金ThisstudywassupportedbythegrantforKeyProjectofNationalNaturalScienceFoundationinChina (No39730170)andthegrantforGeneralProjectofNSFC (No 3 9770 810 )
文摘OBJECTIVE: To study whether recombinant adeno-associated virus (rAAV) mediated foreign gene, LacZ, could pass the blood brain barrier by intra-carotid artery delivery and express in vivo in ischemic brain of the focal embolic stroke rats to investigate a possibility of delivering foreign gene through carotid artery to treat acute ischemic stroke. METHODS: The carotid artery territory in 41 rats was embolized with or without arterial-like fibrin rich clots to make a model of focal embolic stroke rat. rAAV containing LacZ gene (rAAV-LacZ) was constructed in 293 cells by calcium phosphate cotransfection. The rats were assigned to one of the following treatments: 1 control (without embolism) groups, including PBS treated (n = 6), pLacZ treated (n = 6 ) and rAAV-LacZ treated (n = 6): 2 embolic groups, including embolism + PBS (n =7),embolism + pLacZ (n = 8) and embolism + rAAV-LacZ (n = 8). Brains were cryosectioned and kappa-Gal stain was performed at 2, 4, and 8 weeks, respectively, after transfection, and then infarct volume was measured and the percentage of LacZ staining-positive cells was calculated. RESULTS: In all the control groups and embolism + PBS treated animal, no kappa-Gal staining-positive cells were found, but in embolism + pLacZ (n = 8) and embolism+rAAV-LacZ groups a lot of kappa-Gal staining-positive cells were found. The expression cells were in the tissues around the infarction. The gene expression persisted only nearly four weeks in embolic group with pLacZ. In the embolic group with rAAV-LacZ the expression was very stable during the experiment course (eight weeks) and the percentage of the expressed cells was significantly higher than that of its contralateral areas at the same time points, respectively. CONCLUSIONS: The plasmid vector and rAAV could enter the brain through the ischemia-damaged blood barrier and foreign gene can be expressed in brain. The positive gene expression is mainly in the peripheral areas of the infarction. rAAV as a permanent expression vector may ultimately be used for gene therapy of human ischemia cerebravascular diseases.
基金Natural Science Foundation of Shanxi,China (Grant No.2008011082-1)Shanxi Scholarship Council of China (Grant No.2008-86)Natural Science Foundation of Shanxi Datong University(Grant No.2009Q6).
文摘We investigated the effects of glucosamine(GS) on blood-brain barrier(BBB) function and matrix metalloproteinase-9 (MMP-9) expression in rats with experimental autoimmune encephalomyelitis(EAE).Animals were randomly divided into three groups,among which the EAE and GS groups were immunized with complete antigen and pertussis toxin,and the adjuvant group was immunized with complete Freund's adjuvant and pertussis toxin.Rats were treated by peritoneal injection of GS 180 mg/(kg·d) in the GS group and peritoneal injection of phosphate-buffered saline 4.5 mL/(kg·d) in the EAE and adjuvant groups.We proposed to assess the integrity of BBB by calculating cerebrospinal fluid to serum albumin quotient(QA) on days 6,8,10,12,14,16 and 18 post-immunization.At the same time,the brains and spinal cords were removed for MMP-9 immunohistochemical staining. Experiments demonstrated that in the EAE group,QA value and MMP-9 expression were highly elevated and up-regulated and correlated to disease severity.Moreover,there was statistically significantly positive correlation between QA value and MMP-9 expression.In the GS group,we observed that the mean disease onset date was delayed,the incidence and mean score of symptom were suppressed at the peak phase of disease(P<0.05).Furthermore,QA value and MMP-9 expression in the GS group showed stronger inhibition when compared with those of the EAE group(P<0.05).Our study showed that GS would reduce the BBB breakdown and leukocyte trafficking by inhibiting the production of MMP-9 and mitigate EAE.
基金supported by the National Natural Science Foundation of China (No. 30700249, No. 30670723, and No. 30570650)Natural Science Foundation of Liaoning Province (No. 20052102)Special Fund for Scientific Research of Doctor-Degree Subjects in Colleges and Universities of China (No. 20050159005).
文摘Objective To investigate the underlying mechanism for the selective modulation of the permeability of blood-tumor barrier(BTB) by small dose of bradykinin(BK). Methods C6 glioma cells were treated with BK,and changes of intracellular nitric oxide(NO) and intracellular calcium level were measured with fluorescent spectrophotometer. Results The initial application of BK easily triggered extracellular calcium influx,which resulted in intracellular calcium store release in C6 glioma cells. The above mechanism w...
文摘Small vessel disease （SVD） is responsible for brain chronic circular disorder,and accounts for 20%–30%cases of ischemic stroke as well as cerebral hemorrhage,and to a great extent,encephalopathy.Binswanger’s disease and multiple small strokes,which are common in older people,are also closely associated with SVD.These disorders often cause decline in cognition,vascular dementia,impairment in gait and balance,mood depression,and urinary incontinence,and often brings great social and economic burdens.SVD-related encephalopathy increases the incidences of fall,disability and death in elderly people.With the aging of the society,more attention should be paid to the importance of early diagnosis and prophylactic treatment of SVD.Here the clinical manifestations and pathophysiology of SVD are reviewed.
基金National Natural Science Foundation of China(Grant No.201310061931.8)
文摘4-Acylated or 3,4-diacylated caffeic acid phenethyl ester （CAPE） was prepared as prodrug to improve its stability and lipid solubility. Their neuroprotective activities were assessed by H202 model and 6-OHDA model. The results showed that target compounds displayed positive abilities to protect PC 12 nerve cells from oxidative stress injury, superior to that of CAPE. Additionally, target compounds showed high blood-brain barrier permeability.
文摘Objective：To explore the effects of Xingnaojing injection on cerebral edema and blood-brain barrier （BBB） in rats following traumatic brain injury （TBI）.Methods： A total of 108 adult male Sprague-Dawley rats were used as subjects and randomly assigned to three groups：sham-operation,TBI and Xingnaojing injection was set up by the improved device of Feeney＇s weightcontent and BBB permeability expressed as Evans blue content were measured at 1, 3, 5 and 7 days after surgery.Results： In sham-operation group, brain water content and Evans blue content in brain tissue were 78.97%±1.22%and 5.13μg±0.71μg. Following TBI, water content in brain tissue was increased significantly at 1, 3, 5 and 7 days （83.49%±0.54%, 82.74%±0.72%, 80.22%±0.68%, 79.21%±0.60%）, being significantly higher than that in sham operation group （P〈0.05）. Evans blue content was increased in TBI group （16.54 μg±0.60 μg, 14.92μg±0.71μg, 12.44 μg ±0.92μg, 10.14μg±0.52 μg） as compared with sham-operation group（P〈0.05）. After treatment with Xingnaojing injection, brain water content decreased as compared with TBI group （81.91%±1.04%, 80.38%±0.72%, 79.54%±0.58%,78.60%±0.77%, P〈0.05）. Xingnaojing injection also reduced the leakage of BBB as compared with TBI group （15.11 μg± 0.63 μg, 13.62 μg±0.85μg, 10.06 μg±0.67 μg, 9.54 μg±0.41 μg,P〈0.05）.Conclusion： Xingnaojing injection could alleviate cerebral edema following TBI via reducing permeability ofBBB.
基金The National Natural Science Foundation of China (Grant No. 81473383)the Significant New-Drugs Creation of Science and Technology Major Projects (Grant No. 2018ZX09711001-003-019)+1 种基金the Medical and Health Innovation Project of Chinese Academy of Medical Sciences (Grant No. 2016-I2M-3-007)Innovation Fund for Graduate of Beijing Union Medical College (Grant No. 2018-1007-04)。
文摘Ischemic stroke seriously threatens human health and quality of life.Xiao-Xu-Ming(XXM)decoction has been a classical prescription for stroke therapy.In our previous studies,we have found that XXM exerts neuroprotective effects,improves brain injury,and attenuates neuroinflammation in cerebral ischemia rats.In this study,we investigated the effects and possible mechanism of XXM on thrombotic focal cerebral ischemia.After treatment with XXM,the neurological function and motor abilities were improved,and cerebral infarction volume was significantly decreased compared with rats of thrombotic focal cerebral ischemia.Besides,the results of BBB integrity detected by EB leakage and tight junction(TJ)protein expression showed that XXM could maintain BBB integrity and improve the expressions of TJ proteins,including claudin-1,occluding,and ZO-1,in the ischemic ipsilateral cortex disrupted by thrombotic cerebral ischemia.Furthermore,proteomic techniques were used to identify the differentially expressed proteins(DEPs)in the ischemic cerebral cortex,and the results showed that 132 DEPs regulated by XXM were detected in the ischemic cerebral cortex.Bioinformatic analysis showed that these regulated proteins by XXM were mainly involved in complement and coagulation cascade,and lysosome,etc.Furthermore,there was an interaction among DEPs,including Lgals3,Ctsz,Capg,C1qa,S100a4,Grn,Hspb1,Aif1,and Anxa1,etc.In conclusion,XXM ameliorated brain injury of thrombotic focal ischemic stroke,and Lgals3,Ctsz,Capg,C1qa,S100a4,Grn,Hspb1,Aif1,and Anxa1 could help provide possible therapeutic targets of XXM for ischemic stroke and offer research direction for further research.
文摘Objective： To evaluate plasma arginine vasopressin （AVP） level in patients with traumatic brain injury and investigate the role of AVP in the process of brain edema. Methods ： A total of 30 patients with traumatic brain injury were involved in our study. They were divided into two groups by Glasgow Coma Scale： severe tranmatic brain injury group （ STBI, GCS ≤ 8 ） and moderate traumatic brain injury group （ MTBI, GCS 〉 8 ）. Samples of venous blood were collected in the morning at rest from 15 healthy volunteers （control group）and within 24 h after traumatic brain injury from these patients for AVP determinations by radioimmunoassay. The severity and duration of the brain edema were estimated by head CT scan. Results： plasma AVP levels （ng/L） were （mean± SD） control, 3.06 ± 1.49; MTBI, 38. 12 ± 7. 25; andSTBI, 66. 61 ± 17. 10. The plasma level of AVP was significantly increased within 24 h after traumatic brain injury and followed by the reduction of GCS, suggesting the deterioration of cerebral injury （ P 〈 0.01 ）. And the AVP level was correlated with the severity （ STBI r = 0. 919, P 〈 0.01 ; MTBI r = 0. 724, P 〈 0.01 ） and the duration of brain edema （STBI r =0.790, P 〈0.01; MTBI r =0.712, P〈0.01）. Conclusions. The plasma AVP level is dosely associated with the severity of traumatic brain injury. AVP may play an important role in pathogenesis of brain edema after traumatic brain injury.
基金supported by the National Natural Science Foundation of China (92159304, 82171958, 81901812, 81971638, 91859117, 82027803, and 81927807)CAS Key Laboratory of Health Informatics (2011DP173015)+4 种基金the Science and Technology Key Project of Shenzhen(JCYJ20190812163614809, JCYJ20200109114612308, JCYJ2021032 4120011030, JCYJ20190809105207439, JCYJ20220531091408019, and JCYJ20200109114825064)Guangdong Basic and Applied Basic Research Fund (2020A1515110011, 2020A1515010395, and 2022A1515010384)Key Laboratory for Magnetic Resonance and Multimodality Imaging of Guangdong Province (2020B1212060051)the Key Technology and Equipment R&D Program of Major Science and Technology Infrastructure of Shenzhen (202100102, 202100104)Discipline Construction Project of Guangdong Medical University (4SG21017G)
文摘Focused ultrasound(FUS)-induced blood–brain barrier(BBB) opening is crucial for enhancing glioblastoma(GBM) therapies. However, an in vivo imaging approach with a high spatial–temporal resolution to monitor the BBB opening process in situ and synchronously is still lacking. Herein, we report the use of indocyanine green(ICG)-dopped microbubbles(MBs-ICG) for visualizing the FUS-induced BBB opening and enhancing the photothermal therapy(PTT) against GBM. The MBs-ICG show bright fluorescence in the second near-infrared window(NIR-II), ultrasound contrast, and ultrasound-induced size transformation properties. By virtue of complementary contrast properties, MBs-ICG can be successfully applied for cerebral vascular imaging with NIR-II fluorescence resolution of ~168.9 lm and ultrasound penetration depth of ~7 mm. We further demonstrate that MBs-ICG can be combined with FUS for in situ and synchronous visualization of the BBB opening with a NIR-II fluorescence signal-tobackground ratio of 6.2 ± 1.2. Finally, our data show that the MBs-ICG transform into lipid-ICG nanoparticles under FUS irradiation, which then rapidly penetrate the tumor tissues within 10 min and enhance PTT in orthotopic GBM-bearing mice. The multifunctional MBs-ICG approach provides a novel paradigm for monitoring BBB opening and enhancing GBM therapy.
文摘In the present study,novel ester derivatives of CAPE were designed and synthesized as neuroprotective agents.The anti-inflammatory and antioxidant activities of these compounds were evaluated at the cellular level,while the blood-brain barrier(BBB)permeability was predicted by parallel artificial membrane permeability assay(PAMPA).The results revealed that phenolic hydroxyl groups and double bonds in the structure of CAPE had important effects on neuroprotective activities.Accordingly,a preliminary structure-activity relationship was summarized in this paper.In addition,we observed a significant improvement on BBB permeability.These results provided important references for the structural modification and optimization of CAPE in the future.
基金The National New Drug R&D Program(Grant No.2011BAI07B082009ZX09301-010)of China
文摘The blood-brain barrier permeability of 20（S） and 20（R）-protopanaxatriol epimers and dammar-20（22）E,24-diene- 313,6α,12β-triol were investigated using the MDCK-pHaMDR cell monolayer model. The bidirectional permeability tests were carried out, and the apparent permeability coefficients （Papp） were calculated. The two protopanaxatriol epimers showed good permeability with Papp values of-10^-5 cm/s, whereas dammar-20（22）E,24-diene-3β,6α, 12β-triol showed poor permeability with Papp of 〈1 × 10^-7 cm/s. The three compounds showed differences in intracellular accumulations due to their different structures. Inhibition of P-gp with verapamil showed that the transport mechanisms in MDCK-pHaMDR cell monolayer for compounds 1 and 2 epimers were not only simple passive diffusion but also involving an effiux way mediated by P-gp. These findings provided new basis for the further study of compounds 1 and 2 acting on the brain.
文摘In recent years, injuries induced by explosive blast have got more and more attention owing to weapon development and frequent terrorist activities. Tear, bleeding and edema of tissues and organs are the main manifestations of blast shock wave damage. Vascular endothelial barrier is the main defense of tissues and organs＇ integrity. This article aims to discuss possible mechanisms of endothelial barrier damage induced by explosive blast and main manifestations of blood brain barrier, blood-air barrier, and intestinal vascular barrier impairments. In addition, the main regulatory factors of vascular permeability are also summarized so as to provide theoretical basis for prevention and cure of vascular endothelial barrier damaue resultinu from exolosive blast.
