Development Of Brain Edema Research Articles

Absent Filling of Ipsilateral Superficial Middle Cerebral Vein Is Associated With Poor Outcome After Reperfusion Therapy.

Our aim was to study the effect of drainage of cortical veins, including the superficial middle cerebral vein (SMCV), vein of Trolard, and vein of Labbé on neurological outcomes after reperfusion therapy. Consecutive ischemic stroke patients who underwent pretreatment computed tomographic perfusion and 24-hour computed tomographic perfusion or magnetic resonance perfusion after intravenous thrombolysis were included. We defined "absent filling of ipsilateral cortical vein" (eg, SMCV-) as no contrast filling of the vein across the whole venous phase on 4-dimensional computed tomographic angiography in the ischemic hemisphere. Of 228 patients, SMCV-, vein of Trolard- and vein of Labbé- were observed in 50 (21.9%), 27 (11.8%), and 32 (14.0%) patients, respectively. Only SMCV- independently predicted poor outcome (3-month modified Rankin Scale score of >2; odds ratio, 2.710; P=0.040). No difference was found in reperfusion rate after treatment between patients with and without SMCV- (P>0.05). In patients achieving major reperfusion (≥80%), there was no difference in 24-hour infarct volume, or rate of poor outcome between patients with and without SMCV- (P>0.05). However, in those without major reperfusion, patients with SMCV- had larger 24-hour infarct volume (P=0.011), higher rate of poor outcome (P=0.012), and death (P=0.032) compared with those with SMCV filling. SMCV- was significantly associated with brain edema at 24 hours (P=0.037), which, in turn, was associated with poor 3-month outcome (P=0.002). Lack of SMCV filling contributed to poor outcome after thrombolysis, especially when reperfusion was not achieved. The main deleterious effect of poor venous filling appears related to the development of brain edema.

No benefits of hypothermia in patients treated with hemicraniectomy for large ischemic stroke.

Background Space-occupying middle cerebral artery brain infarcts are associated with the development of brain edema, which may lead to cerebral herniation and death despite early hemicraniectomy. Aims To evaluate the benefit of therapeutic hypothermia in patients with space-occupying cerebral infarction treated with hemicraniectomy within 48 h of stroke onset. Methods Patients aged 18-60 years with space-occupying cerebral infarction treated with hemicraniectomy within 48 h and hypothermia (33-34°C) were selected from a single university hospital between 2001 and 2010 (n = 53). Patients treated with hemicraniectomy alone served as comparison group (n = 58), originating from three randomized controlled trials evaluating the effects of early decompressive surgery (DECIMAL, DESTINY, HAMLET). Primary outcome was the score on the modified Rankin scale at 12 months dichotomized between modified Rankin scale 0-3 and modified Rankin scale 4-6. Secondary outcome measures were modified Rankin scale score 0-4 and survival. Risk ratios were adjusted with Poisson regression. Results Mean patient age was 48 years. Median time from stroke onset to hemicraniectomy was 23.5 h in both treatment groups. Treatment with hypothermia had no effect on the primary outcome (modified Rankin scale 0-3 versus 4-6 (13/53 (25%) versus 24/58 (41%)); adjusted risk ratio 0.66, 95% confidence interval 0.38-1.13). Fewer patients treated with hypothermia had a modified Rankin scale score of 0-4 (21/53 (40%) versus 42/58 (72%); adjusted risk ratio 0.53, 95% confidence interval 0.37-0.76) and fewer patients survived (26/53 (49%) versus 46/58 (79%); adjusted risk ratio 0.60, 95% confidence interval 0.44-0.82). Conclusions In patients with space-occupying cerebral infarction, treatment with hypothermia had no additional benefit on functional outcome compared with treatment with hemicraniectomy alone.

Correlation between serum levels of IL-6, TNF-α, SOD and MDA in patients with acute cerebral hemorrhage and edema of peripheral brain tissue

Objective To investigate the correlation between serum levels of IL-6, TNF-α, SOD, MDA and the amount of edema around brain tissue in patients with acute cerebral hemorrhage (ICH). Methods Fron May 2012 to May 2015, 90 cases with acute ICH in the Department of Neurology of our hospital were selected, and 60 healthy subjects were selected as control group.The general information, peripheral blood at different time ( including after admission, 24h, 72h, 7d) IL-6, TNF-α, SOD, MDA levels were analyzed in the two groups.The situation at the same time brain edema was recorded, and the correlation between serum inflammatory cytokines and oxidative stress product and surrounding brain tissue edema was studied. Results The IL-6, TNF-α concentrations and MDA level in acute ICH patients began to increase at 24-72h, 3-7d gradually decreased, but still higher than the control group, there were statistically significant differences between the two groups (P<0.05). While the serum SOD level decreased in 24-72h, 3-7d began to increase, but still lower than the control group, there was statistically significant difference between the two groups (P<0.05). Patients with no edema at admission, 0-24h began to rise at 24h when the maximum amount of edema, then gradually subsided, at different time the difference was statistically significant (F=432.67, P<0.01). There was significantly positive correlation between IL-6 and edema volume (r=0.292, P<0.05); a significantly positive correlation between TNF-α and edema volume (r=0.312, P<0.05). There was significantly positive correlation between MDA and edema volume (r=0.337, P<0.05). There was a negative correlation between SOD and edema volume (r=-0.364, P<0.05 ). Conclusion The blood serum inflammatory factors and the levels of oxidative stress in acute ICH patients are significantly higher than the control group, and showed a trend of first increased and then decreased, and inflammatory cytokines and oxidative stress levels and edema volume exist linear dependence, SOD has the greatest effect on brain edema in patients with acute ICH, MDA times, IL-6 is minimal.This indicates that serum IL-6, TNF-α, SOD, MDA levels may be involved in the occurrence and development of brain edema. Key words: Cerebral hemorrhage; Oxidative stress; Inflammatory factors; Brain edema

Inhibition of stress fiber formation preserves blood–brain barrier after intracerebral hemorrhage in mice

Intracerebral hemorrhage (ICH) represents the deadliest subtype of all strokes. The development of brain edema, a consequence of blood–brain barrier (BBB) disruption, is the most life-threatening event after ICH. Pathophysiological conditions activate the endothelium, one of the components of BBB, inducing rearrangement of the actin cytoskeleton. Upon activation, globular actin assembles into a filamentous actin resulting in the formation of contractile actin bundles, stress fibers. The contraction of stress fibers leads to the formation of intercellular gaps between endothelial cells increasing the permeability of BBB. In the present study, we investigated the effect of ICH on stress fiber formation in CD1 mice. We hypothesized that ICH-induced formation of stress fiber is triggered by the activation of PDGFR-β and mediated by the cortactin/RhoA/LIMK pathway. We demonstrated that ICH induces formation of stress fibers. Furthermore, we demonstrated that the inhibition of PDGFR-β and its downstream reduced the number of stress fibers, preserving BBB and resulting in the amelioration of brain edema and improvement of neurological functions in mice after ICH.

Erratum to: Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion.

Effective therapeutic measures against the development of brain edema, a life-threatening complication of cerebral ischemia, are necessary to improve the functional outcome for the patient. Here, we identified a beneficial role of purinergic receptor P2X7 activation in acute ischemic stroke. Involvement of P2X7 in the development of neurological deficits, infarct size, brain edema, and glial responses after ischemic cerebral infarction has been analyzed. Neurologic evaluation, magnetic resonance imaging, and immunofluorescence assays were used to characterize the receptor’s effect on the disease progress during 72 h after transient middle cerebral artery occlusion (tMCAO). Sham-operated animals were included in all experiments for control purposes. We found P2X7-deficient mice to develop a more prominent brain edema with a trend towards more severe neurological deficits 24 h after tMCAO. Infarct sizes, T2 times, and apparent diffusion coefficients did not differ significantly between wild-type and P2X7−/− animals. Our results show a characteristic spatial distribution of reactive glia cells with strongly attenuated microglia activation in P2X7−/− mice 72 h after tMCAO. Our data indicate that P2X7 exerts a role in limiting the early edema formation, possibly by modulating glial responses, and supports later microglia activation.

Continuous IV Infusion is the Choice Treatment Route for Arginine-vasopressin Receptor Blocker Conivaptan in Mice to Study Stroke-evoked Brain Edema.

Stroke is one of the major causes of morbidity and mortality in the world. Stroke is complicated by brain edema and other pathophysiological events. Among the most important players in the development and evolution of stroke-evoked brain edema is the hormone arginine-vasopressin and its receptors, V1a and V2. Recently, the V1a and V2 receptor blocker conivaptan has been attracting attention as a potential drug to reduce brain edema after stroke. However, animal models which involve conivaptan applications in stroke research need to be modified based on feasible routes of administration. Here the outcomes of 48 hr continuous intravenous (IV) are compared with intraperitoneal (IP) conivaptan treatments after experimental stroke in mice. We developed a protocol in which middle cerebral artery occlusion was combined with catheter installation into the jugular vein for IV treatment of conivaptan (0.2 mg) or vehicle. Different cohorts of animals were treated with 0.2 mg bolus of conivaptan or vehicle IP daily. Experimental stroke-evoked brain edema was evaluated in mice after continuous IV and IP treatments. Comparison of the results revealed that the continuous IV administration of conivaptan alleviates post-ischemic brain edema in mice, unlike the IP administration of conivaptan. We conclude that our model can be used for future studies of conivaptan applications in the context of stroke and brain edema.

Gene expression profiling of brain cortex microvessels may support brain vasodilation in acute liver failure rat models.

Development of brain edema in acute liver failure can increase intracranial pressure, which is a severe complication of the disease. However, brain edema is neither entirely cytotoxic nor vasogenic and the specific action of the brain microvasculature is still unknown. We aimed to analyze gene expression of brain cortex microvessels in two rat models of acute liver failure. In order to identify global gene expression changes we performed a broad transcriptomic approach in isolated brain cortex microvessels from portacaval shunted rats after hepatic artery ligation (HAL), hepatectomy (HEP), or sham by array hybridization and confirmed changes in selected genes by RT-PCR. We found 157 and 270 up-regulated genes and 143 and 149 down-regulated genes in HAL and HEP rats respectively. Western blot and immunohistochemical assays were performed in cortex and ELISA assays to quantify prostaglandin E metabolites were performed in blood of the sagittal superior sinus. We Identified clusters of differentially expressed genes involving inflammatory response, transporters-channels, and homeostasis. Up-regulated genes at the transcriptional level were associated with vasodilation (prostaglandin-E synthetase, prostaglandin-E receptor, adrenomedullin, bradykinin receptor, adenosine transporter), oxidative stress (hemoxygenase, superoxide dismutase), energy metabolism (lactate transporter) and inflammation (haptoglobin). The only down-regulated tight junction protein was occludin but slightly. Prostaglandins levels were increased in cerebral blood with progression of liver failure. In conclusion, in acute liver failure, up-regulation of several genes at the level of microvessels might suggest an involvement of energy metabolism accompanied by cerebral vasodilation in the cerebral edema at early stages.

Treatment of Acute Liver Failure in Resource-Constrained Settings without Transplantation Facilities Can Be Improved.

Treatment of Acute Liver Failure in Resource-Constrained Settings without Transplantation Facilities Can Be Improved.

Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity

Effects of ammonia on astrocytes play a major role in hepatic encephalopathy, acute liver failure and other diseases caused by increased arterial ammonia concentrations (e.g., inborn errors of metabolism, drug or mushroom poisoning). There is a direct correlation between arterial ammonia concentration, brain ammonia level and disease severity. However, the pathophysiology of hyperammonemic diseases is disputed. One long recognized factor is that increased brain ammonia triggers its own detoxification by glutamine formation from glutamate. This is an astrocytic process due to the selective expression of the glutamine synthetase in astrocytes. A possible deleterious effect of the resulting increase in glutamine concentration has repeatedly been discussed and is supported by improvement of some pathologic effects by GS inhibition. However, this procedure also inhibits a large part of astrocytic energy metabolism and may prevent astrocytes from responding to pathogenic factors. A decrease of the already low glutamate concentration in astrocytes due to increased synthesis of glutamine inhibits the malate-aspartate shuttle and energy metabolism. A more recently described pathogenic factor is the resemblance between NH4+ and K+ in their effects on the Na+,K+-ATPase and the Na+,K+, 2 Cl- and water transporter NKCC1. Stimulation of the Na+,K+-ATPase driven NKCC1 in both astrocytes and endothelial cells is essential for the development of brain edema. Na+,K+-ATPase stimulation also activates production of endogenous ouabains. This leads to oxidative and nitrosative damage and sensitizes NKCC1. Administration of ouabain antagonists may accordingly have therapeutic potential in hyperammonemic diseases.

Ipsilateral Sinus Hypoplasia and Poor Leptomeningeal Collaterals as Midline Shift Predictors

We explore the role of dural sinus morphology, leptomeningeal collaterals, and clot localization in the development of malignant brain edema in acute ischemic stroke in anterior circulation. This is a single-center retrospective study of consecutive stroke patients with acute occlusion (middle cerebral artery M1 ± intracranial internal carotid artery) treated with intravenous thrombolysis (from November 2009 to November 2014). Admission computed tomography angiography data were evaluated for hypoplasia of dural sinuses, leptomeningeal collaterals, and clot location. Primary outcome was midline shift (<5 mm versus ≥5 mm) on follow-up computed tomography. Secondary outcomes were infarct volume and modified Rankin Scale score of 2 or lower at 90 days. Multivariate logistic regression was used. Of 86 patients (49 females), 36 (42%) had poor collaterals, 26 (30%) had ipsilesional sinus hypoplasia, and 38 (44%) had proximal clots. A midline shift of 5 mm or higher was diagnosed in 14 patients (16%). Infarct volume was larger in the group with midline shift (median: 318 mL [interquartile range {IQR} = 260-350]) than in the group without midline shift (median: 44 mL [IQR = 28-60]) (P = .007). In multivariate analysis, poor leptomeningeal collaterals (odds ratio [OR] = .11, 95% confidence interval [CI] = .03-.44, P = .002 for good collaterals) and ipsilesional sinus hypoplasia (OR = 6.43, 95% CI = 1.5-46.1, P = .008) were independently associated with a midline shift of 5 mm or higher. Patients with poor leptomeningeal collaterals and ipsilesional hypoplasia of dural sinuses are more likely to develop midline shift.

Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion.

Effective therapeutic measures against the development of brain edema, a life-threatening complication of cerebral ischemia, are necessary to improve the functional outcome for the patient. Here, we identified a beneficial role of purinergic receptor P2X7 activation in acute ischemic stroke. Involvement of P2X7 in the development of neurological deficits, infarct size, brain edema, and glial responses after ischemic cerebral infarction has been analyzed. Neurologic evaluation, magnetic resonance imaging, and immunofluorescence assays were used to characterize the receptor's effect on the disease progress during 72h after transient middle cerebral artery occlusion (tMCAO). Sham-operated animals were included in all experiments for control purposes. We found P2X7-deficient mice to develop a more prominent brain edema with a trend towards more severe neurological deficits 24h after tMCAO. Infarct sizes, T2 times, and apparent diffusion coefficients did not differ significantly between wild-type and P2X7(-/-) animals. Our results show a characteristic spatial distribution of reactive glia cells with strongly attenuated microglia activation in P2X7(-/-) mice 72h after tMCAO. Our data indicate that P2X7 exerts a role in limiting the early edema formation, possibly by modulating glial responses, and supports later microglia activation.

Tongxinluo reduces brain edema and inhibits post-ischemic inflammation after middle cerebral artery occlusion in rats

Ethnopharmacological relevanceTongxinluo (TXL), a widely used traditional Chinese medicine, has been proved multiple therapeutic effects in cerebral ischemic infraction. The purpose of this study was to investigate the protective effects of TXL on the brain edema and post-ischemic inflammatory response. Materials and MethodsMiddle cerebral artery occlusion in the rat was used as the ischemia model. Rats were treated with TXL. In the first stage, the best dosage was chosen based on functional assessment and infarct size. In the second stage, rats were randomly divided into 5 groups: sham control (sham), ischemia and reperfusion (IR) 24h, TXL24h, I/R72h, TXL72h. TXL(1.6g/kg/day) administration was pre-performed for 3 days in TXL groups, and was post-performed for 24h (TXL24h group) or 72h (TXL72h group). Brain edema was measured by water content, MRI and AQP4 expression. Iba1, HMGB1, TLR4, NF-κB expression were examined by immunofluorescence staining or Western blot. TNF-α was determined by enzyme-linked immunosorbent assay. ResultsHigh dose (1.6g/kg/day) of TXL remarkably reduced neurological deficit scores and cerebral infarct area. Compared with those results of I/R24h group, pre-post treatment with TXL for 3 days decreased brain water content, down-regulated AQP4 expression, lowered relative signal intensity of T2WI, reduced lesion volume ratio, and inhibited the activation of microglia, HMGB1, TLR4, NF-κB and TNF-α. ConclusionsThese results indicated that the TXL pre-post treatment for 3 days could be an effective therapy for brain ischemia by inhibiting the development of brain edema and post-ischemic inflammation.

Nanowired Drug Delivery Across the Blood-Brain Barrier in Central Nervous System Injury and Repair.

The blood-brain barrier (BBB) is a physiological regulator of transport of essential items from blood to brain for the maintenance of homeostasis of the central nervous system (CNS) within narrow limits. The BBB is also responsible for export of harmful or metabolic products from brain to blood to keep the CNS fluid microenvironment healthy. However, noxious insults to the brain caused by trauma, ischemia or environmental/chemical toxins alter the BBB function to small as well as large molecules e.g., proteins. When proteins enter the CNS fluid microenvironment, development of brain edema occurs due to altered osmotic balance between blood and brain. On the other hand, almost all neurodegenerative diseases and traumatic insults to the CNS and subsequent BBB dysfunction lead to edema formation and cell injury. To treat these brain disorders suitable drug therapy reaching their brain targets is needed. However, due to edema formation or only a focal disruption of the BBB e.g., around brain tumors, many drugs are unable to reach their CNS targets in sufficient quantity. This results in poor therapeutic outcome. Thus, new technology such as nanodelivery is needed for drugs to reach their CNS targets and be effective. In this review, use of nanowires as a possible novel tool to enhance drug delivery into the CNS in various disease models is discussed based on our investigations. These data show that nanowired delivery of drugs may have superior neuroprotective ability to treat several CNS diseases effectively indicating their role in future therapeutic strategies.

Deficiency of tenascin-C and attenuation of blood-brain barrier disruption following experimental subarachnoid hemorrhage in mice.

OBJECT Tenascin-C (TNC), a matricellular protein, is induced in the brain following subarachnoid hemorrhage (SAH). The authors investigated if TNC causes brain edema and blood-brain barrier (BBB) disruption following experimental SAH. METHODS C57BL/6 wild-type (WT) or TNC knockout (TNKO) mice were subjected to SAH by endovascular puncture. Ninety-seven mice were randomly allocated to WT sham-operated (n = 16), TNKO sham-operated (n = 16), WT SAH (n = 34), and TNKO SAH (n = 31) groups. Mice were examined by means of neuroscore and brain water content 24-48 hours post-SAH; and Evans blue dye extravasation and Western blotting of TNC, matrix metalloproteinase (MMP)-9, and zona occludens (ZO)-1 at 24 hours post-SAH. As a separate study, 16 mice were randomized to WT sham-operated, TNKO sham-operated, WT SAH, and TNKO SAH groups (n = 4 in each group), and activation of mitogen-activated protein kinases (MAPKs) was immunohistochemically evaluated at 24 hours post-SAH. Moreover, 40 TNKO mice randomly received an intracerebroventricular injection of TNC or phosphate-buffered saline, and effects of exogenous TNC on brain edema and BBB disruption following SAH were studied. RESULTS Deficiency of endogenous TNC prevented neurological impairments, brain edema formation, and BBB disruption following SAH; it was also associated with the inhibition of both MMP-9 induction and ZO-1 degradation. Endogenous TNC deficiency also inhibited post-SAH MAPK activation in brain capillary endothelial cells. Exogenous TNC treatment abolished the neuroprotective effects shown in TNKO mice with SAH. CONCLUSIONS Tenascin-C may be an important mediator in the development of brain edema and BBB disruption following SAH, mechanisms for which may involve MAPK-mediated MMP-9 induction and ZO-1 degradation. TNC could be a molecular target against which to develop new therapies for SAH-induced brain injuries.

Mannitol Improves Brain Tissue Oxygenation in a Model of Diffuse Traumatic Brain Injury.

Based on evidence supporting a potential relation between posttraumatic brain hypoxia and microcirculatory derangements with cell edema, we investigated the effects of the antiedematous agent mannitol on brain tissue oxygenation in a model of diffuse traumatic brain injury. Experimental study. Neurosciences and physiology laboratories. Adult male Wistar rats. Thirty minutes after diffuse traumatic brain injury (impact-acceleration model), rats were IV administered with either a saline solution (traumatic brain injury-saline group) or 20% mannitol (1 g/kg) (traumatic brain injury-mannitol group). Sham-saline and sham-mannitol groups received no insult. Two series of experiments were conducted 2 hours after traumatic brain injury (or equivalent) to investigate 1) the effect of mannitol on brain edema and oxygenation, using a multiparametric magnetic resonance-based approach (n = 10 rats per group) to measure the apparent diffusion coefficient, tissue oxygen saturation, mean transit time, and blood volume fraction in the cortex and caudoputamen; 2) the effect of mannitol on brain tissue PO2 and on venous oxygen saturation of the superior sagittal sinus (n = 5 rats per group); and 3) the cortical ultrastructural changes after treatment (n = 1 per group, taken from the first experiment). Compared with the sham-saline group, the traumatic brain injury-saline group had significantly lower tissue oxygen saturation, brain tissue PO2, and venous oxygen saturation of the superior sagittal sinus values concomitant with diffuse brain edema. These effects were associated with microcirculatory collapse due to astrocyte swelling. Treatment with mannitol after traumatic brain injury reversed all these effects. In the absence of traumatic brain injury, mannitol had no effect on brain oxygenation. Mean transit time and blood volume fraction were comparable between the four groups of rats. The development of posttraumatic brain edema can limit the oxygen utilization by brain tissue without evidence of brain ischemia. Our findings indicate that an antiedematous agent such as mannitol can improve brain tissue oxygenation, possibly by limiting astrocyte swelling and restoring capillary perfusion.

Is genistein neuroprotective in traumatic brain injury?

The concerns about negative consequences of estrogen therapy have led to introduce other strategies to obtain estrogen's benefits in the brain. The present study tests the hypothesis that a major isoflavone of soy; genistein with estrogen-like activity can be neuroprotective in traumatic brain injury (TBI). The male Wistar rats were randomly divided to four groups: sham, TBI, vehicle and genistein. The TBI was induced by Marmarou method. The brain edema and the disruption of blood–brain-barrier (BBB) were evaluated 48h post-TBI. Genistein (15mg/kg) or dimethyl sulfoxide (DMSO) was injected i.p., twice after TBI. The intracranial pressure (ICP), the motor performance, and the beam-walk task (WB) were determined before trauma, on trauma day (D0), and first (D1) and second (D2) days post-TBI. Genistein inhibited a development of brain edema and a BBB permeability in TBI animals. An increase of ICP and a defect in motor and WB performance were showed following TBI, in all times evaluated. An increase of ICP induced by TBI was suppressed by genistein on D1 and D2 times. Genistein improved a motor disorder induced by TBI, on D1 and D2 times. Also an increase of traversal time in WB task was suppressed by genistein in TBI animals, on D1 and D2 times. The results of this study demonstrated that genistein can be neuroprotective in TBI. Genistein inhibited the disruption of BBB, the brain edema and the increase of ICP, and the disturbance of neurobehavioral performance in TBI.

Photothrombosis combined with thrombin injection establishes a rat model of cerebral venous sinus thrombosis

Objective: Cerebral venous sinus thrombosis (CVST) is a rare but life-threatening disease and an animal model for in-depth study of CVST is needed. This study aimed to develop a rat model suitable for studying clinically relevant aspects of CVST and investigating its dynamic pathophysiological changes during a 7-day period. Method: A photothrombosis method was used to create a rat sinus-vein thrombosis model. A spot size-adjustable Diode Pumped Solid State laser (DPSS) combined with thrombin injection occluded the rostral and caudal superior sagittal sinus (SSS). The model was used to evaluate pathophysiological changes at different time points over 7days. Evans Blue dye injection was used to detect alterations in blood–brain barrier (BBB) permeability. Brain water content was also measured. Moreover, we examined changes in brain infarct volume, neurological function, as well as histology after induction of CVST. Result: CVST in rats significantly altered BBB permeability, consistent with the development of brain edema. It was accompanied by an increase in brain infarct volume and deficits in neurological function that began on day 1, peaked on day 2, and typically improved by day 7 due to the neuroprotective effects of angiogenesis and gliocyte proliferation. Conclusion: In this study, we describe a rat model that produces clinically relevant pathophysiology and pathology that will facilitate evaluation of therapeutic regimens for CVST. Furthermore, our results indicate a period of optimal clinical intervention for patients with CVST, which may reduce the probability of dependency and death.

Detecting diffuse axonal injury in rat brainstems by diffusion tensor imaging and AQP4 expression.

This study investigated the correlation between AQP4 expression and DTI in rat brainstems after diffuse axonal injuries (DAI). Forty rats were imaged before injury and reimaged at 3, 6, 12, 24 and 72 h post-injury. A control group of 8 rats was imaged and sacrificed for histology but not injured. After brain injury, AQP4 expression and ADC values in the brainstems increased gradually, reaching peak values at 24 h and 12 h, respectively. FA values decreased within 72 h. There was a negative correlation between ADC values and brainstem AQP4 expression at 12 h, and a positive correlation at 24 h or 72 h (P<0.01), respectively. Changes in the ADC and FA values in the brainstems indicated brain edema and severe axonal injuries. The correlations between AQP4 expression and time-dependent ADC values aid in understanding brain edema development after DAI.

Roles of Aquaporins in Brain Disorders

Aquaporin (AQP) is a water channel protein that is expressed in the cell membranes. AQPs are related to several kinds of human diseases such as cataract. In the mammalian central nervous system (CNS), AQP4 is specifically expressed in the astrocyte membranes lining the perivascular and periventricular structures. AQP4 plays a role in the development of brain edema associated with certain brain disorders. Neuromyelitis optica (NMO) is a demyelinating disorder, and patients with NMO develop autoimmune antibodies against AQP4 in their serum. Therefore, AQP4 is involved in NMO pathogenesis. A new concept referred to as "glymphatic pathway" has been recently proposed to explain the lymphatic system in the CNS. Dysfunction of the "glymphatic pathway" may cause several neurodegenerative diseases and mood disorders. Importantly, AQP4 may play a role in the "glymphatic pathway". Further investigation of AQP4 in CNS disorders is necessary, and a new drug against AQP4 is expected.

Brain pericytes are the most thrombin-sensitive matrix metalloproteinase-9-releasing cell type constituting the blood–brain barrier in vitro

In the acute phase of intracerebral hemorrhage (ICH), hemorrhagic transformation and brain edema are associated with blood–brain barrier (BBB) disruption. Elevated levels of thrombin, a coagulation factor, contribute to the development of brain edema during ICH through matrix metalloproteinase (MMP)-9 production. Thrombin directly induces a variety of cellular responses through its specific receptors known as protease-activated receptors (PARs). However, it remains unclear which cell types constituting the BBB mainly produce MMP-9 in response to thrombin. Here, we compared the MMP-9 release induced by thrombin using primary cultures of rat brain microvascular endothelial cells, astrocytes, and pericytes. Brain pericytes exhibited the highest levels of MMP-9 release due to thrombin stimulation among the BBB cells. The pattern of PAR mRNA expression in pericytes was characterized by high expression of PAR1 and moderate expression of PAR4. Heat-inactivated thrombin failed to stimulate pericytes to release MMP-9. A selective PAR1 inhibitor SCH79797 blocked the thrombin-induced MMP-9 release from pericytes. These findings suggest that both PAR1 and PAR4 mediate thrombin-induced MMP-9 release from pericytes. The present study raises the possibility that brain pericytes could play a pivotal role as a highly thrombin-sensitive and MMP-9-producing cell type at the BBB in brain damage including ICH.