Protection Of Blood-brain Barrier Integrity Research Articles

Norrin protected blood-brain barrier via frizzled-4/β-catenin pathway after subarachnoid hemorrhage in rats.

Norrin and its receptor Frizzled-4 have important roles in the blood-brain barrier development. This study is to investigate a potential role and mechanism of Norrin/Frizzled-4 on protecting blood-brain barrier integrity after subarachnoid hemorrhage (SAH). One hundred and seventy-eight male Sprague-Dawley rats were used. SAH model was induced by endovascular perforation. Frizzled-4 small interfering RNA was injected intracerebroventricularly 48 hours before SAH. Norrin was administrated intracerebroventricularly 3 hours after SAH. SAH grade, neurological scores, brain water content, Evans blue extravasation, western blots, and immunofluorescence were used to study the mechanisms of Norrin and its receptor regulation protein TSPAN12, as well as neurological outcome. Endogenous Norrin and TSPAN12 expression were increased after SAH, and Norrin was colocalized with astrocytes marker glial fibrillary acidic protein in cortex. Exogenous Norrin treatment significantly alleviated neurobehavioral dysfunction, reduced brain water content and Evans blue extravasation, promoted β-catenin nuclear translocation, and increased Occludin, VE-Cadherin, and ZO-1 expressions. These effects were abolished by Frizzled-4 small interfering RNA pretreated before SAH. Norrin protected blood-brain barrier integrity and improved neurological outcome after SAH, and the action of Norrin appeared mediated by Frizzled-4 receptor activation, which promoted β-catenin nuclear translocation, which then enhanced Occludin, VE-Cadherin, and ZO-1 expression. Norrin might have potential to protect blood-brain barrier after SAH.

Mesenchymal stem cells maintain blood-brain barrier integrity by inhibiting aquaporin-4 upregulation after cerebral ischemia.

Cerebral ischemia upregulates aquaporin-4 expression, increases blood-brain barrier (BBB) permeability, and induces brain edema. Mesenchymal stem cells (MSCs) can repress inflammatory cytokines and show great potential for ischemic stroke therapy. However, the effect of MSCs regarding the protection of ischemia-induced BBB break down is unknown. We test whether MSCs therapy protects BBB integrity and explore the molecular mechanisms of aquaporin-4 on BBB integrity. Two hundred and twenty-eight adult CD1 male mice underwent 90 minutes transient middle cerebral artery occlusion and received 2 × 10(5) MSCs intracranial transplantation. The neurological severity score was improved and both ischemia-induced brain edema and BBB leakage were reduced in MSC-treated mice. MSCs therapy reduced astrocyte apoptosis and inhibited ischemia-induced aquaporin-4 upregulation. In addition, small-interfering RNA knockdown of aquaporin-4 after cerebral ischemia effectively reduced aquaporin-4 expression, brain edema, BBB leakage, and astrocyte apoptosis. Conditional medium from lipopolysaccharide (LPS)-activated microglia enhanced aquaporin-4 expression, p38 and JNK phosphorylation, and apoptosis of cultured astrocytes. MSC treatment reduced the expression of inflammatory cytokines in LPS-activated microglia, and subsequently reduced aquaporin-4 expression and apoptosis of astrocytes. Knockdown of aquaporin-4 in cultured astrocytes also reduced apoptosis. Treatment with p38 and JNK inhibitors showed that p38, but not the JNK signaling pathway, was responsible for the aquaporin-4 upregulation. MSCs protected BBB integrity by reducing the apoptosis of astrocytes after ischemic attack, which was due to the attenuation of inflammatory response and downregulation of aquaporin-4 expression via p38 signaling pathway.

Attenuated Blood-Brain Barrier Dysfunction by XQ-1H Following Ischemic Stroke in Hyperlipidemic Rats.

Following ischemic stroke, blood-brain barrier (BBB) is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which exacerbates cerebral ischemic injury as a result. Here, we report that 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a novel analog of ginkgolide B, alleviates BBB breakdown in hyperlipidemic rats and protects endothelial cells against inflammatory response. Middle cerebral artery occlusion (MCAO) modeled ischemic stroke in rats. Before surgery, these rats were fed a cholesterol-rich diet to induce an experimental hyperlipidemic condition. Additionally, lipopolysaccharide (LPS) incubation with rat brain microvessel endothelial cells (rBMECs) was applied to mimic hyperlipidemia-induced inflammatory injury of BBB. The results indicated more severe infarct size, increased BBB permeability, excessive secretion of pro-inflammatory cytokines, and exaggerated inflammation infiltration of the brain in hyperlipidemic rats following MCAO when compared to rats fed with normal diet. XQ-1H protected BBB integrity, lessoned brain edema and inflammation penetration, downregulated MMP-9 and VCMA-1 expressions, and extenuated ischemic infarction. XQ-1H alleviated LPS-induced inflammatory response in rBMECs, characterized by promoting cell viability, inhibiting TNF-α, IL-1β, and IL-6 releasing, and downregulating NF-κB inflammatory signal and downstream proteins, such as VCAM-1 and iNOS. In conclusion, the present study shows that XQ-1H stabilizes BBB function following ischemic stroke in hyperlipidemic rats, and the possible mechanisms may be related to inflammation inhibition.

Calycosin-7-O-β-d-glucoside regulates nitric oxide /caveolin-1/matrix metalloproteinases pathway and protects blood–brain barrier integrity in experimental cerebral ischemia–reperfusion injury

Ethnopharmacology relevanceAstragali Radix (AR) has been used for thousands years to treat ischemic stroke. Calycosin and its glycoside form calycosin-7-O-β-d-glucoside (CG) are two representative isoflavones in Astragali Radix. However, its neurological effects and related molecular mechanisms are largely unknown. The present study aims to evaluate the neuroprotective effects of CG on blood–brain barrier (BBB) integrity of ischemic brain tissue and explore the relevant signaling mechanisms. Material and methodMale adult Sprague-Daweley rats were subjected to 2h of middle cerebral artery occlusion (MCAO) plus 24h or 14 days of reperfusion. CG (26.8 mg/kg) was intraperitoneally administered into the rats at 15min before onset of ischemia. The neuroprotective effects of CG were evaluated by measuring infarct volume, histological damage and BBB permeability. Furthermore, the effects of CG on scavenging nitric oxide (NO), and modulating matrix metalloproteinases (MMPs) and caveolin-1 (cav-1) were investigated with in vitro cultured brain microvascular endothelial cells treated with NO donor or oxygen–glucose deprivation (OGD) and/or in vivo rat model of MCAO cerebral ischemia–reperfusion injury. ResultsCG treatment significantly reduced infarct volume, histological damage and BBB permeability in the in vivo MCAO ischemia–reperfusion rat model. CG treatment remarkably inhibited the expression and activities of MMPs, and secured the expression of cav-1 and tight junction proteins in the microvessels isolated from ischemic rat cortex. Furthermore, CG was revealed to scavenge NO, inhibit the activities of MMP-2 and MMP-9, and attenuate cell death in the in vitro cultured brain microvascular endothelial cells under OGD condition. ConclusionCG could protect BBB integrity in experimental cerebral ischemia–reperfusion injury via regulating NO/cav-1/MMPs pathway.

Hydrogen sulfide protects blood–brain barrier integrity following cerebral ischemia

By using two structurally unrelated hydrogen sulfide (H2 S) donors 5-(4-methoxyphenyl) -3H-1, 2-dithiole-3-thione (ADT) and sodium hydrosulfide (NaHS), this study investigated if H2 S protected blood-brain barrier (BBB) integrity following middle cerebral artery occlusion (MCAO). ICR mice underwent MCAO and received H2 S donors at 3 h after reperfusion. Infarction, neurological scores, brain edema, Evans blue (EB) extravasation, and tight junction protein expression were examined at 48 h after MCAO. We also investigated if ADT protected BBB integrity by suppressing post-ischemic inflammation-induced Matrix Metalloproteimase-9 (MMP9) and Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). ADT increased blood H2 S concentrations, decreased infarction, and improved neurological deficits. Particularly, ADT reduced EB extravasation, brain edema and preserved expression of tight junction proteins in the ischemic brain. NaHS also increased blood H2 S levels and reduced EB extravasation following MCAO. Moreover, ADT inhibited expression of pro-inflammatory markers induced Nitric Oxide Synthase (iNOS) and IL-1β while enhanced expression of anti-inflammatory markers arginase 1 and IL-10 in the ischemic brain. Accordingly, ADT attenuated ischemia-induced expression and activity of MMP9. Moreover, ADT reduced NOX-4 mRNA expression, NOX activity, and inhibited nuclear translocation of Nuclear Factor Kappa-B (NF-κB) in the ischemic brain. In conclusion, H2 S donors protected BBB integrity following experimental stroke possibly by acting through NF-κB inhibition to suppress neuroinflammation induction of MMP9 and NOX4-derived free radicals. To determine H2 S effects on blood-brain barrier (BBB) disruption following stroke, we used two structurally unrelated H2 S donors ADT and NaHS. Both ADT and NaHS remarkably protected BBB integrity following experimental stroke. The slow-releasing donor ADT also reduced post-ischemic inflammation-induced expression and activity of MMP9 and NOX4 in the ischemic brain possibly by inhibiting NF-κB activation.

Drug delivery to the ischemic brain.

Cerebral ischemia occurs when blood flow to the brain is insufficient to meet metabolic demand. This can result from cerebral artery occlusion that interrupts blood flow, limits CNS supply of oxygen and glucose, and causes an infarction/ischemic stroke. Ischemia initiates a cascade of molecular events in neurons and cerebrovascular endothelial cells including energy depletion, dissipation of ion gradients, calcium overload, excitotoxicity, oxidative stress, and accumulation of ions and fluid. Blood-brain barrier (BBB) disruption is associated with cerebral ischemia and leads to vasogenic edema, a primary cause of stroke-associated mortality. To date, only a single drug has received US Food and Drug Administration (FDA) approval for acute ischemic stroke treatment, recombinant tissue plasminogen activator (rt-PA). While rt-PA therapy restores perfusion to ischemic brain, considerable tissue damage occurs when cerebral blood flow is reestablished. Therefore, there is a critical need for novel therapeutic approaches that can "rescue" salvageable brain tissue and/or protect BBB integrity during ischemic stroke. One class of drugs that may enable neural cell rescue following cerebral ischemia/reperfusion injury is the HMG-CoA reductase inhibitors (i.e., statins). Understanding potential CNS drug delivery pathways for statins is critical to their utility in ischemic stroke. Here, we review molecular pathways associated with cerebral ischemia and novel approaches for delivering drugs to treat ischemic disease. Specifically, we discuss utility of endogenous BBB drug uptake transporters such as organic anion transporting polypeptides and nanotechnology-based carriers for optimization of CNS drug delivery. Overall, this chapter highlights state-of-the-art technologies that may improve pharmacotherapy of cerebral ischemia.

Vagus nerve stimulation inhibits seizure activity and protects blood–brain barrier integrity in kindled rats with cortical dysplasia

AimsThis study investigates the effects of vagus nerve stimulation (VNS) on seizure severity and blood–brain barrier (BBB) integrity in kindled rats with cortical dysplasia (CD). Main methodsPregnant rats were exposed to 145cGy of gamma-irradiation on day 17 of pregnancy. In offsprings, kindling was induced by giving subconvulsive doses of pentylenetetrazole. Left VNS was performed for 48h at output currents of 0.5 or 1mA. Horseradish peroxidase (HRP) was used to study the BBB permeability. Immunohistochemistry for occludin and P-glycoprotein (P-gp) was also performed. Key findingsKindled rats with CD exhibited seizures with mean Racine's scores of 3.57±1.2 during video EEG recording. Kindled animals with CD receiving VNS at 0.5 and 1.0mA did not exhibit either clinical or electrophysiological signs of seizure. Immunostaining for occludin, a tight junction protein, in hippocampus remained relatively intact in all groups. VNS-treated and -untreated kindled animals with CD revealed intense immunostaining for P-gp in hippocampal formation (P<0.01). Electron microscopic observations revealed frequent transport vesicles containing electron-dense HRP reaction products in the cytoplasm of brain capillary endothelial cells in both cerebral cortex and hippocampus of kindled animals with CD. Those which were exposed to 1mA VNS were observed to have brain capillary endothelial cells largely devoid of HRP reaction products in both cerebral cortex and hippocampus. SignificanceThe results of this study suggest that VNS therapy at 1mA inhibits seizure activity and protects BBB integrity by limiting the enhancement of transcellular pathway in kindled animals with CD.

Statins Protect the Blood Brain Barrier Acutely after Experimental Intracerebral Hemorrhage

The goal of this study was to measure the impact of simvastatin and atorvastatin treatment on blood brain barrier (BBB) integrity after experimental intracerebral hemorrhage (ICH). Primary ICH was induced in 27 male Wistar rats by stereotactic injection of 100 µL of autologous blood into the striatum. Rats were divided into three groups (n= 9/group): 1) oral treatment (2 mg/kg) of atorvastatin, 2) oral treatment (2 mg/kg) simvastatin, or 3) phosphate buffered saline daily starting 24-hours post-ICH and continuing daily for the next 3 days. On the fourth day, the animals underwent magnetic resonance imaging (MRI) for measurements of T1sat (a marker for BBB integrity), T2 (edema), and cerebral blood flow (CBF). After MRI, the animals were sacrificed and immunohistology or Western blotting was performed. MRI data for animals receiving simvastatin treatment showed significantly reduced BBB dysfunction and improved CBF in the ICH rim compared to controls (P<0.05) 4 days after ICH. Simvastatin also significantly reduced edema (T2) in the rim at 4 days after ICH (P<0.05). Both statin-treated groups demonstrated increased occludin and endothelial barrier antigen levels within the vessel walls, indicating better preservation of BBB function (P<0.05) and increased number of blood vessels (P<0.05). Simvastatin treatment administered acutely after ICH protects BBB integrity as measured by MRI and correlative immunohistochemistry. There was also evidence of improved CBF and reduced edema by MRI. Conversely, atorvastatin showed a non-significant trend by MRI measurement.

CXCR4 Antagonist AMD3100 Protects Blood–Brain Barrier Integrity and Reduces Inflammatory Response After Focal Ischemia in Mice

Inflammatory response plays a critical role in propagating tissue damage after focal cerebral ischemia. CXCL12 is a key chemokine for leukocyte recruitment. However, the role of CXCL12 and its receptor CXCR4 in ischemia-induced inflammatory response is unclear. Here we use the pharmacological antagonist of CXCR4, AMD3100, to investigate the function of CXCL12/CXCR4 in regulating inflammatory response during acute ischemia. Adult male CD-1 mice (n=184) underwent permanent suture middle cerebral artery occlusion (MCAO). AMD3100 was injected for 3 days (1 mg/kg/day) after MCAO. Brain water content, infarct volume, neurological score, and myeloperoxidase (MPO) expression and activity were examined at 24, 48, and 72 hours after MCAO. Proinflammatory cytokine RNA and protein levels in brain tissue were measured by RT-PCR and enzyme linked immunosorbent assay. Neurological score was greatly improved in AMD3100-treated mice compared with the control mice 3 days after MCAO (P<0.05). Brain edema-induced change of water content, IgG protein leakage, Evans blue extravasation, occludin, and ZO-1 expression in ipsilateral hemisphere were alleviated by acute treatment of AMD3100. MPO expression and activity revealed that AMD3100 profoundly reduced the number of MPO-positive cells in the ischemic region (P<0.05). It also attenuated proinflammatory cytokines including interleukin 6, tumor necrosis factor α, and interferon γ; their mRNA and protein levels changed accordingly compared with the controls (P<0.05). CXCR4 antagonist AMD3100 significantly suppressed inflammatory response and reduced blood-brain barrier disruption after MCAO. AMD3100 attenuated ischemia-induced acute inflammation by suppressing leukocyte migration and infiltration, in addition to reducing proinflammatory cytokine expression in the ischemic region.

Caffeic Acid Phenethyl Ester Protects Blood–Brain Barrier Integrity and Reduces Contusion Volume in Rodent Models of Traumatic Brain Injury

A number of studies have established a deleterious role for inflammatory molecules and reactive oxygen species (ROS) in the pathology of traumatic brain injury (TBI). Caffeic acid phenethyl ester (CAPE) has been shown to exert both antioxidant and anti-inflammatory effects. The primary objective of the present study was to examine if CAPE could be used to reduce some of the pathological consequences of TBI using rodent models. Male Sprague-Dawley rats and C57BL/6 mice were subjected to controlled cortical impact (CCI) injury. Blood-brain barrier (BBB) integrity was assessed by examining claudin-5 expression and the extravasation of Evans blue dye. The effect of post-injury CAPE administration on neurobehavioral function was assessed using vestibulomotor, motor, and two hippocampus-dependent learning and memory tasks. We report that post-TBI administration of CAPE reduces Evans blue extravasation both in rats and mice. This improvement was associated with preservation of the levels of the tight junction protein claudin-5. CAPE treatment did not improve performance in either vestibulomotor/motor function (tested using beam balance and foot-fault tests), or in learning and memory function (tested using the Morris water maze and associative fear memory tasks). However, animals treated with CAPE were found to have significantly less cortical tissue loss than vehicle-treated controls. These findings suggest that CAPE may provide benefit in the treatment of vascular compromise following central nervous system injury.

Reactive Nitrogen Species:Dual Roles for Blood Brain Barrier Disruption and Brain Repairs in Cerebral Ischemia and Reperfusion Injury

Free radicals play an important role in cerebral ischemia-reperfusion injury. Cerebral ischemia and reperfusion insults induce the production and accumulation of free radicals and trigger numerous molecular cascades, leading to increased blood-brain barrier (BBB) permeability, brain edema, hemorrhage and inflammation, and cell death. As an important component of free radicals, reactive nitrogen species (RNS), such as nitric oxide (NO) and peroxynitrite (ONOO ), is critical player in the process of cerebral ischemia-reperfusion injury. Activation of matrix metalloproteinases (MMPs) mediated by RNS is one of the key steps in BBB opening. As proteolytic zinc-containing enzymes, MMPs induce the degradation of the extracellular matrix around cerebral blood vessels and neurons. Both NO and ONOO can activate MMPs and degrade tight junctions (TJs), leading to BBB breakdown in cerebral ischemia-reperfusion injury. On the other hand, recent progress indicates that RNS also participate in the regulations of spontaneous neurogenesis and brain repair in post-ischemic brains. It is of interesting why and how such small and short lifetime species have the complex biological activites on mediating BBB disruption as well as regulating neurogenesis. Caveolin-1, a membrane integral protein located at caveolae, appears to be a key player in the process. Caveolin-1 can protect BBB integrity through inhibiting MMPs activation, but inhibit neural differentiation of neural progenitor/stem cells through regulating multiple cell growth signaling pathways. NO could down-regulate caveolin-1 whereas the down-regulation of caveolin-1 subsequently induce the increase of NOS activity and produce more NO in the ischemic brains. The interaction of RNS and caveolin-1 forms a positive feedback loop through MMP activations, which provides amplified impacts on BBB dysfunction during cerebral ischemia-reperfusion injury. RNS production also potentially regulates neurogenesis through interacting with caveolin-1 and other cell signaling mechanisms. Herewith, we reviewed the recent progress in the roles of RNS on BBB permeability and neurogenesis. In conclusion, RNS can be a cytotoxic factor as well as neurogenesis signaling. The neurotoxicity or neurogenesis properties of RNS depend on the amount of RNS production in neurons, endothelial cells and their microenvironment during cerebral ischemia-reperfusion injury.

Free Radicals and Matrix Metalloproteinases in Blood-Brain Barrier Disruption after Cerebral Ischemia

Cerebral ischemia results in the compromise of blood-brain barrier(BBB) integrity,leading to neurovascular complications,including cerebral hemorrhage,edema,and inflammation.Free radicals and matrix metalloproteinases(MMPs) are critically involved in the mechanism of BBB breakdown following cerebral ischemia and reperfusion.Scavenging free radicals and inhibiting activation of MMPs are potential strategies to protect BBB integrity and reduce ischemia complications.In this review,we will focus on the the role of free radicals and MMPs activation in BBB damages in cerebral ischemia.

Telencephalin protects blood–brain barrier integrity against acute ischemic damage

Telencephalin protects blood–brain barrier integrity against acute ischemic damage

Blood‐Brain Barrier Disruption Following Hypoxic Stress Requires Activation of Myosin Light Chain Kinase

When blood‐brain barrier (BBB) endothelial cells are exposed to hypoxic stress for prolonged periods of time, they undergo a morphological change and round up, disrupting cell‐cell junctions which leads to increased paracellular permeability. In this study, we investigated the hypothesis that myosin light chain kinase (MLCK) is integral to this process, and investigated alterations in tight junction structure after hypoxic stress. iTRAQ proteomic analysis identified a number of proteins in BBB endothelial cells that are involved in modulation of the actin cytoskeleton that were significantly altered after 6 hrs of hypoxia. Western blotting confirmed the changes in actin, moesin and vasodilatory stimulated phosphoprotein (VASP). We treated cells with ML‐7, a selective MLCK inhibitor, and assessed barrier function; ML‐7 completely blocked the hypoxia‐induced barrier disruption seen in untreated monolayers. This protection of BBB integrity was correlated with a prevention of stress fiber formation and decreased ZO‐1 expression at tight junction sites, implicating contraction of the actin‐myosin cytoskeleton in BBB disruption following hypoxic stress.

Rho-mediated regulation of tight junctions during monocyte migration across the blood-brain barrier in HIV-1 encephalitis (HIVE)

AbstractThe blood-brain barrier (BBB) is compromised during progressive HIV-1 infection, but how this occurs is incompletely understood. We studied the integrity of tight junctions (TJs) of brain microvascular endothelial cells (BMVECs) in an in vitro BBB system and in human brain tissues with HIV-1 encephalitis (HIVE). A downregulation of TJ proteins, claudin-5 and occludin, paralleled monocyte migration into the brain during HIVE. Because small G proteins (such as Rho) can play a role in BMVEC TJ assembly, an artificial BBB system explored the relationship among TJs, Rho/Rho kinase (RhoK) activation, and transendothelial monocyte migration. Coculture of monocytes with endothelial cells led to Rho activation and phosphorylation of TJ proteins. Rho and RhoK inhibitors blocked migration of infected and uninfected monocytes. The RhoK inhibitor protected BBB integrity and reversed occludin/claudin-5 phosphorylation associated with monocyte migration. BMVEC transfection with a constitutively active mutant of RhoK led to dislocation of occludin from the membrane and loss of BMVEC cell contacts. When dominant-negative RhoK-transfected BMVECs were used in BBB constructs, monocyte migration was reduced by 84%. Thus, loss of TJ integrity was associated with Rho activation caused by monocyte brain migration, suggesting that Rho/RhoK activation in BMVECs could be an underlying cause of BBB impairment during HIVE.

254. Protecting the CNS Using AntiOxidant Gene Transfer: HIV-1 Glycoprotein gp120 Induces Blood-Brain Barrier Abnormalities That May Be Prevented by rSV40 Gene Transfer of AntiOxidant Enzymes

HIV dementia is a form of subcortical dementia in which abnormalities of the blood-brain barrier (BBB) may be important in mediating some of the tissue damage that accompanies CNS HIV-1 infection, as well as in facilitating viral entry into the CNS. This study was undertaken to analyze the potential of HIV-1 components to disrupt the BBB and of rSV40-mediated gene delivery of antioxidant enzymes to protect BBB integrity.

Albumin Treatment Reduces Neurological Deficit and Protects Blood–Brain Barrier Integrity After Acute Intracortical Hematoma in the Rat

Acute intracerebral hemorrhage (ICH) is a common and severe form of stroke. To date, medical management of ICH has had scant impact on morbidity and mortality. Because albumin therapy is markedly neuroprotective in preclinical models of ischemic stroke, and because ischemic and hemorrhagic stroke share several common injury mechanisms, we hypothesized that albumin therapy might also benefit ICH. Acute intracortical hematoma was produced in anesthetized, normothermic rats by the single stereotaxic injection of 50 muL of autologous, nonheparinized whole blood over 5 minutes. Separate animal groups were treated either with 25% human albumin, 1.25 g/kg, or with intravenous saline vehicle at 60 minutes after ICH. Neurobehavior was quantified sequentially over the next 2 to 7 days. Damage to the blood-brain barrier was assessed at 2 days after ICH by fluorometric measurement of Evans blue extravasation in dissected brain regions. High-grade neurological deficits were present in all rats at 50 minutes after ICH (score 10.3+/-0.2, mean+/-SEM [maximal score 12]). Albumin-treated rats showed improved neuroscores relative to saline-treated animals beginning within hours of treatment and persisting throughout the 7-day survival period. At 3 and 7 days, mean total neuroscores of the albumin group were 38% to 43% lower than in saline-treated animals. Perihematomal Evans blue discoloration was readily evident in saline-treated ICH rats but was reduced by albumin treatment. Hemispheric Evans blue content ipsilateral to the hematoma was reduced by 49% by albumin treatment (albumin 93.9+/-13.3 versus saline 184.7+/-33.7 mg/g, P<0.05). Hematoma volume and brain swelling were not affected by albumin treatment. Prompt albumin therapy improves neurological function and blood-brain barrier integrity after acute intracortical hematoma. These observations have important potential clinical implications.