Brain edema and intracranial hypertension in fulminant hepatic failure:Pathophysiology and management

Intracranial hypertension is a major cause of morbidity and mortality of patients suffering from fulminant hepatic failure. The etiology of this intracranial hypertension is not fully determined, and is probably multifactorial, combining a cytotoxic brain edema due to the astrocytic accumulation of glutamine, and an increase in cerebral blood volume and cerebral blood flow, in part due to inflammation, to glutamine and to toxic products of the diseased liver. Validated methods to control intracranial hypertension in fulminant hepatic failure patients mainly include mannitol, hypertonic saline, indomethacin, thiopental, and hyperventilation. However all these measures are often not sufficient in absence of liver transplantation, the only curative treatment of intracranial hypertension in fulminant hepatic failure to date. Induced moderate hypothermia seems very promising in this setting, but has to be validated by a controlled, randomized study. Artificial liver support systems have been under investigation for many decades. The bioartiflcial liver, based on both detoxification and swine liver cells, has shown some efficacy on reduction of intracranial pressure but did not show survival benefit in a controlled, randomized study. The Molecular Adsorbents Recirculating System has shown some efficacy in decreasing intracranial pressure in an animal model of liver failure, but has still to be evaluated in a phase Ⅲ trial.

Aquaporin-4 and ischemic brain edema

OBJECTIVE： To investigate the relationship of aquaporin 4 （AQP4） and brain edema. DATA SOURCES： Using the terms of ＂aquaporin-4, brain edema＂, we searched PubMed database to identify studies published from January 1997 to April 2006 in the English languages. Meanwhile, we also searched China National Knowledge Infrastructure （CNKI） for related studies. STUDY SELECTION： The collected data were selected firstly. Studies on AQP4 and brain edema were chosen and their full-texts were searched for, and those with repetitive or review studies were excluded. DATA EXTRACTION： Totally 146 related studies were collected, 42 of them were involved and the other 104 studies were used for reading reference data. DATA SYNTHESIS： AQP4 is a selective water permeable integral membrane protein. It is mainly expressed in astrocytes and ependymocyte, and is the important structural basis for water regulation and transportation between glial cells and cerebrospinal fluid or vessels. Phosphorylation is involved in the regulation of AQP4. AQP4 participates in the formation of brain edema caused by various factors. Studies on the structure and pathological changes of AQP4 are still in the initial stage, and the role and mechanism of AQP4 in the formation of brain edema is very unclear. CONCLUSION： AQP4 plays a critical regulating role in the formation of ischemic brain edema, but whether it is regulated by drugs lacks reliable evidence.

Hyperammonemia,brain edema and blood-brain barrier alterations in prehepatic portal hypertensive rats and paracetamol intoxication

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.

Enhanced Expression of Aquaporin-9 in Rat Brain Edema Induced by Bacterial Lipopolysaccharides

To investigate the role of AQP9 in brain edema, the expression of AQP9 in an infectious rat brain edema model induced by the injection of lipopolysaccharide （LPS） was examined. Immuno- histochemistry and reverse transcription-polymerase chain reaction （RT-PCR） analysis demonstrated that the expressions of AQP9 mRNA and protein at all observed intervals were significantly increased in LPS-treated animals in comparison with the control animals. Time-course analysis showed that the first signs of blood-brain barrier disruption and the increase of brain water content in LPS-treated animals were evident 6 h after LPS injection, with maximum value appearing at 12 h, which coincided with the expression profiles of AQP9 mRNA and protein in LPS-treated animals. The further correlation analysis revealed strong positive correlations among the brain water content, the disruption of the blood-brain barrier and the enhanced expressions of AQP9 mRNA and protein in LPS-treated animals. These results suggested that the regulation of AQP9 expression may play im- portant roles in water movement and in brain metabolic homeostasis associated with the pathophysi- ology of brain edema induced by LPS injection.

Occludin and connexin 43 expression contribute to the pathogenesis of traumatic brain edema

The experimental model of traumatic brain injury was established in Sprague-Dawley rats according to Feeney＇s free falling method. The brains were harvested at 2, 6 and 24 hours, and at 3 and 5 days after injury. Changes in brain water content were determined using the wet and dry weights. Our results showed that water content of tissue significantly increased after traumatic brain injury, and reached minimum at 24 hours. Hematoxylin-eosin staining revealed pathological impairment of brain tissue at each time point after injury, particularly at 3 days, with nerve cell edema, degenera- tion, and necrosis observed, and the apoptotic rate significantly increased. Immunohistochemistry and western blot analysis revealed that the expression of occludin at the injured site gradually de- creased as injury time advanced and reached a minimum at 3 days after injury; the expression of connexin 43 gradually increased as injury time advanced and reached a peak at 24 hours after in-jury. The experimental findings indicate that changes in occludin and connexin 43 expression were consistent with the development of brain edema, and may reflect the pathogenesis of brain injury.

Rifaximin,but not growth factor 1,reduces brain edema in cirrhotic rats

AIM:To compare rifaximin and insulin-like growth factor(IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion.METHODS:Rats with CCl4-induced cirrhosis with ascites plus portal vein occlusion and controls were randomized into six groups:Cirrhosis;Cirrhosis + IGF-1;Cirrhosis + rifaximin;Controls;Controls + IGF-1;and Controls + rifaximin.An oral glutamine-challenge test was performed,and plasma and cerebral ammonia,glucose,bilirubin,transaminases,endotoxemia,brain water content and ileocecal cultures were measured and liver histology was assessed.RESULTS:Rifaximin treatment significantly reduced bacterial overgrowth and endotoxemia compared with cirrhosis groups,and improved some liver function parameters(bilirubin,alanine aminotransferase and aspartate aminotransferase).These effects were associated with a significant reduction in cerebral water content.Blood and cerebral ammonia levels,and area-underthe-curve values for oral glutamine-challenge tests were similar in rifaximin-treated cirrhotic rats and control group animals.By contrast,IGF-1 administration failed to improve most alterations observed in cirrhosis.CONCLUSION:By reducing gut bacterial overgrowth,only rifaximin was capable of normalizing plasma and brain ammonia and thereby abolishing low-grade brain edema,alterations associated with hepatic encephalopathy.

Research on the relationship between reduced scattering coefficient and intracranial pressure in brain edema model

Intracranial hypertension is a serious threat to the health of neurosurgical patients.At present,there is a lack of a safe and e®ective technology to monitor intracranial pressure(ICP)accurately and nondestructively.In this paper,based on near infrared technology,the continuous nonde-structive monitoring of ICP change caused by brain edema was studied.The rat brain edema models were constructed by lipopolysaccharide.The ICP monitor and the self-made near infrared tissue parameter measuring instrument were used to monitor the invasive intracranial pressure and the reduced scattering coe±cient of brain tissue during the brain edema development.The results showed that there was a negative correlation between the reduced scattering coe±cient(690nm and 834nm)and ICP,and then the mathematical model was established.The experimental results promoted the development of nondestructive ICP monitoring based on near infrared technology.

THERAPEUTIC EFFECT OF CYPROHEPTADINE ON TRAUMATIC BRAIN EDEMA IN RATS

Acute traumatic brain edema models were established in SD rats by dropping weight methods.We observed the therapeutic effect of Cyproheptadine(Cyp)on traumatic brain edema.It was shown that Cyp could obviously reduce the brain water content,decrease the releae or LDH,reduce the seventy of the pathological changes at the injury areas,increase the SOD activity and decrease the production of MDA in SD rats.The results suggest that Cyp has obvious.therapeutic effect on traumatic brain edema.The mechanism may be that it can increase the activity or clearance enzyme of free radical,inhibit lipid peroxldation and reduce intracellular Ca2+-overload.

Suppressive effect of dexamethasone on the neutrophil expression of CD18 in rats with radiation induced brain edema

BACKGROUND： Stereo-tactic radiation therapy （SRT） is widely used to treat intracranial diseases, but some patients suffered from radiation induced brain edema after SRT. Once radiation induced brain edema occurs, the treatment is quite difficult, and it always leads to a poor outcome. Dexamethasone has certain therapeutic effect on traumatic brain edema, but the biological mechanism is still unclear. OBJECTIVE ： To observe the effect of dexamethasone on the neutrophil expression of CD18.DESIGN ： A randomized control observation.SETTING： Changhai Hospital of the Second Military Medical University of Chinese PLA. MATERIALS ： The experiment was carried out in Changhai Hospital of the Second Military Medical University of Chinese PLA from January 1999 to December 1999. Twenty SD rats （male and female each in half） weighing （250±50） g were used. METHODS： Twenty SD rats were divided into four groups at random. ① Blank control group （n=5）： The rats were not treated without dexamethasone or irradiation;② Irradiation group （n=5）： The rats were given irradiation but no dexamethasone treatment; ③ Irradiation＋1 mg/kg dexamethasone group （n=5）; The rats were treated with irradiation and dexamethasone of 1 mg/kg; ④Irradiation＋5 mg/kg dexamethasone group （n=5）： The rats were treated with irradiation and dexamethasone of 5 mg/kg. The heads of the rats were irradiated with 10 MeV X-ray （30 Gy）, and brain tissue was removed after 2 weeks to observe the pathological changes. Blood samples were taken from the carotid artery, gradient centrifugation was used, and neutrophile layer was obtained, the level of neutrophile expression of CD18 mRNA and quantity of membrane proteins in blood were detected with Northern blot and flow cytometry respectively. MAIN OUTCOME MEASURES： ① Blood cell count; ② Pathological results; ③ level of neutrophile expression of CD18 mRNA and quantity of membrane proteins. RESULTS ： All the 20 SD rats were involved in the analysis of results without deletion. At 2 weeks after irradiation, obvious cell injury could be observed under light microscope. The level of neutrophile expression of CD18 mRNA and quantity of membrane proteins in blood were obviously increased, but the severity of cell injury was relieved in the irradiation＋1 and 5 mg/kg dexamethasone groups, and the CD18 expression was markedly suppressed （P 〈 0.05）, and the suppression was more obvious in the irradiation＋5 mg/kg dexamethasone group than in the irradiation＋1 mg/kg dexamethasone group （P 〈 0.01 ）. CONCLUSION： Dexamethasone can reduce the radiation induced brain edema by inhibiting the expression of CD18.

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.

Study of the AQP4 expression in traumatic brain edema and multimodal MRI imaging

The aquaporin-4(AQP4)is a highly selective membrane protein.It is important for the body to maintain the water balance between internal and external environment of cells,the studies have found that the abnormal expression of AQP4 is related to the occurrence of many diseases.The cerebral edema is the most common and serious complication of brain trauma,and its pathogenesis is closely related to AQP4.The development of multimodal magnetic resonance imaging(M-MRI)could been provided imaging basis for accurate diagnosis of traumatic brain edema.In recent years,the correlation between AQP4 and M-MRI has become a hotspot of research.This paper reviews the research progress on the correlation between AQP4 expression in traumatic cerebral edema and M-MRI.

THE RELATIONSHIP BETWEEN PERITUMORAL BRAIN EDEMA AND VASCULAR ENDOTHELIAL GROWTH FACTOR EXPRESSION IN PATIENTS WITH MENINGIOMA

Objective: To determine whether VEGF plays a role in the development of peritumoral brain edema. Methods 50 meningioma patients and their VEGF expression were studied. We took a monoclonal antibody from mouse to VEGF to stain the tumor cells, the vascular endothelial cells and the interstitial cells. The severity of brain edema was evaluated according to CT or MR scans by the following equation: edema index= V tumor +edema /Vtumor. The relationship between VEGF expression and edema index was analyzed statistically. Results VEGF was expressed in meningioma tumor cells, which is usually concentrated at the peripheral sites of the tumor. There was a positive linear correlation between the expression and the brain edema index. Conclusion VEGF may play a role in the development of peritumoral brain edema in meningioma patient.

Study on glucocorticoid receptor of brain cytosol in rats with traumatic brain edema

The high-affinity glucocorticoid binding sites（HAGS）and the low-affinity glucocor-ticoid binding sites（LAGS）with steroid specificity were demonstrated in cerebral cytosol ofrats by using the radioligand binding assay.The equilibrium dissocation constant（Kd）of HAGSand LAGS were（2.78+0.71）×10-8mol/L and（2.12±1.06）×10-6mol/L respectively as esti-mated by Scatchard and Pseudoseatchard analysis.Glucocorticoid receptors（GR）in the trau-matized（left）hemisphere cytosol were decreased more significantly than those in both the con-trol（right）hemisphere cytosol at 6 h postinjury and normal brain tissue（P【0.05）,but Kd ofGR showed no significant changes.GR of liver cytosol at 6h postinjury were more markedly de-creased than normal hepatic cytosol,but Kd of GR underwent no significant changes.These da-ta demonstrate that high-dose glucocorticoid（GC）used in the treatment of traumatic brain ede-ma might maintain target-cell reactions by increasing the production of GC receptor complexesand is most likely to be mediated by LAGS.

Ki67 Proliferative Index and Peritumoral Brain Edema in Meningiomas: Do They Correlate? A Clinical Study on 56 Patients

Introduction: Meningiomas are the most common type of extra-axial neoplasm. Peritumoral brain edema (PTBE) can be seen around meningiomas while it may be absent in others. Despite that Ki67 proliferative index has been previously correlated with meningioma grades, no definite relationship has been established in relation to PTBE in meningioma patients. Objective: Correlate the peritumoral brain edema with the Ki67 proliferative index of meningiomas. Patients & Methods: Aclinical prospective study was conducted on 56 patients (47 women, 9 men;mean age 50.89 ± 12.55 years) diagnosed with meningiomas. All patients were evaluated regarding the presence of brain edema surrounding the lesion in pre-operative neuroimaging using T2W and FLAIR MR images. Immunohistochemical staining of Ki67 index (representing proliferative activity) was done. Correlation between presence of PTBE and Ki67 index values was evaluated. Results: PTBE was found in nearly half of the patients (48.2%), while the remaining (51.8%) of patients did not exhibit PTBE in their pre-operative neuroimaging. The mean value of Ki67 index in meningioma patients with PTBE was 4.83% compared to a value of 1.83% in patients without PTBE, P value = 0.014. Conclusion: High Ki67 indices are evident in meningiomas with surrounding peritumoral brain edema (PTBE).

Correlation between aquaporin-4 and brain edema in an animal model of astrocytic oxygen-glucose deprivation and reintroduction

BACKGROUND：Previous studies have demonstrated that aquaporin-4 （AQP4） plays a key role in the formation and resolution of brain edema.However,the molecular mechanisms and role of AQP4 in hypoxia-ischemia-induced brain edema remain poorly understood.OBJECTIVE：To establish a newborn animal model of astrocytic oxygen-glucose deprivation and reintroduction,to observe the correlation between AQP4 and cellular volume,and to investigate the role of AQP4 in the development of brain edema following oxygen deprivation and reintroduction.DESIGN,TIME AND SETTING：A comparative experiment was performed at the Experimental Center of West China Second University Hospital between October 2007 and April 2009.MATERIALS：Astrocytes were derived from the neocortex of Sprague Dawley rats aged 3 days.METHODS：Astrocytes were incubated in glucose/serum-free Dulbecco＇s modified Eagle＇s medium,followed by 1% oxygen for 6 hours.Finally,oxygen-glucose deprivation and reintroduction models were successfully established.MAIN OUTCOME MEASURES：Real-time polymerase chain reaction and Western blot analysis were used to measure expression of AQP4 mRNA and protein in cultured rat astrocytes following oxygen-glucose deprivation and reintroduction.Astrocytic cellular volume,as determined by [3H]-3-O-methyl-D-glucose,was used to represent the extent of astrocytic swelling.RESULTS：During oxygen-glucose deprivation,AQP4 mRNA and protein expression gradually decreased in astrocytes,whereas cellular volume increased in a time-dependent manner （P〈 0.01）.Following oxygen-glucose reintroduction,AQP4 mRNAand protein expression was upregulated,peaked at day 7,and then gradually decreased,but still higher than normal levels （P 〈 0.05）.However,cellular volume gradually decreased （P 〈 0.01）,and then reached normal levels at day 7.CONCLUSION：AQP4 expression highly correlated with cellular volume changes,suggesting that AQP4 played an important role in modulating brain water transport in an astrocytic oxygen-glucose deprivation and reintroduction model.

Effects of bloodletting puncture at Jing-Well points in distal ends of finger and toe on survival rate and brain edema in cerebral ischemic rats

OBJECTIVE:To observe the effects of bloodletting puncture at Jing-Well points in the distal ends of the finger and toe on survival rate,survival time,and brain edema in rats with cerebral ischemia.METHODS:Fifty-four male Sprague-Dawley rats were randomly divided into five groups:normal,sham operation,model,bloodletting puncture at Jing-Well points in distal ends of finger and toe,and puncture without bloodletting at these points.Middle cerebral artery occlusion models were established according to Longa's method.The brains were taken 48 h after the model was established.Brain water content,brain density,brain coefficient,survival rate,and survival time in each group were measured.RESULTS:After bloodletting puncture,the survival time of the rats was prolonged,their brain water content and brain coefficient were reduced,and brain density was increased.CONCLUSION:Bloodletting puncture at Jing-Well points in the distal ends of the finger and toe can improve function in ischemic brain edema.

RELATIONS OF INTRACRANIAL PRESSURE, CREATINE KINASE AND BRAINSTEM AUDITORY EVOKED POTENTIAL IN PATIENTS WITH TRAUMATIC BRAIN EDEMA

We studied the relations of intracranial pressure (ICP),creatine kinase (CK) and bralnstem auditory evoked potential (BAEP) in 44 patients with traumatic brain edema who were admitted to our hospital from June 1990 to February 1991. There were 30 males and 14 females, with age range from 9 to 67 years. The results showed that the abnormal BAEP could reflect the severity of cerebral edema in acute head injury and was related to ICP and serum CK levels. When ICP>30 mmHg (4kPa), the abnormality of BAEP was more obvious than that of the control group (P<0.05); the serum CK levels were also elevated markedly. In patients with ICP over and below 4kPa, the rate of abnormal BAEP was 38.46% and 77.78% respectively (P<0.05). The serum CK level in the normal group or in the group with moderate abnormality of BAEP was significantly different from that in the group with severe abnormality or lack of BAEP (274.8± 98.24 U/L vs 705.3± 364.27 U/L; P<0.001). After treatment, the ICP returned to normal, and the BAEP norm

Aquaporin-4 is a potential drug target for traumatic brain injury via aggravating the severity of brain edema

Background:Traumatic brain edema(TBE)is caused by a specific water channel mediated by membrane aquaporins.Aquaporin-4(AQP4)plays an especially important role in this process,but the relationship between AQP4 and TBE remains unclear.The purpose of this study was to explore expression of AQP4 in the hippocampus after traumatic brain injury(TBI),as well as the effect of brain edema on skeletal protein and its function in hippocampal neurons.Methods:The adult male Wistar rats we divided into a sham group and a TBI group,the latter of which was further divided into 1,3,6,12,24 and 72 hours(h)and 15 days(d)post injury subgroups.A proper TBI model was established,and brain edema was assessed in each group by water content.We measured the abundance of various proteins,including hypoxia inducible factor-1α(HIF-1α),AQP4,microtubule-associated protein 2(MAP2),tau-5 protein,phosphorylated level of TAU,synaptophysin,cyclic adenosine monophosphate response element binding protein(CREB),phosphorylated CREB and general control nonrepressed 2,in each group.Hippocampal neurons and spatial memory test were analyzed in different time points.Results:Compared with that in the sham group,the level of AQP4 in hippocampal neurons began to significantly increase at 1 h post TBI and then decreased at 15 d post TBI.During this time frame,AQP4 level peaked at 12 and 72 h,and these peaks were closely correlated with high brain water content.HIF-1αdisplayed a similar trend.Conversely,levels of MAP2 began to decrease at 1 h post TBI and then increase at 15 d post TBI.In addition,the most severe brain edema in rats was found at 24 h post TBI,with neuronal loss and hippocampal dendritic spine injury.Compared to those in the sham group,rats in the TBI groups had significantly prolonged latency and significantly shortened exploration time.Conclusions:AQP4 level was closely correlated with severity of brain edema,and abnormal levels thereof aggravated such severity after TBI.

Effects of ganglioside GM1 on reduction of brain edema and amelioration of cerebral metabolism after traumatic brain injury

Objective: To observe the effects of ganglioside GM1 on reduction of brain edema and amelioration of cerebral metabolism after traumatic brain injury (TBI). Methods: An acute experimental closed TBI model in rats was induced by a fluid percussion brain injury model. At five and sixty minutes after TBI, the animals were intraperitoneally injected by ganglioside GM1 (30 mg/kg) or the same volume of saline. At the 6th hour after TBI, effects of ganglioside GM1 or saline on changes of mean arterial pressure (MAP), contents of water, lactic acid (LA) and lipid peroxidation (LPO) in the injured cerebral tissues were observed. Results: After TBI, MAP decreased and contents of water, LA and LPO increased in brain injury group; however, MAP was back to normal levels and contents of water, LA and LPO decreased in ganglioside GM1 treated group, compared with those in brain injury group (P< 0.05 ). No significant difference between the saline treated group and the brain injury group (P> 0.05 ) was observed.Conclusions: Ganglioside GM1 does have obvious neuroprotective effect on early TBI.

Correlation of cell apoptosis with brain edema and elevated intracranial pressure in traumatic brain injury

Objective: To study the correlation between brain edema, elevated intracranial pressure (ICP) and cell apoptosis in traumatic brain injury (TBI). Methods: In this study, totally 42 rabbits in 7 groups were studied. Six of the animals were identified as a control group, and the remaining 36 animals were equally divided into 6 TBI groups. TBI models were produced by the modified method of Feeney. After the impact, ICP of each subject was recorded continuously by an ICP monitor until the animal was sacrificed at scheduled time. The apoptotic brain cells were detected by an terminal deoxynucleotide-transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay. Cerebral water content (CWC) was measured with a drying method and calculated according to the Elliott formula. Then, an analysis was conducted to determine the correlation between the count of apoptotic cells and the clinical pathological changes of the brain. Results: Apoptotic cell count began to increase 2 h after the impact, and reached its maximum about 3 days after the impact. The peak value of CWC and ICP appeared 1 day and 3 days after the impact, respectively. Apoptotic cell count had a positive correlation with CWC and ICP. Conclusions: In TBI, occurrence of brain edema and ICP increase might lead to apoptosis of brain cells. Any therapy which can relieve brain edema and/or decrease ICP would be able to reduce neuron apoptosis, thereby to attenuate the secondary brain damage.