Effect of hypertonic saline on permeability of blood-brain barrier in a rat model of intracerebral hemorrhage
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Abstract:
Objective
To investigate the effect of hypertonic saline (HS) on the permeability of blood-brain barrier in a rat model of intracerebral hemorrhage (ICH).
Methods
Sixty healthy male Sprague-Dawley rats, aged 8 weeks, weighing 260-300 g, were randomly divided into 4 groups (n=15 each) using a random number table: sham operation group (group S), sham operation+ HS group (group HS), ICH group, and ICH+ HS group.ICH was commonly induced in anesthetized rats by intraparenchymal injection of autologous blood 50 μl.The equal volume of normal saline was given instead in group S. The neurologic deficits were scored on a five-point scale, and a score of 1-3 indicated successful establishment of the model.At 48 h after establishment of the model, the rats were sacrificed, and brains were removed for determination of brain water content, expression of occludin in brain tissues (by Western blot), and Evans blue content.
Results
Compared with group S, the brain water content and Evans blue content were significantly increased, and the expression of occludin was down-regulated in ICH and ICH+ HS groups, and no significant change was found in the indices mentioned above in group S+ HS.Compared with group ICH, the brain water content and Evans blue content were significantly decreased, and the expression of occludin was up-regulated in group ICH+ HS.
Conclusion
HS can inhibit increase in the permeability of blood-brain barrier, and reduce the cerebral edema in a rat model of ICH.
Key words:
Cerebral hemorrhage; Saline solution, hypertonic; Blood-brain barrierKeywords:
Evans Blue
Occludin
Hypertonic saline
Cerebral edema
Objective To study the expression of neuroglobin (Ngb) in brain tissue in rats with intracerebral hemorrhage (ICH) and the relationship between the expression of Ngb and brain edema following ICH. Methods The rats were randomly divided into normal control group, sham-operated group and ICH group. Sham-operated group and ICH group were divided into 5 subgroups respectively according to 1, 6, 24, 48 and 72 h after the animal modal formation. ICH was induced by stereotaxic injection of autologous blood into right caudate nucleus of rats (saline was injected in sham-operated group). Wet and dry weight methods were used to measure the changes of brain water content, and Western blot were used to detect the expression of Ngb in brain tissue. Results Compared with normal control group or sham-operated group, the expression of Ngb in peri-hematomal brain tissue started to increase at 1 h (P0.05), and the brain water content increased at 24 h in ICH group (P0.05). Both peaked at 48 h and maintained the level until 72 h (P0.01) in ICH group.Conclusion Expression of Ngb increases in brain tissue after ICH. The change of Ngb expression is not totally coincident with the formation of brain edema after ICH.
Neuroglobin
Brain Edema
Brain tissue
Autologous blood
Cerebral edema
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Objective To explore the mechanism of neuronal injury in intracerebral hemorrhage(ICH) through observing the change of the apoptosis and expression level of matrix metalloproteinase-9 in the brain after experimental ICH in rats.Methods The ICH rat models were established by intracranial injection of fresh quantitative autologous blood(by slowly injecting autologous blood in rats).The healthy male Wistar rats were randomly divided into a sham operation group,a normal saline control group and ICH model group.The fresh quantitative autologous blood or pure saline solution was slowly injected into caudate nucleus of rats.The water content in perihematoma were measured and the brain frozen sections were made respectively at(in) 6 h,12 h,48 h,24 h,3 d,5 d and 7 d after the operation in each group,respectively.The sections were stained by TUNEL to find the apoptotic cells.The expression of MMP-9 was observed by immunohistochemistry and in situ hybridization.Results At 6 hours,the apoptotic cells appeared in the ICH model group,and peaked in 3 days,but only a few apoptotic cells were found in the normal saline control brains.In the ICH group,compared with the control,autologous arterial blood injection significantly increased the brain water content(P 0.05) and the brain water content began to increase at 6 h and peaked at 72 h,and followed by decrease.The expressions of mRNA and protein of MMP-9 changed as the apoptosis and brain water content.Both the mRNA and protein expressions of MMP-9 were positively correlated with both the brain water content(r = 0.612 and r = 0.679 respectively) and apoptosis(r = 0.671 and r = 0.735 respectively).Conclusions The apoptosis of neurocyte and brain edema exist around the hematoma after cerebral hemorrhage.The high expression of MMP-9 can promote the apoptosis of neurocyte and increase water content of brain tissue.
Autologous blood
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Objective To investigate cerebral tissue damage degree and the expression of complement C9 and NO in rats at different time after hypertensive intracerebral hemorrhage( ICH). Methods Rat ICH model was established by Collagenase infusion. 96 rats were divided into 3 groups,32 rats in each group. Each group was randomly subdivided into sham group and model group. Brain water content and the levels of nitric oxide( NO) and C9 were determined at 2h,12h,24h and 72h after ICH. Results Brain water contents and expression of C9 in model group were increased remarkably 24 to 72 hours after operations,while the content of NO was decreased as compared to sham group. Conclusion Cerebral tissue damage degree in acute intracerebral hemorrhage was associated with content of NO,expression of C9 in rats 'cerebral tissues. It's important to improve brain circulation and alleviate inflammatory response.
Brain tissue
Brain damage
Rat model
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Objective: To study the characteristics of brain edema after intracerebral hemorrhage (ICH) and the effects of losartan on ICH induced brain edema in rats. Methods: Experimental ICH model of rats was built up with stereotactic apparatus and infusing autologous blood into the left caudate nucleus of rats. Water content in the brain tissue was quantitated by wet/dry weight measurement. Losartan was given to ICH model rats of experimental group at the dose of 10mg.kg~ -1 .d~ -1 orally from one week before the blood infusing until the day when the specimen be taken. Results: The water content in the brain tissue increased significantly in 6h and peaked on the third day after the blood infusing, while the water contents on the first day and third day after ICH in the brain tissue of rats of losartan treatment group were significantly lower than those of rats that did not receive losartan treatment. Conclusion: Brain edema forms within 6h and peaks on the third day after ICH. Losartan can reduce brain edema induced by ICH.
Brain Edema
Caudate nucleus
Brain tissue
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Objective To study the effect of nimodipine on the expression of Hsp-70 in the tissue around an intracerebral hematoma(ICH) in rats so as to probe into the protective action of the drug on the ischemic brain tissue around the ICH. Methods 120 healthy male SD rats were randomly divided into 3 groups:① the sham operation group(n=20),②ICH treatment group(n=50) and ③ICH model group(n=50).For each of the rats in groups ②and ③ an ICH model was established by injecting 50 μL of autoblood taken from the animal's femoral artery into the right caudate nucleus.In rats of the sham operation group(group ①),needle was inserted into the same region as mentioned but no blood was injected.After the operation,rats of each of 3 groups were further divided into 5 equal subgroups scheduled for corresponding experimentations to be carried out 6,24,48,72 and 120 hours later.Immediately after the establishment of the ICH model,rats of the treatment group(group②) were given each an intraperitoneal injection of 1.6 mg·kg~(-1) of nimodipine followed by the same injection q.d..Rats of the model group(group ③) were given each an equivalent amount of 0.9% sodium chloride solution via the same route.Nerve defect scoring was performed by a blind collaborator according to the method described by Bederson after the animals with the model awoke from the anesthesia.Animals of the ICH treatment group and model group with scores greater than 2 or equal to 2,reflecting a successful establishment of the model,were admitted into the experiment while all of the rats in the sham operation group were admitted.The admitted animals in each of the 15 subgroups described above were anesthetized with chloral hydrate and subjected to cardiac perfusion with 200 mL of 0.9%sodium chloride solution per rat followed by prompt decapitation for taking brain specimens 6,24,48,72 and 120 hours after the establishment of the model,respectively.Coronal sections across the caudate nucleus were made for the determination of the brain water content and assay of the expression of Hsp-70 with the immunohistochemical method. Results ①Brain water content: No apparent change was shown in the water content of the brain in rats of the model group 6h after the ICH.However,the water content began to increase 24h afterwards and reached its peak at 48-72 h,and then gradually declined.Dynamic changes in the brain water content in rats of the ICH treatment group followed a pattern similar to that in rats of the model group but the values at the different time points were lower(P0.05).The values of the brain water content in rats of the model group and ICH treatment group were by and large greater than those in rats of the sham operation group.②Expression of Hsp-70 in the brain tissue around the ICH: A few cells expressing Hsp-70 were seen in the specimen from rats of the sham operation group throughout the period from 6 h to 5 d.Cells expressing Hsp-70 in the brain tissue began to appear 6 h after the establishment of the ICH model,reached the peak 24-48 h thereafter and remained at high level until 120h in rats of both the model group and ICH treatment group.However,the values obtained from rats of the latter group were significantly greater than those obtained from rats of the former group(P0.01).The numbers of Hsp-70 expressing cells in the brain tissues from rats of he model group and ICH treatment group were also strikingly greater than those from rats of the sham operation group(P0.01). Conclusion Increased number of cells expressing Hsp-70 after ICH may be related to the injury of the brain tissue around the hematoma.Increased expression of Hsp-70 induced by nimodipine decreased the level of apoptosis around the hematoma,thus bringing about a protective effect on the nerve cells.Decreased content of brain water in rats treated with nimodipine suggests that the drug may also alleviate brain edema.
Nimodipine
Intraperitoneal injection
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To explore the effects of the Hemopexin (Hx) on the generation of free radicals and brain edema after intracerebral hemorrhage (ICH).One hundred SD rats were randomly and evenly divided into four groups (25 rats in each group) which named Sham group, ICH control group, Hx removal group and Hx intervention group respectively. There were five observation points (1 d, 3 d, 7 d, 14 d, 21 d) and which contain five rats for each. The stereotactic injection technique was used to make the ICH model, which adopted rat autologous Whole blood that was removed or mixed with Hx and then injected to the right caudate nucleus of the brain. Sham group were only injected with 50 µL saline to the right caudate nucleus and ICH control group were injected with 50 pL autologous whole blood; Hx removal group were injected 50 µL autologous whole blood of removal Hx and Hx intervention group were injected 50 µL autologous whole blood which contain 0. 25 mg (5 µg/ µL) Hx. Bederson's method was applied to evaluate whether the model was established successfully or not. Garcia' s method was used to estimate the neurological dysfunction scores by. Water contents of brain tissue around the hematoma was detected by dry-wet weigh method . The superoxide dismutase (SOD) activity were measured with the xanthine oxidase method. The content of the malonyldialdehyde (MDA) was measured by the thiobarbituric acid method. Pathological changes of brain tissue around the hematoma were detected by immunohistochemical method at each observation time points; and the immunohistochemical scores result was judged by the double semiquantitative evaluation method.Compared with Sham group, at 3-21 d, there were statistically significant differences (P<0. 05) in the neurological disorders and water content of the brain tissue and immunohistochemistry scores within ICH control group, Hx intervention group and Hx removal group. Compared with Sham group, at 1-21 d, there were statistically significant differences (P<0. 05) in SOD activity and the content of the MDA within ICH control group, Hx intervention group and Hx removal group. All the indexes above were superior in Hx intervention group to ICH control group (P<0. 05), and inferior in Hx removal group to ICH control group (P< 0. 05).The Hemopexin may attenuate the generation of the free radicals and encephalaedema in the brain tissue around the hematoma after intracerebral hemorrhage.
Caudate nucleus
Autologous blood
Thiobarbituric acid
Hemopexin
Brain Edema
Dismutase
Malondialdehyde
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Background Endothelin-1 (ET-1) has deleterious effects on water homeostasis, cerebral edema, and blood-brain barrier (BBB) integrity. Highly expressed ET-1 was observed after intracerebral hemorrhage (ICH); however, ET-1 changes and their relationship with BBB disruption within 24 hours of ICH have not been thoroughly investigated. The aim of the present study was to observe the changes in perihematomal ET-1 levels in various phases of ICH and their correlation with the BBB integrity in a rabbit model of ICH. Methods Twenty-five rabbits (3.2–4.3 kg body weight) were randomly divided into a normal control group (five rabbits) and a model group (20 rabbits). Animals in the model group were equally divided into four subgroups (five rabbits each to be sacrificed at 6, 12, 18, and 24 hours following ICH establishment). An ICH model was prepared in the model group by infusing autologous arterial blood into the rabbit brain. ET-1 expression in perihematomal brain tissues was determined using immunohistochemistry and color image analysis, and the permeability of the BBB was assayed using the Evan's Blue (EB) method. A repeated measures analysis of variance was used to make comparisons of the ET-1 and EB content across the entire time series. Results The number of perihematomal endothelial cells with ET-1 positive expressions following 6, 12, 18, and 24 hours ICH model establishment was 9.32, 13.05, 15.90, and 20.44, respectively, but as low as 6.67 in the control group. The average transmittance of ET-1-positive cell bodies at 6, 12, 18, and 24 hours after ICH was 99.10, 97.40, 85.70, and 80.80, respectively, but 100.12 in the control group. These data reveal that the expression of ET-1 was significantly increased at 6, 12, 18, and 24 hours after ICH compared with the control group, and a marked decrease in the average transmittance of ET-1-positive cell bodies was noted ( P <0.05). Similarly, the perihematomal EB content at 6, 12, 18, and 24 hours after ICH was 29.39±1.16, 32.20±0.73, 33.63±1.08, and 35.26±1.12, respectively, in the model group and 28.06±0.80 in the control group. The results indicate that a significant increase in the EB content in the model group was observed compared with that of the control group ( P <0.05). Moreover, a positive correlation between the number of ET-1-positive endothelial cells and BBB permeability was observed ( r =0.883, P <0.05). Conclusions High levels of ET-1 are closely associated with BBB disruption. ET-1 may play an important role in the pathogenesis of secondary brain injury after ICH.
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Objectives To observe the effect of Annaopingchong tang on brain water content and aquaporin-4(AQP-4) in the perhematoma after intracerebaral hemorrhage(ICH) in rats.Methods Ninty-six male rats were randomly divided into normal group,sham operation group and operation group.Cerebral hemorrhage model in rats was established by local injection of type Ⅳ collagenase.The operation group was divided into model group and treated group according to nervous function score.The sham operation group,model group and treated group was divided to 12,24,48,72,120 h sub-group respectively.The brain water content and the expression of AQP-4 was observed after intracerebral hemorrhage.Results Compared with ICH model group,the brain water content was reduced,the expression of AQP-4 in treatment group was reduced at the range of 24-120 h and there were no difference at 12 h.Conclusion Annaopingchong tang can reduce the expression of AQP-4 and relieve brain edema in ICH rats.
Brain Edema
Cerebral edema
Aquaporin 4
Rat model
Normal group
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Objective To explore the change of leukocyte and apoptosis at brain tissue around hematoma and their relationship with brain water content in rats with intracerebral hemorrhage(ICH).Methods ICH models was made by nonthrombogenic autologous blood injection method in 48 rats,and then the rats were randomly divided into 8 groups: sham operation group,ICH 6 h group,ICH 12 h group,ICH 24 h group,ICH 48 h group,ICH 72 h group,ICH 1 week group and ICH 2 weeks group.The brain of rats was taken out at corresponding time point respectively,and the brain water content was measured.The HE staining and TUNEL staining was made and the leukocyte and apoptosis were counted.Results The brain water content of rats at 6 h-1 week after ICH was significantly higher than sham operation group,and which was the highest at 72 h after ICH(all P0.05).The leukocyte was not found at sham operation group,ICH 6 h group and ICH 2 weeks group.The leukocyte was interspersed and infiltrated at 12 h-1 week after ICH,and which was the most at 48 h after ICH(all P0.05).The number of apoptosis of ICH rats at each time point was significantly higher than sham operation group,and which was the highest at 72 h after ICH(all P0.05).The leukocyte and apoptosis at brain tissue around hematoma were both positively related with the brain water content(r=0.615,P0.01;r=0.578,P0.01).Conclusion The increase of leukocyte and apotosis at brain tissue around hematoma in ICH rats may be related with the formation of encephaledema.
Brain tissue
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Objective To observe the protective effect of edaraven on brain tissue and the therapeutic mechanism in rats following intracerebral hemorrhage(ICH).Methods In this series,96 Sprague-Dawley rats were divided into three groups at random(n=32 in each group):sham-operative group,ICH model group and edaraven therapy group.ICH model was induced by infusion of autologous whole blood into the caudate-putamen.Rats in sham-operative group were treated the same as above,but no blood injected.Rats in edaraven therapy group were treated with edaraven(3 mg/kg)by peritoneal injection 30 min before operation and once per 12 hours after operation.These rats were killed at 6,24,72,and 168 h after neurologic impairment test with Longa criteria.Brain water content was measured by dry-wet weight method.Malondialdehyde and TNF-alpha in the vicinity of the hematoma were measured by thio-barbituric acid method and ELISA respectively.Results Compared with sham operative group,neurologic impairment score,brain water content,malondialdehyde and TNF-alpha in brain tissues were obviously higher in ICH model group(P0.05).Compared with ICH model group,neurologic impairment score,brain water content,malondialdehyde and TNF-alpha in brain tissues were significantly decreased in edaraven therapy group(P0.05).Conclusion Edaraven has an evident protective effect on injured brain tissue through inhibiting malondialdehyde and TNF-alpha content in the vicinity of the hematoma.
Malondialdehyde
Edaravone
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