Human-induced pluripotent stem cell-derived neural stem cell exosomes improve blood-brain barrier function after intracerebral hemorrhage by activating astrocytes via PI3K/AKT/MCP-1 axis

Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.

Gene interference regulates aquaporin-4 expression in swollen tissue of rats with cerebral ischemic edema Correlation with variation in apparent diffusion coefficient

To investigate the effects of mRNA interference on aquaporin-4 expression in swollen tissue of rats with ischemic cerebral edema, and diagnose the significance of diffusion-weighted MRI, we injected 5 pL shRNA- aquaporin-4 （control group） or siRNA- aquaporin-4 solution （1：800） （RNA interference group） into the rat right basal ganglia immediately before occlusion of the middle cerebral artery. At 0.25 hours after occlusion of the middle cerebral artery, diffusion-weighted MRI displayed a high signal; within 2 hours, the relative apparent diffusion coefficient decreased markedly, aquaporin-4 expression increased rapidly, and intracellular edema was obviously aggravated; at 4 and 6 hours, the relative apparent diffusion coefficient slowly returned to control levels, aquaporin-4 expression slightly increased, and angioedema was observed. In the RNA interference group, during 0.25- 6 hours after injection of siRNA- aquaporin-4 solution, the relative apparent diffusion coefficient slightly fluctuated and aquaporin-4 expression was upregulated; during 0.5 4 hours, the relative apparent diffusion coefficient was significantly higher, while aquaporin-4 expression was significantly lower when compared with the control group, and intracellular edema was markedly reduced; at 0.25 and 6 hours, the relative apparent diffusion coefficient and aquaporin-4 expression were similar when compared with the control group; obvious angioedema remained at 6 hours. Pearson＇s correlation test results showed that aquaporin-4 expression was negatively correlated with the apparent diffusion coefficient （r = -0.806, P 〈 0.01）. These findings suggest that upregulated aquaporin-4 expression is likely to be the main molecular mechanism of intracellular edema and may be the molecular basis for decreased relative apparent diffusion coefficient. Aquaporin-4 gene interference can effectively inhibit the upregulation of aquaporin-4 expression during the stage of intracelfular edema with time-effectiveness. Moreover, diffusion-weighted MRI can accurately detect intracellular edema.

Nimodipine for treatment of perifocal edema following aspiration and drainage in patients with cerebral hemorrhage

BACKGROUND： After cephalophyma removal, perifocal edema does not disappear subsequently, but progresses occasionally. Nimodipine can improve cerebral blood flow, so it maybe reduce cerebral edema area, and speed up the absorption of edematous fluid. OBJECTIVE： To observe the effect of nimodipine on perifocal edema area and neurologic function in patients with hypertensive intracerebral hemorrhage （HICH） following stereotaxic aspiration. DESIGN： Clinical controlled observation. SETTING： Department of Neurology, Third Hospital Affiliated to Liaoning Medical University. PARTICIPANTS： Totally 116 HICH inpatients admitted to the Department of Neurology, Third Hospital Affiliated to Liaoning Medical University from January 2003 to January 2005 were involved in this experiment. They all met the classification and diagnosis of cerebrovascular disease proposed in 1995 4th National Conference on Cerebrovascular Disease. The bleeding volume ≥ 35 mL was confirmed by skull CT. The involved patients, 64 male and 52 femlae, averaged 63 years old, ranging from 40 to 70 years. All the patients suffered from unilateral cerebral hemisphere hemorrhage, and muscle strength of paralyzed limb was less than degree Ⅲ. Informed consents of therapeutic items were obtained from all the patients and relatives. METHODS： ① According to different wills, the patients were assigned into treatment group （n =60） and control group （n =56）. In the treatment group, the involved patients, 32 male, 28 female, averaged 63 years. They underwent operation and administration of nimodipine. In the control group, the involved patients, 30 male and 26 female, averaged 62 years old. They all underwent operation simply. Patients in the two groups all received stereotaxic aspiration, drainage, dehydration, haemostasis, antiinflammation, blood pressure controlling and other treatments. Patients in the treatment group were also intravenously injected with 0.2 g/L nimodipine（Bayer Medicine Health Care Co., Ltd., Lot No. 021127） at 10 mg/d. One course of treatment was 15 days. ② According to the clinical neurologic function deficit score of stroke proposed in the 4th National Conference on Cerebrovascular Disease （mild： 0-15 points; moderate： 16-30 points; severe： 31-45 points）, neurologic function deficit score and the largest perifocal edema area of patients in two groups were recorded on the 1st, 7th and 15th days after operation. The differences in perifocal edema area and neurologic deficit score between on the 1st and 7th days and between on the 7th and 15th days were calculated. MAIN OUTCOME MEASURES： Changes in the neurologic function deficit score and the largest perifocal edema area. RESULTS： Two of treatment group and 16 of control group died. Finally, 98 patients participated in the final analysis. ①In the treatment group, the difference in the largest perifocal edema area on the postoperative 7th and 15th days and on the 1st day was （1.02±0.07） and （1.86±0.10） cm2, respectively, which changed more significantly as compared with control group, respectively [（0.02±0.04）,（0.61±0.09） cm2,P 〈 0.01]. ② The difference in neurologic function deficit score between on the postoperative 15th and 1st days in the treatment group was larger than that in the control group [（7.23±0.22）,（2.68±0.32） points,P 〈 0.01]. CONCLUSION： Nimodipine obviously reduces perifocal edema area of patients with cerebral hemorrhage following aspiration and drainage, and promotes the recovery of neurologic function.

Telmisartan Reduced Cerebral Edema by Inhibiting NLRP_3 Inflammasome in Mice with Cold Brain Injury

The aim of this study was to investigate the possible beneficial role of telmisartan in cerebral edema after traumatic brain injury（TBI） and the potential mechanisms related to the nucleotide-binding oligomerization domain（NOD）-like receptor（NLR） pyrin domain-containing 3（NLRP3） inflammasome activation. TBI model was established by cold-induced brain injury. Male C57BL/6 mice were randomly assigned into 3, 6, 12, 24, 48 and 72 h survival groups to investigate cerebral edema development with time and received 0, 5, 10, 20 and 40 mg/kg telmisartan by oral gavage, 1 h prior to TBI to determine the efficient anti-edemic dose. The therapeutic window was identified by post-treating 30 min, 1 h, 2 h and 4 h after TBI. Blood-brain barrier（BBB） integrity, the neurological function and histological injury were assessed, at the same time, the m RNA and protein expression levels of NLRP3 inflammasome, IL-1β and IL-18 concentrations in peri-contused brain tissue were measured 24 h post TBI. The results showed that the traumatic cerebral edema occurred from 6 h, reached the peak at 24 h and recovered to the baseline 72 h after TBI. A single oral dose of 5, 10 and 20 mg/kg telmisartan could reduce cerebral edema. Post-treatment up to 2 h effectively limited the edema development. Furthermore, prophylactic administration of telmisartan markedly inhibited BBB impairment, NLRP3, apoptotic speck-containing protein（ASC） and Caspase-1 activation, as well as IL-1β and IL-18 maturation, subsequently improved the neurological outcomes. In conclusion, telmisartan can reduce traumatic cerebral edema by inhibiting the NLRP3 inflammasome-regulated IL-1β and IL-18 accumulation.

Edema and neuronal apoptosis in the hippocampus and cortex of elderly rats following transient cerebral ischemia/reperfusion injury

BACKGROUND： Previous studies of cerebral ischemia have used young animals, with an ischemic time greater than 5 minutes （safe time limit）. Despite an increased understanding of neuronal apoptosis, it remains uncertain whether brief cerebral ischemic events of 5 minutes or less damage brain tissue in elderly rodents. OBJECTIVE： To investigate the effects of transient cerebral ischemia （5 minutes）/reperfusion injury on brain cortical and hippocampal edema, aquaporin-4 （AQP-4） expression, and neuronal apoptosis in aged rats, and to compare ischemic sensitivity between cortex and hippocampus. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Institute of Cerebrovascular Disease, Qingdao University Medical School from April 2008 to March 2009. MATERIALS： Rabbit anti-AQP-4 polyclonal antibody, TUNEL kit, and SABC immunohistochemistry kit were purchased from Wuhan Boster Bioengineering, China. METHODS： A total of 160 healthy, male, aged 19-21 months, Wistar rats were randomly assigned to 4 groups： sham-surgery, and ischemia 1-, 3-, and 5-minute groups, with 40 rats in each group. The global cerebral ischemia model was established using the Pusinelli four-vessel occlusion, and the three cerebral ischemia groups were subdivided into reperfusion 12-hour, 1-, 2-, 3-, and 7-day subgroups, with 8 rats in each subgroup. The sham-surgery group was subjected to exposure of the first cervical bilateral alar foramina and bilateral common carotid arteries. MAIN OUTCOME MEASURES： The dry-wet weight assay was used to measure brain water content and histopathology of the cortex and hippocampus was observed following hematoxylin-eosin staining. In addition, cortical and hippocampal AQP-4 expression was detected by streptavidin-biotin complex immunohistochemistry, and neuronal apoptosis was detected by the TUNEL method. RESULTS： There was no significant difference in brain water content or AQP-4 expression in the cortex and hippocampus between ischemia 1- and 3-minute groups and the sham-surgery group or brain water content or AQP-4 expression in the cortex between ischemia 5-minute group and sham-surgery group （P 〉 0.05）. However, brain water content and AQP-4 expression in the hippocampus after 5 minutes of cerebral ischemia were significantly increased compared with the sham-surgery group （P 〈 0.05 or P 〈 0.01）. Several TUNEL-positive cells were observed in the cortex and hippocampus of the sham-surgery group and ischemia 1-minute group, as well as in the cortex of the ischemia 3-minute group. In addition, the number of apoptotic neurons in the hippocampus of ischemia 3-minute group and in the cortex and hippocampus of ischemia 5-minute group was significantly increased （P 〈 0.05 or P 〈 0.01 ）. Neuronal apoptosis was increased after 12 hours of ischemia/reperfusion, and it reached a peak by 2 days （P 〈 0.01）. CONCLUSION： Transient cerebral ischemia （5 minutes） resulted in increased hippocampal edema, AQP-4 expression, and neuronal apoptosis. Moreover, cerebral ischemia had a greater effect on neuronal apoptosis than brain edema or AQP-4 expression, and the hippocampus was more sensitive than the cortex.

Effects of the mitochondrial calcium uniporter on cerebral edema in a rat model of cerebral ischemia reperfusion injury

The present study investigated the effects of the mitochondrial calcium uniporter inhibitor ruthenium red and the agonist spermine on cerebral edema in rats with cerebral ischemia reperfusion injury. Left middle cerebral artery occlusion （MCAO） was induced in rats using the suture method. Following 24 hours of ischemic reperfusion, neurological function scores of rats with MCAO, and rats pretreated with ruthenium red and spermine were significantly lower, however, water content of brain tissue, aquaporin 4 expression and immunoglobulin G （IgG） exudation were significantly higher than those of sham-operated rats. Compared with MCAO rats and spermine-treated rats, neurological function scores were considerably higher, and brain tissue water content, aquaporin 4 expression and IgG exudation decreased in ruthenium red-treated rats. These findings suggest that preventive application of the mitochondrial calcium uniporter inhibitor ruthenium red can significantly decrease aquaporin 4 and IgG expression, influence the permeability of the blood brain barrier, and thereby decrease the extent of cerebral edema.

Transcranial focused ultrasound stimulation reduces vasogenic edema after middle cerebral artery occlusion in mice

Blood-brain barrier(BBB)disruption underlies the vasogenic edema and neuronal cell death induced by acute ischemic stroke.Reducing this disruption has therapeutic potential.Transcranial focused ultrasound stimulation has shown neuromodulatory and neuroprotective effects in various brain diseases including ischemic stroke.Ultrasound stimulation can reduce inflammation and promote angiogenesis and neural circuit remodeling.However,its effect on the BBB in the acute phase of ischemic stroke is unknown.In this study of mice subjected to middle cerebral artery occlusion for 90 minutes,low-intensity low-frequency(0.5 MHz)transcranial focused ultrasound stimulation was applied 2,4,and 8 hours after occlusion.Ultrasound stimulation reduced edema volume,improved neurobehavioral outcomes,improved BBB integrity(enhanced tight junction protein ZO-1 expression and reduced IgG leakage),and reduced secretion of the inflammatory factors tumor necrosis factor-αand activation of matrix metalloproteinase-9 in the ischemic brain.Our results show that low-intensity ultrasound stimulation attenuated BBB disruption and edema formation,which suggests it may have therapeutic use in ischemic brain disease as a protector of BBB integrity.

Aquaporin-4 in the formation of cerebral edema following severe burns What role do arginine vasopressin levels play?

BACKGROUND： Aquaporin-4 （AQP-4）, which is able to rapidly transport water within the brain, is highly expressed in brain tissue. It also plays an important role in the formation of cerebral edema following brain injury. However, the role of AQP-4 in the formation of cerebral edema following severe bums remains unknown. OBJECTIVE： To study changes in AQP-4 protein and mRNA expression during formation of cerebral edema following severe burns, and to explore the correlation between AQP-4 protein and mRNA expression with plasma levels of arginine vasopressin （AVP）. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Research Center of Neuroscience, Chongqing Medical University from 2007 to 2008. MATERIALS： Biotin-labeled goat anti-rabbit antibody was provided by Beijing Zhongshan Biotechnology, China; in situ hybridization kit was provided by Wuhan Boster Biotechnology, China; rabbit anti-AQP-4 polyclonal antibody and horseradish peroxidase-labeled goat anti-rabbit IgG were provided by Chemicon, USA; AVP radioimmunoassay kit was provided by the Research Department of Neurobiology, the Second Military Medical University of Shanghai, China. METHODS： A total of 180 adult, healthy, Wistar rats were randomly assigned to control and burn groups with 30 rats in each group. The burn group was observed at five different time points： 2, 6, 12, 24, and 48 hours after burn. Hair on the mouse back was removed to expose skin on the back. After 1 day, skin with the hair removed was dipped into 100℃ water for 15 seconds to induce grade III bum injury that measures 30% of total bum surface area. MAIN OUTCOME MEASURES： Brain water content was measured using the dry-wet weight method. AQP-4 protein and mRNA expressions were detected using immunohistochemistry, in situ hybridization, Western blot, and reverse transcription-polymerase chain reaction; dynamic changes in plasma AVP were detected using radioimmunoassay. RESULTS： Brain water content gradually increased following severe burn injury. AQP-4 protein and mRNA expressions were upregulated in the supraoptic nucleus, suprachiasmatic nucleus, paraventricular nucleus, hippocampus, choroid plexus, and cerebral cortex. Plasma AVP levels increased following burn injury. AQP-4 protein and mRNA expressions positively correlated with brain water content and AVP levels during formation of cerebral edema （r= 0.870, 0.848, P 〈 0.01）. CONCLUSION： AQP-4 participated in the formation of cerebral edema following burn injury. Plasma AVP upregulated AQP-4 expression in brain tissue, thereby promoting formation of cerebral edema.

Relationship between AQP4 expression and DWI of the cerebral ischemic edema in rats

Objective: To study the correlation between aquaporin-4 ( AQP4) expression and diffusion-weighted imaging ( DWI) in the process of ischemic brain edema for the molecular biologic mechanism of DWI. Methods: A total of 34 Wistar rats were divided into 8 groups randomly: Non-operated group (n = 4) , sham-operated group (n = 6) , and operated group, receiving right middle cerebral artery occlusion ( MCAO) for 15 and 30 min, and 1,3,6 and 24 h respectively (6 subgroups, n =4). All groups were imaged with DWI and T2WI. The apparent diffusion coefficient (ADC) , relevant density (rd) and relevant area (rs) of hyperintensity of the lesions on DWI and T2WI were measured. Relevant ADC (rADC) , relevant area of immunohistochemical staining for AQP4 (rS) , optical density of AQP4 hybridization (a) were calculated. After that the animals were sacrificed and perfused at different time intervals, correlations between DWI, ADC, and AQP4 expression (rS, a) in ischemic tissue was made. Results: There was a significant correlation between rS and a ( r = 0. 949 ). The abnormal high intensity was found in DWI of the ipsilateral MAC territory at 15 min after MCAO. The ADC value decreased quickly within 1 h after MCAO, the rd and rs of DWI increased rapidly and the expression of AQP4 increased quickly, too. However, there was no change on the T2WI. In the period of time (15 min - 1 h) , the AQP4 expression( a) had a strong relation to the rd and rs( r = 0. 914, 0. 895). With the progress of the time, the ADC value of MCAO decreased further to (2.1±0.6)×10-4 mm2/s at 3 h, and then followed an increased slowly till 24 h, but the rd and the rs as well as the expression of AQP4 continuously increased during the stage. The T2WI detected the lesion at the average time (1.4 h) after MCAO, and the rs of T2WI was less than that of DWI at the same time in the same layer (P < 0.05). Conclusion: The results imply that high expression of AQP4 may play a key role in ischemic brain edema. It is, certainly, one of the important reasons of the DWI molecular biologic mechanism in the cerebral ischemia.

Exendin-4 inhibits high-altitude cerebral edema by protecting against neurobiological dysfunction

The anti-inflammatory and antioxidant effects of exendin-4（Ex-4） have been reported previously.However,whether（Ex-4） has anti-inflammatory and antioxidant effects on high-altitude cerebral edema（HACE） remains poorly understood.In this study,two rat models of HACE were established by placing rats in a hypoxic environment with a simulated altitude of either 6000-or 7000-m above sea level（MASL） for 72 hours.An altitude of 7000 MASL with 72-hours of hypoxia was found to be the optimized experimental paradigm for establishing HACE models.Then,in rats where a model of HACE was established by introducing them to a 7000 MASL environment with 72-hours of hypoxia treatment,2,10 and,100 μg of Ex-4 was intraperitoneally administrated.The open field test and tail suspension test were used to test animal behavior.Routine methods were used to detect change in inflammatory cells.Hematoxylin-eosin staining was performed to determine pathological changes to brain tissue.Wet/dry weight ratios were used to measure brain water content.Evans blue leakage was used to determine blood-brain barrier integrity.Enzyme-linked immunosorbent assay（ELISA） was performed to measure markers of inflammation and oxidative stress including superoxide dismutase,glutathione,and malonaldehyde values,as well as interleukin-6,tumor necrosis factor-alpha,cyclic adenosine monophosphate levels in the brain tissue.Western blot analysis was performed to determine the levels of occludin,ZO-1,SOCS-3,vascular endothelial growth factor,EPAC1,nuclear factor-kappa B,and aquaporin-4.Our results demonstrate that Ex-4 preconditioning decreased brain water content,inhibited inflammation and oxidative stress,alleviated brain tissue injury,maintain blood-brain barrier integrity,and effectively improved motor function in rat models of HACE.These findings suggest that Ex-4 exhibits therapeutic potential in the treatment of HACE.

Ataxia,acute mountain sickness,and high altitude cerebral edema

Previous investigations suggest that ataxia is common and often one of the most reliable warning signs of high altitude cerebral edema(HACE). The aim of this study was to investigate the diagnostic role of ataxia in acute mountain sickness(AMS)and HACE among mountain rescuers on the quake areas,and in approaching the relation between AMS and HACE. After the earthquake on April 14,2010,approximately 24 080 lowland rescuers were rapidly transported from sea level or lowlands to the mountainous rescue sites at 3 750 ~ 4 568 m,and extremely hardly worked for an emergency treatment after arrival. Assessments of acute altitude illness on the quake areas were using the Lake Louise Scoring System. 73 % of the rescuers were found to be developed AMS. The incidence of high altitude pulmonary edema(HAPE)and HACE was 0.73 % and 0.26 %,respectively,on the second to third day at altitude. Ataxia sign was measured by simple tests of coordination including a modified Romberg test. The clinical features of 62 patients with HACE were analyzed. It was found that the most frequent,serious neurological symptoms and signs were altered mental status(50/62,80.6 %)and truncal ataxia(47/62,75.8 %). Mental status change was rated slightly higher than ataxia,but ataxia occurred earlier than mental status change and other symptoms. The earliest sign of ataxia was a vague unsteadiness of gait,which may be present alone in association with or without AMS. Advanced ataxia was correlated with the AMS scores,but mild ataxia did not correlate with AMS scores at altitudes of 3 750~4 568 m. Of them,14 patients were further examined by computerized tomographic scanning of the brain and cerebral magnetic resonance imagines were examined in another 15 cases. These imaging studies indicated that the presence of the cerebral edema was in 97 % of cases who were clinically diagnosed as HACE(28/29). Ataxia seems to be a reliable sign of advanced AMS or HACE,so does altered mental status.

Effect of Glycerol Fructose Combined with Mannitol on Patients with Cerebral Hemorrhage and Cerebral Edema

Objective:To observe the effect of glycerol fructose combined with mannitol in the treatment of patients with clinical intracerebral hemorrhage complicated by cerebral edema and increased intracranial pressure,and to evaluate the clinical application value of this treatment.Methods:Seventy patients with cerebral hemorrhage complicated by brain edema were randomly divided into observation and control groups.Both groups had exactly the same number of study participants.There were some differences in specific treatment methods.The specific process is as follows:The control group was treated with mannitol,while the observation group was treated with dual-purpose glycerol fructose.Several important indicators after treatment in the two groups were scored,the effects between different groups were compared,and the effect of clinical treatment was evaluated.Results:The final effect was compared and analyzed.After data analysis,we found that the intracranial pressure of the observation group was lower,the volume of brain edema was significantly reduced(P<0.05),and the NIH Stroke Scale/Score(NIHSS)was lower(P<0.05).Conclusion:Using mannitol combined with glycerol fructose can achieve better treatment effect by significantly improving the problem of brain edema.

The changes of neuronal Ca^（2＋） channel and its effects on BBB permeability and cerebral edema associated with brain injury

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Over hydration in diabetic ketoacidosis may increase the risk of cerebral edema in children

Objectives Over-hydration in diabetic ketoacidosis(DKA) may increase the risk of cerebral edema in children.Methods We have organized a prospective descriptive cohort study of 38pediatric patients aged 1month to 14years,who were diagnosed with DKA with 41episodes of diabetic ketoacidosis,presented to the pediatric emergency department at the First Affiliated Hospital of Xinjiang Medical University from January 2010to February 2012.This study was approved by the Ethics Committee of The First Affiliated Hospital of Xinjiang Medical University.Results The magnitude presentation of the percentile 25%-70% was in the ratio of 5.6%(3.4%-8.2%)(6.1±4).So there was no clinical and biochemical assessment variation needed.These both of the variations,all of the diabetic ketoacidosis patient approached.Further all the patient variations were not correlated with the amplitude of variation and magnitude presentation and did not affect the fluid concentration and the quantity of the fluid was 47.8mL / kg(36.556.3) in the first 12hours.Conclusion For the conclusion of the exact parameters and the magnitude variations of the fluid in the patients of diabetic ketoacidosis,all of the conformations need study on the larger scale.

Malignant Cerebral Edema Secondary to Gliadel Wafers in the Early Postsurgical Period

High grade gliomas are the commonest intrinsic brain tumours and account for more average years of life lost than all the common cancers. It has become the commonest cause of cancer death in men under the age of 45 and women under the age of 35. Although surgical resection can greatly reduce tumour bulk, complete excision is virtually impossible due to the infiltrative nature of these tumours. In an attempt to treat the infiltrating tumour cells, there has been much interest in using local therapies inserted at the time of surgery. The authors report a case of fatal cerebral edema unresponsive to aggressive medical and surgical assessment that finally evolved to premature death in the early postsurgical period, after the craniotomy and implantation of Gliadel wafers. They note that high doses of dexamethasone were insufficient to prevent cerebral edema and death. A search for corticosteroid use and dosing for patients treated with Gliadel wafers in the published literature revealed no recommendations on the doses of steroids to be administered. In our opinion this is a very important issue and maybe the key point for the treatment of this disease, and may need to be addressed with treatment guidelines in the near future in order to ensure better results on patient’s survival. Prior to this case review there had been two similar report but a later presentation. So we think that this is the first case report of acute fulminant cerebral edema secondary to gliadel wafers in the early period.

EFFECT OF DL-3-N-BUTYLPHTHALIDE ON BRAIN EDEMA IN RATS SUBJECTED TO FOCAL CEREBRAL ISCHEMIA

The present study evaluated the effect of dl-3-n-butylphthalide(NBP) ,a novel brain protective agent, on brain edema in rats following focal ischemia. Edema was induced by occluding the right middle cerebral artery (MCAO).producing permanent focal ischemia in the right cerebral hemisphere,which developed ip-silateral brain edema reproducibly. Edema was assessed 24 h after MCA occlusion by determining the brain water content from wet and dry weight measurements,and the sodium,potassium concentrations with ion-selective electrodes. In this model,NBP at the dose of 80,160 and 240 mg/kg po 15 min after MCAO prevented from brain edema in a dose-dependent manner. A significant reduction of sodium content and an increase in potassium level were observed in all drug-treated groups. It showed that NBP strongly attenuated brain water entry,sodium accumulation and potassium loss. Nimodipine treatment(5mg/kg sc) also reduced brain edema (P<0. 05). The results suggest that a strong anti-edema activity of NBP may play an important role to contribute to the treatment of ischemic damage.

Influence of rotating magnetic field on cerebral infarction volume, cerebral edema and free radicals metabolism after cerebral ischemia/reperfusion injury in rats

BACKGROUND: It has shown that magnetic field can improve blood circulation, decrease blood viscosity, inhibit free radicals, affect Ca2+ flow in nerve cells, control inflammatory and immunological reaction, and accelerate nerve cell regeneration. In addition, protective effect of magnetic field, which acts as an iatrophysics, on ischemic brain tissues has been understood gradually. OBJECTIVE: To investigate the effects of rotating magnetic field (RMF) on volume of cerebral infarction, cerebral edema and metabolism of free radicals in rats after cerebral ischemia/reperfusion injury. DESIGN: Randomized controlled animal study. SETTING: Rehabilitation Center of disabled children, Liaoniang; Department of Rehabilitation, the Second Affiliated Hospital, China Medical University; Department of Rehabilitation Physiotherapy, the First Affiliated Hospital, China Medical University. MATERIALS: A total of 70 healthy Wistar rats aged 18-20 weeks of both genders were selected and randomly divided into 3 groups: sham operation group with 12 rats, control group with 20 rats and treatment group with 38 rats. The treatment group included 4 time points: immediate reperfusion with 6 ones, 6-hour reperfusion with 20 ones, 12-hour reperfusion with 6 ones and 18-hour reperfusion with 6 rats. Main instruments were detailed as follows: magnetic head of rotating magnetic device was 6 cm in diameter; magnetic induction intensity at the surface of magnetic head was 0.25 T in silence; the maximal magnetic induction intensity was 0.09 T at the phase of rotation; the average rotating speed was 2500 r per minute. METHODS: The experiment was carried out in the China Medical University in March 2003. Focal cerebral ischemic animal models were established with modified Longa’s method. Operation was the same in the sham operation, but the thread was inserted as 10 mm. Neurologic impairment was assessed with 5-rating method to screen out cases. Those survivals with grade 1 and grade 2 after ischemia for 2 hours and reperfusion for 24 hours were included in the control group and treatment group. Those in the sham operation group and control group were not treated with RMF. Magnetic head was directed towards the head of rats of the treatment group, and the magnetic head was about 7 mm from skin, treated for 15 minutes. The rats were decapitated to take out brains at 24 hours after reperfusion in each group. Water content of brain and volume of cerebral infarction were assessed with wet-dry weight method and TTC staining, respectively. Activity of superoxide dismutase (SOD), content of malondialdehyde (MDA) and change of brain histomorphology in brain tissue of ischemic side were analyzed. MAIN OUTCOME MEASURES: ① Volume of cerebral infarction and changes of water content in brain; ② measurements of SOD and MDA contents in brain tissue of rats in all groups. RESULTS: A total of 70 qualified animals were involved in the final analysis after rejecting the death and unqualified animal models. ① Water content of brain: Water content of brain in the treatment was less than that in the control group at any time point except the immediate time point, and cerebral edema was relieved [(2.48±0.22)%, (2.32±0.19)%, (2.23±0.36)%, (2.91±0.44)%, P < 0.05]. In addition, there were no significant differences among 6-hour, 12-hour and 18-hour reperfusion groups (P > 0.05). ② Volume of cerebral infarction: The absolute volume of cerebral infarction in the treatment group was smaller than that in the control group [(128.21±15.05), (171.22±40.50) mm3, t =2.438, P < 0.05], and the relative volume of cerebral infarction was smaller than that in the control group [(20.22±1.44)%, (25.17±3.85)%, t =2.95, P < 0.05]. ③ Contents of SOD and MDA in brain tissues: Compared with the control group, the SOD content in the brain tissue in the treatment group increased [(54.54±3.85), (69.52±5.88) kNU/g, t =5.568, P < 0.05], while the MDA content decreased [(0.85±0.06), (1.03±0.09) μmol/g, t =4.076, P < 0.05]. ④ General morphological observation: General morphology manifested that the edema was distinct in the right cerebral hemisphere in the control group, showing fat-like white, shallow anfractuosity, flat gyria, brittle tissue and easy to break up. The edema of right cerebral hemisphere was light and surface was hyperaemia in the treatment group. CONCLUSION: RMF may improve anti-oxidative ability of brain tissue of rats with acute focal cerebral ischemia/reperfusion injury and reduce volume of cerebral infarction and degrees of cerebral edema.

脑水肿(Cerebral edema)的治疗

脑水肿是由于多种病因引起的脑细胞水肿而致的脑体积增大,颅内压增高,常危及生命。治疗原则一、去除病因,切断继续的诱发因素。二、降低颅内压力,保持脑组织的灌注压。三、改善脑缺氧及脑代谢障碍。治疗方案在治疗原发病的基础上,消除脑水肿与降低颅内压的基本方法是减少脑容积、脑脊液量、脑减压及改善脑循环(CBF)等。(一)减少脑容积此方案列为首选。1.脱水治疗(1)脱水原则①患者血压必须维持在80~90/50~60mmHg以上,肾功能良好;②脱水程度恰到好处,如两眼稍下陷,眼球张力减低,压之稍软,皮肤仍保持弹性。

Study on cerebral edema in the rat model with closed craniocerebral injury and its relationship with apoptosis, inflammatory factor generation and AQPs expression

Objective:To study the relationship of cerebral edema with apoptosis, inflammatory factor generation and AQPs expression in the rat model with closed craniocerebral injury.Methods:Male SD rats were selected as experimental animals and divided into model group and control group. Model group were established into the closed craniocerebral injury models and control group received sham operation. The water content of damaged brain tissue as well as the expression of apoptosis molecules, the generation of inflammatory factors and the expression of aquaporins (AQPs) molecules were measured 7 d after model establishment.Results:The water content of brain tissue of model group was significantly higher than that of control group;Homer1a, Pim-3, Bcl-2, AQP1, AQP4 and AQP9 mRNA expression in brain tissue of model group were significantly lower than those of control group while Cdk5, FasL and Caspase-3 mRNA expression as well as NF-kB, TNF-α, IL-1β, IL-6 and p-JNK generation were significantly higher than those of control group. Homer1a, Pim-3, Bcl-2, AQP1, AQP4 and AQP9 mRNA expression in brain tissue of model group were negatively correlated with water content while Cdk5, FasL and Caspase-3 mRNA expression as well as NF-kB, TNF-α, IL-1β, IL-6 and p-JNK generation were positively correlated with water content.Conclusion:The excessive apoptosis, increased inflammatory factor generation and decreased AQPs expression are closely related to the occurrence of cerebral edema in the process of closed craniocerebral injury.

Study on the relationship of cytochrome C expression and cerebral edema in perihematomal brain tissue in patients with hypertensive cerebral hemorrhage

Objective To investigate the expression of cytochrome C in perihematomal brain tissue and its relationship with the histopathological change and formation of cerebral edema in patients with hypertensive cerebral hemorrhage.Methods Thirty four patients(23 male,11 female) of hypertensive cerebral hemorrhage in hospital from Sep.2001 to Sep.2002 were selected with a mean age 55.6± 10.2 years(from 35 to 75 years).The mean volume of hemorrhagic blood was 50.4±11.6 ml(from 25 to 85 ml).The perihematomal brain tissue was obtained from the minimally invasive surgery.Histopathological change and expressions of cytochrome C in perihematomal brain tissue was detected by histopathological and immunohistochemical techniques.The volume of perihematomal cerebral edema was determined by computed tomographic scan before operation.The results of staining and the volume of perihematomal cerebral edema were analyzed with double blind fashion.Results Perihematomal cerebral edema were found 12-72h after cerebral hemorrhage.Myelin sheath degeneration,condensation of nucleus and typical apopototic body were observed in perihematomal brain tissue.Expression of cytochrome C in perihematomal brain tissue was observed at 4 h and reached peak around 48-72 h after cerebral hemorrhage.Cytochrome C expressed higher positively in 16 patients and lower positively in 13 patients.Cytochrome C expression was not detected only in 5 patints.There were significant differences in volume of perihematomal cerebral edema with different expression of cytochrome C in perihematomal brain tissue(P<0.01).Conclusions Cytochrome C expression was upregulated in perihematomal brain tissue in patients with hypertensive cerebral hemorrhage.Cytochrome C might involve in the histopathological change and the formation of perihematomal cerebral