doi: 10.1161/hs0402.105555
(Stroke. 2002;33:1077.)
© 2002 American Heart Association, Inc.
Original Contributions |
Albumin Therapy of Transient Focal Cerebral Ischemia
In Vivo Analysis of Dynamic Microvascular Responses
From the Cerebral Vascular Disease Research Center, Department of Neurology, University of Miami School of Medicine, Miami, Fla (L.B., Y.L., W.Z., R.B., M.D.G.); Laboratoire de Recherches Cérébrovasculaires, CNRS UPR 646, Université Paris 7, Paris, France (E.P., H.N., J.S.); and Department of Electrical and Computer Engineering, University of Miami College of Engineering, Coral Gables, Fla (P.R.).
Reprint requests to Ludmila Belayev, MD, Department of Neurology (D4-5), University of Miami School of Medicine, PO Box 016960, Miami, FL 33101. E-mail lbelayev{at}stroke.med.miami.edu
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Abstract |
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Background and Purpose— To study whether intravascular or hemodynamic factors contribute to the marked neuroprotective effect of albumin therapy in focal cerebral ischemia, 2 complementary methods were applied: laser-scanning confocal microscopy (LSCM) and laser-Doppler perfusion imaging (LDPI).
Methods— In the LSCM study, Sprague-Dawley rats were anesthetized with halothane/nitrous oxide, and a cranial window was placed over the dorsolateral frontoparietal cortex. Rats received 2-hour middle cerebral artery occlusion (MCAO) by an intraluminal suture and were treated with human albumin (1.25 g/kg; n=4) or saline (n=3) after 30 minutes of recirculation. Video images of cortical vessels were continually acquired and were digitized offline to measure diameters and fluorescent erythrocyte velocities. In the LDPI study, cortical perfusion was measured in anesthetized Sprague-Dawley rats that received 2-hour MCAO and were treated with albumin (2.5 g/kg; n=6) or saline (n=5) at 30 minutes after recirculation.
Results— In the LSCM study, MCAO was associated with arteriolar dilation and slowing of capillary and venular erythrocyte perfusion. During the first 15 to 30 minutes of postischemic recirculation, prominent foci of vascular stagnation developed within cortical venules, associated with thrombuslike foci and adherent corpuscular structures consistent in size with neutrophils. Saline administration failed to affect these phenomena, while albumin therapy was followed by significant increases in arteriolar diameter (
12%; P=0.007) and by a prompt improvement of venular and capillary erythrocyte perfusion and a partial disappearance of adherent thrombotic material. Albumin therapy increased erythrocyte flow velocity in both capillaries (288±73% versus 76±18% in the saline group; P=0.023) and venules (2.7-fold [P=0.001] versus 1.0-fold in the saline group [P=NS]). In the LDPI study, cortical perfusion declined during MCAO and rose initially with recirculation (to 135% of baseline) in both groups. Mean cortical perfusion improved slightly (14%; P=NS) in albumin-treated animals.
Conclusions— These results reveal a beneficial effect of albumin therapy in reversing stagnation, thrombosis, and corpuscular adherence within cortical venules in the reperfusion phase after focal ischemia and support its utility in the treatment of acute ischemic stroke.
Key Words: albumin • middle cerebral artery occlusion • neuroprotection • perfusion • rats
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Introduction |
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We have recently shown that human serum albumin therapy confers marked neurological and histological protection in focal1–3 and global cerebral ischemia,4 as well as in traumatic brain injury in rats.5 The use of albumin solutions in the treatment of focal cerebral ischemia was initially prompted in part by the belief that hemodilution and reduction of blood viscosity would prove hemodynamically beneficial to ischemic tissue.6,7 Only a few previous studies have considered the effect of albumin treatment on cerebral perfusion after ischemia or related insults,7,8 and these studies have not provided definitive insights. In a recent autoradiographic study, we assessed local cerebral blood flow (CBF) at a single time point after albumin treatment of focal ischemia; we found that albumin therapy improved perfusion subtly within the former penumbra at 1 hour of recirculation after a 2-hour period of middle cerebral artery occlusion (MCAO). Because cerebral infarction is an evolving phenomenon, however, it is desirable to follow cerebral perfusion throughout the early recirculation period.
Albumin is known to have multifaceted intravascular effects. It exerts complex influences on erythrocyte aggregation, increasing low-shear viscosity but decreasing erythrocyte sedimentation under no-flow conditions.9 Albumin is also a specific inhibitor of endothelial cell apoptosis.10 Several albumin-binding proteins have been identified on endothelial cells from many organs, including brain, that mediate its transcytosis and endocytosis.11,12 Albumin also constitutes a major antioxidant defense against oxidizing agents generated both by endogenous processes (such as neutrophil myeloperoxidase) and by exogenous compounds.13,14 By binding copper ions, albumin inhibits copper ion-dependent lipid peroxidation and the formation of the highly reactive hydroxyl radical species.13,15 Albumin also plays crucial roles in the transport of fatty acids16,17 and in the binding of metabolites and drugs.18
The recent introduction of laser-scanning confocal microscopy (LSCM) has permitted the real-time dynamic imaging of pial and cortical microcirculatory dynamics and the measurement of microvessel diameters and erythrocyte flow velocities in capillaries and venules.19 Another complementary method, laser-Doppler perfusion imaging (LDPI), measures relative parenchymal blood flow over a wide region of superficial cortical tissue within a short period of time by scanning a low-power laser beam across the brain, using the Doppler-shift signal to construct an image of relative blood flow within the measured region. (By contrast, conventional laser-Doppler flowmetry is restricted to a single point on the cortical surface.)
In the present study we used both LSCM and LDPI to explore whether hemodynamic alterations within the microvasculature are responsible for the marked neuroprotective effect of albumin in focal cerebral ischemia.
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Materials and Methods |
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Laser-Scanning Confocal Microscopy
Animal Preparation
Male Sprague-Dawley rats (R. Janvier Breeding Center, France) weighing 274 to 326 g were studied after an overnight fast. Experiments were performed under permit No. 02934 from the French Ministry of Agriculture. After administration of atropine sulfate (0.5 mg/kg IP), animals were anesthetized with halothane (3.5% for induction, 1% for maintenance), 70% nitrous oxide, and a balance of oxygen; immobilized with pancuronium bromide (0.6 mg/kg IV); and mechanically ventilated. Rectal and cranial (left temporalis muscle) temperatures were separately monitored with temperature probes and were regulated at 37.0°C to 37.5°C via a heating lamp and a feedback-controlled heating pad (Harvard Apparatus). Femoral artery and vein catheters were inserted to monitor arterial blood pressure (model RS3200 polygraph, Gould); to measure arterial blood gases (model 248, Ciba-Corning Diagnostics Corp), hematocrit, and plasma glucose (MediSense); and for infusion of drug and fluorescent tracers.
Middle Cerebral Artery Occlusion
The right common carotid artery was isolated from surrounding tissue through a midline incision, and the occipital branches of the external carotid artery were coagulated. A 4-cm length of 3-0 monofilament nylon suture was inserted via the proximal external carotid artery into the internal carotid artery, at a distance of 15 mm from the common carotid artery bifurcation. Before use, the suture was coated with poly-L-lysine solution as previously described20 to enhance its adhesion to the surrounding endothelium and increase the reproducibility of the resulting infarct.
The animal was then placed in a stereotaxic head frame in the lateral position (David Kopf Instruments), and a midline skin incision approximately 1.5 cm in length was made parallel to the sagittal suture. To prepare the cranial window for LSCM, the cranial bone was thinned to translucency by means of a water-cooled dental drill over the right parietal cortex just behind the bregma. The thinned bone was carefully removed, and the dura mater was then lifted over an area of approximately 4 mm2. Small incisions in the dura enabled it to be reflected at the cranial window periphery. A 150-µm-thick quartz microscope coverglass was cut to a size corresponding to the cranial window and was sealed to the bone by means of dental cement to make the preparation watertight. A right frontal craniotomy (diameter 2 mm) was also performed 2 mm rostral to the bregma and 2 mm lateral to the sagittal suture. The dura mater was left intact. An Ag/AgCl wire (diameter 0.07 mm, uncoated tip 1.5 mm) was placed between the calvarium and the meningeal surface to record the DC potential and the electrocorticogram. An Ag/AgCl disk electrode was inserted under the skin of the neck as a reference electrode.
The rat was then placed under the confocal microscope on a custom-built stereotaxic device closely fitting the confocal microscope stage. Fluorescein-isothiocyanate (FITC)-dextran (molecular weight=70 000; 2.5 mg/mL) in 0.9% NaCl was injected (0.5 mL) intravenously to visualize microvessels and delineate their lumen. FITC-labeled erythrocytes (previously prepared in vitro19) were injected via the same route at a tracer dose (<2%).
LSCM was performed as previously described.19 A confocal laser-scanning unit (Viewscan, BioRad), attached to a microscope (Optiphot-2, Nikon), was used. The scanning unit scanned 50 fields per second. The light source was an argon-krypton laser whose wavelengths were 488, 568, and 647 nm. After baseline images were collected, the middle cerebral artery (MCA) was occluded for 2 hours; the intraluminal suture was then carefully removed. Video images of cortical arterioles, capillaries, and venules were sequentially recorded before and during MCAO and for 2 hours of reperfusion.
Treatment
Human serum albumin (Alpha Therapeutic Corp, Los Angeles, Calif; 25% solution, 1.25 g/kg; n=4) or vehicle (sodium chloride 0.9%; n=3) was infused intravenously at a constant rate over 3 minutes, at 30 minutes after suture removal after a 2-hour period of MCAO.
Laser-Doppler Perfusion Imaging
Fasted Sprague-Dawley rats [weight, 276 to 337 g; Crl:CD (SD)BR strain, Charles River Laboratories, Wilmington, Mass] were anesthetized with 3.5% halothane in a mixture of 70% nitrous oxide and a balance of oxygen, then orally intubated, immobilized with pancuronium bromide, and mechanically ventilated. General surgical preparation and MCAO were the same as described above for the LSCM studies.
The animal was then placed in a stereotaxic head frame in the lateral position (David Kopf Instruments), and a midline skin incision approximately 1.5 cm in length was made parallel to the sagittal suture and extended laterally to the midpoint between the right orbit and the external auditory canal. The temporalis muscle was elevated from the skull and retracted anteriorly. The zygoma was kept intact. To expose the distal MCA, an approximately 4-mm-diameter craniectomy was created between the frontal and squamosal-temporal bone, 5 mm anterior to the parietosquamosal suture, under direct visualization with a Zeiss surgical microscope. The MCA and its distal branches were clearly visible through the intact dura.
Cortical perfusion was measured with the Laser-Doppler Perfusion Imager (LDPI) (Moor Instruments). A computer-controlled optical scanner directed a low-power helium-neon laser beam over the exposed cortex. The scanner head was positioned parallel to the cerebral cortex at a distance of 26 cm. Each scan required 1.35 minutes for measurements of approximately 42x40 pixels (pixel size, 100 µm), covering an area of approximately 16 mm2. At each measuring site, the beam illuminated the tissue to a depth of 0.5 mm. An image color coded to denote relative perfusion levels was displayed on a video monitor. After several baseline images were collected, the MCA was occluded for 2 hours, and the intraluminal suture was then carefully removed. Images were collected at 10-minute intervals before and during MCAO and after initial reperfusion and at 5-minute intervals after treatment.
Treatment
Human serum albumin (25% solution, 2.5 g/kg; n=6) or vehicle (sodium chloride 0.9%; n=5) was infused intravenously at a constant rate over 3 minutes, at 30 minutes after suture removal after a 2-hour period of MCAO.
LDPI Analytical Strategy
In the course of MCAO and reperfusion, some degree of animal movement was inevitable. To preserve pixel-by-pixel alignment while tracking CBF changes by LDPI, we designed a new image-registration algorithm using an adaptive correlation approach to match the sequence of laser-Doppler images in the same spatial domain (P. Riyamongkol, MS, et al, unpublished data, 2001). In the first step, feature pixels were selected in a laser-Doppler baseline reference image. Local correlations were then performed between a "correlation window" of mxm pixels in the reference image and another window of nxn pixels (n>m) (termed the search window) in an image of the sequence to be registered. An iterative routine was used to obtain the alignment position yielding the maximum correlation coefficient. In the third step, image matching was performed by 2-dimensional polynomial transformation with bilinear interpolation. Once corresponding pixels were determined between images, each image in the sequence could then be mapped into the same spatial template as the reference image, and the whole image sequence could be automatically analyzed. Relative CBF data were then acquired by placing a polygon sample tool on each of the images, positioned 2 pixels away from vascular profiles.
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Results |
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Physiological Variables
Albumin- and saline-treated animals of the respective series showed similar values for rectal and cranial temperatures, blood pressure, arterial blood gases, and plasma glucose (Table). Albumin therapy led to the expected moderate reduction in hematocrit (mean reduction, 28% to 29%; Table).
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LSCM Study
Pial arterioles and venules under the closed cranial window were easily distinguishable from one another by the much more rapid flow of fluorescent erythrocytes through arterioles than through venules (Figure 1). Intraparenchymal capillaries were visible up to 200 µm beneath the surface of the brain by changing the focus of the microscope. They were characterized by a high tortuosity and by the heterogeneity of erythrocyte flow. MCAO was followed by arteriolar dilatation (Figure 1) with slowing of capillary and venular erythrocyte perfusion. The occurrence of recurrent transient shifts in DC potential indicated peri-infarct depolarizations typical of the ischemic penumbra and confirmed the efficacy of MCAO.
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After removal of the intravascular suture following 2-hour MCAO, no increase in arteriolar blood flow was visible, and prominent vascular stasis developed within cortical venules, associated with thrombuslike stagnant foci (Figures 1 and 2) and adherent corpuscular structures (consistent in size with activated neutrophils) on venular endothelium (Figures 2 and 3). Administration of intravenous albumin after 30-minute recirculation was followed by a prompt improvement of venular and capillary erythrocyte perfusion and a partial disappearance of adherent intravenular thrombotic material (Figures 1 and 2). One rat with 2-hour MCAO was treated with saline at 30-minute recirculation and was subsequently administered albumin as well (2.5 g/kg IV) after 2 hours of recirculation (Figure 2). In this animal, adherent material within venules persisted after saline administration Figure 2, middle), while subsequent albumin administration in this animal was followed by the prompt clearing of this adherent material (Figure 2, bottom).
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Quantitative Analysis
Quantitative assessment of the cortical microvasculature was performed on videotaped images of cranial-window fields by an examiner blinded to the experimental conditions (J.S.). The diameter of arterioles (n=13) under basal conditions averaged 38.0±4.8 µm. Arteriolar diameters could be quantified sequentially during MCAO in 6 and 5 vessels of albumin- and saline-treated rats, respectively. For the pooled data, there were nonsignificant trends for arterioles to dilate (to 118±11% of their preischemic diameter) at the onset of MCAO and to recede (to 103±8% of preischemic diameter) by the end of MCAO (P=0.13, paired t test). After albumin administration, there was a highly significant increase in mean arteriolar diameter of 11.6±2.8% over the ensuing 30 minutes (P=0.007, paired t test). By contrast, over the 30 minutes after saline treatment, mean arteriolar diameter decreased slightly (by 16±5%; P=NS, paired t test).
Erythrocyte flow velocity was measured in 11 cortical capillaries from 5 rats. Mean capillary flow velocity averaged 0.64±0.09 mm/s before MCAO and declined to 0.17±0.02 mm/s during early postischemic recirculation, before treatment. Thirty minutes after albumin treatment, capillary erythrocyte flow velocity increased by 288±73%, while 30 minutes after saline treatment, flow velocity was 76±18% of its value before therapy; this difference was highly significant (P=0.023; Figure 4).
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Venular diameter estimated under basal conditions averaged 44.7±6.3 µm. Venular diameters were unaffected by MCAO, recirculation, or albumin or saline administration. Measurements of venular erythrocyte flow velocity made in the course of albumin or saline treatment are shown in Figure 4. Venular erythrocyte flow velocity failed to change significantly after saline treatment. By contrast, albumin treatment was followed by highly significant increases in venular erythrocyte flow velocity over the ensuing 30 minutes, amounting on average to 2.7-fold (Figure 4).
Laser-Doppler Perfusion Imaging
During MCAO, relative cortical perfusion declined to an identical extent in the 2 groups (saline group, 44.6±7.0% of preischemic baseline [mean±SEM]; albumin group, 44.6±5.3%; Figure 5). The initial increases in cortical perfusion during the first 30 minutes of recirculation after suture removal were also similar in the 2 groups (saline group, 139.5±23.2%; albumin group, 130.6±21.2%; Figure 5). After treatment (155 to 240 minutes; Figure 5), mean cortical perfusion tended to stabilize in the albumin group and to decline slightly in the saline group, but this difference was not statistically significant (mean values, 118.3±11.6% of baseline in the saline group and 135.2±10.6 in the albumin group; P=NS, repeated-measures ANOVA).
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Discussion |
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LSCM and LDPI provide complementary information on the state of the cerebral circulation. While LSCM permits direct visualization of pial microvessels and allows the quantification of erythrocyte flow velocities within individual capillaries and venules, LDPI yields a relative measure of parenchymal blood flow in the superficial cortex. In the present study the salient (and unexpected) observation by LSCM related to prominent abnormalities developing within cortical venules of the ischemic penumbra in the early postischemic recirculation period, consisting of stagnation of flow, adherent thrombuslike material, and adherent corpuscular structures thought to be neutrophils. Administration of intravenous albumin after 30-minute recirculation tended to reverse these abnormalities, while treatment with saline was ineffective. LSCM quantification of erythrocyte flow velocities within capillaries and venules revealed increases after albumin (but not saline) treatment (Figure 4).
In contrast to the LSCM observations, relative cortical parenchymal flow as measured by LDPI was not significantly affected. The latter observation agrees with the results of our previous autoradiographic study of local CBF in this model: albumin-associated perfusion changes took the form of subtle CBF increases within a narrow circumferential zone of the former ischemic penumbra, which required the application of sophisticated computer-assisted image-processing methods for its detection.21 Within the LDPI region of interest (Figure 5), cortical perfusion declined to approximately 45% of control during MCAO—a level consistent with the ischemic penumbra.22 Since the coefficient of variation of this measurement was 32%, however, it is evident that the LDPI measurement polygon also included pixels lying within the ischemic core.
Taken together, our results suggest that, while albumin does not induce major increases in parenchymal perfusion, it nonetheless is highly effective in reversing stagnation and corpuscular adherence within the postcapillary microcirculation during the postischemic reperfusion period.
Dirnagl et al23,24 introduced LSCM to study the cortical microcirculation of anesthetized rats via an implanted cranial window after the intravenous injection of fluorescein; a single line-scanning approach was used with 3-dimensional reconstruction, requiring several minutes for the acquisition of a 3-dimensional data set. Hudetz et al25,26 developed an alternative method, using epifluorescence-intensified videomicroscopy in conjunction with FITC-labeled red cells to study the dynamics of the capillary microcirculation in the superficial cortex of anesthetized rats. LSCM used in conjunction with fluorescent plasma markers and 3-dimensional morphometry has also proven useful in studying fixed, stained serial brain sections derived from experimental insults.27,28
The LSCM method used in the present study was first introduced by Seylaz et al19 and became possible with the development of a 2-dimensional real-time confocal microscope permitting optical sectioning from the pial level to approximately 200 µm within the cortical parenchyma. The method allows rapid microcirculatory responses to brief forebrain ischemia to be visualized through a closed cranial window in anesthetized rats after fluorescent labeling of erythrocytes and plasma. Its advantages include its increased image resolution and improved depth of tissue penetration. Using this method, Pinard et al29 characterized microvascular responses to 15-minute periods of global forebrain ischemia followed by recirculation. That study demonstrated an absence of nonperfused capillaries and of capillary recruitment as well as an effect of the relatively selective type I nitric oxide synthase inhibitor 7-nitro-indazole in reducing arteriolar dilation and blunting the increase in erythrocyte velocity during early reperfusion. Interestingly, that study also called attention to thrombosis or sluggish blood flow occurring within venules during early reperfusion.29
Hallenbeck et al30 first demonstrated the progressive accumulation of polymorphonuclear leukocytes in regions of low CBF during early postischemic reperfusion. Several subsequent investigations have used intravital fluorescence videomicroscopy with rhodamine-labeled leukocytes to study leukocyte accumulation in focal and global ischemia.31,32 A recent study of 2-hour MCAO by the intraluminal filament method observed marked increases in leukocyte adhesion to venules at 15 to 60 minutes of recirculation (4.5-fold at 15 to 30 minutes, 25-fold at 1 hour), together with leukocyte rolling and significantly reduced shear rate in venules during the early reperfusion period.33 Other ischemia studies have confirmed that the preponderant locus of leukocyte adherence is to venular endothelium, which occurs during the first 3 hours of reperfusion and is suppressed by moderate hypothermia.31,34,35 By contrast, leukocyte adhesion within arterioles is less prominent.33,34 Transient MCAO with reperfusion appears to result in earlier neutrophil accumulation than permanent MCAO.36,37 When complete cerebral ischemia is of brief duration, accumulated leukocytes are dislodged from cerebral capillaries,38 while under conditions of persistently diminished cerebral perfusion, leukocytes may accumulate for several hours.39
The adhesion of leukocytes to postcapillary venules has been identified as a critical first step in inflammatory processes affecting many organs, and strategies to impede neutrophil-endothelial adhesion and inhibit cellular injury have emerged as a promising therapeutic strategy in a variety of inflammatory states associated with ischemia/reperfusion, circulatory shock, and organ transplantation.40 Many studies in cerebral ischemia (especially in models of transient focal ischemia with reperfusion37) have demonstrated the success of antileukocyte interventions in reducing infarct size and brain edema and in improving neurological dysfunction; recent reviews summarize many of these studies.41–43 Among the strategies shown in various models to antagonize leukocyte adherence and increased vascular permeability are glycerol44 and hydroxyethyl starch45—agents that, like albumin, are osmotically active. By contrast, nitric oxide synthase inhibition augments and prolongs postischemic leukocyte adhesion by mechanisms thought to involve principally a decrease in velocity or shear rate,46 although others have suggested that nitric oxide exerts a chronic antiadherent effect in the cerebral microcirculation by inactivating adhesion-promoting superoxide radical formation.47 The latter observation is pertinent here in that serum albumin, via its free sulfhydryl group, reacts with oxides of nitrogen to form a stable S-nitrosothiol with properties resembling endothelium-derived relaxing factor.48 By this means, albumin may both affect vascular tone and exert antiplatelet effects within the microcirculation.48,49
In summary, the present findings suggest that a component of the neuroprotective effect of human albumin in acute ischemic stroke resides in its antagonism of stagnation, thrombosis, and leukocyte adhesion within the postcapillary microcirculation in the early reperfusion phase after focal ischemia, resulting in improved erythrocyte perfusion within the ischemic penumbra.
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Acknowledgments |
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These studies were supported by National Institutes of Health program project grant NS-05820; American Heart Association Initial Investigator Award (No. 9930263V) (Dr Belayev); the National Center of Scientific Research (CNRS), University of Paris 7; and an equipment loan from Moor Instruments, Ltd.
Received October 9, 2001; revision received November 21, 2001; accepted December 14, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Belayev L, Busto R, Zhao W, Clemens JA, Ginsberg MD. Effect of delayed albumin hemodilution on infarction volume and brain edema after transient middle cerebral artery occlusion in rats. J Neurosurg. 1997; 87: 595–601.[Medline] [Order article via Infotrieve]
2.
Belayev L, Zhao W, Pattany PM, Weaver RG, Huh PW, Lin B, Busto R, Ginsberg MD. Diffusion-weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin therapy in focal cerebral ischemia. Stroke. 1998; 29: 2587–2599.
3.
Belayev L, Liu Y, Zhao W, Busto R, Ginsberg MD. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke. 2001; 32: 553–560.
4. Belayev L, Saul I, Huh PW, Finotti N, Zhao W, Busto R, Ginsberg MD. Neuroprotective effect of high-dose albumin therapy against global ischemic brain injury in rats. Brain Res. 1999; 845: 107–111.[CrossRef][Medline] [Order article via Infotrieve]
5. Belayev L, Alonso OF, Huh PW, Zhao W, Busto R, Ginsberg MD. Posttreatment with high-dose albumin reduces histopathological damage and improves neurological deficit following fluid percussion brain injury in rats. J Neurotrauma. 1999; 16: 445–453.[Medline] [Order article via Infotrieve]
6.
Heros RC, Korosue K. Hemodilution for cerebral ischemia. Stroke. 1989; 20: 423–427.
7. Cole DJ, Drummond JC, Patel PM, Marcantonio S. Effects of viscosity and oxygen content on cerebral blood flow in ischemic and normal rat brain. J Neurol Sci. 1994; 124: 15–20.[CrossRef][Medline] [Order article via Infotrieve]
8. Matsui T, Asano T. The hemodynamic effects of prolonged albumin administration in beagle dogs exposed to experimental subarachnoid hemorrhage. Neurosurgery. 1993; 32: 79–83.[Medline] [Order article via Infotrieve]
9. Reinhart WH, Nagy C. Albumin affects erythrocyte aggregation and sedimentation. Eur J Clin Invest. 1995; 25: 523–528.[Medline] [Order article via Infotrieve]
10. Zoellner H, Hofler M, Beckmann R, Hufnagl P, Vanyek E, Bielek E, Wojta J, Fabry A, Lockie S, Binder BR. Serum albumin is a specific inhibitor of apoptosis in human endothelial cells. J Cell Sci. 1996; 109: 2571–2580.[Abstract]
11.
Schnitzer JE, Sung A, Horvat R, Bravo J. Preferential interaction of albumin-binding proteins, gp30 and gp18, with conformationally modified albumins: presence in many cells and tissues with a possible role in catabolism. J Biol Chem. 1992; 267: 24544–24553.
12. Antohe F, Dobrila L, Heltianu C, Simionescu N, Simionescu M. Albumin-binding proteins function in the receptor-mediated binding and transcytosis of albumin across cultured endothelial cells. Eur J Cell Biol. 1993; 60: 268–275.[Medline] [Order article via Infotrieve]
13. Halliwell B. Albumin: an important extracellular antioxidant? Biochem Pharmacol. 1988; 37: 569–571.[CrossRef][Medline] [Order article via Infotrieve]
14. Wasil M, Halliwell B, Hutchison DC, Baum H. The antioxidant action of human extracellular fluids: effect of human serum and its protein components on the inactivation of alpha 1-antiproteinase by hypochlorous acid and by hydrogen peroxide. Biochem J. 1987; 243: 219–223.[Medline] [Order article via Infotrieve]
15. Emerson TE. Unique features of albumin: a brief review. Crit Care Med. 1989; 17: 690–694.[Medline] [Order article via Infotrieve]
16. Curry S, Mandelkow H, Brick P, Franks N. Crystal structure of human serum albumin complexed with fatty acid reveals an asymmetric distribution of binding sites. Nat Struct Biol. 1998; 5: 827–835.[CrossRef][Medline] [Order article via Infotrieve]
17. Trigatti BL, Gerber GE. A direct role for serum albumin in the cellular uptake of long-chain fatty acids. Biochem J. 1995; 308: 155–159.
18. Koch-Weser J, Sellers EM. Binding of drugs to serum albumin (first of two parts). N Engl J Med. 1976; 294: 311–316.[Medline] [Order article via Infotrieve]
19. Seylaz J, Charbonne R, Nanri K, Von Euw D, Borredon J, Kacem K, Meric P, Pinard E. Dynamic in vivo measurement of erythrocyte velocity and flow in capillaries and of microvessel diameter in the rat brain by confocal laser microscopy. J Cereb Blood Flow Metab. 1999; 19: 863–870.[CrossRef][Medline] [Order article via Infotrieve]
20.
Belayev L, Alonso OF, Busto R, Zhao W, Ginsberg MD. Middle cerebral artery occlusion in the rat by intraluminal suture: neurological and pathological evaluation of an improved model. Stroke. 1996; 27: 1616–1622.
21. Huh PW, Belayev L, Zhao W, Busto R, Saul I, Ginsberg MD. The effect of high-dose albumin therapy on local cerebral perfusion after transient focal cerebral ischemia in rats. Brain Res. 1998; 804: 105–113.[CrossRef][Medline] [Order article via Infotrieve]
22. Belayev L, Zhao W, Busto R, Ginsberg MD. Transient middle cerebral artery occlusion by intraluminal suture, I: three-dimensional autoradiographic image-analysis of local cerebral glucose metabolism-blood flow interrelationships during ischemia and early recirculation. J Cereb Blood Flow Metab. 1997; 17: 1266–1280.[CrossRef][Medline] [Order article via Infotrieve]
23. Dirnagl U, Villringer A, Gebhardt R, Haberl RL, Schmiedek P, Einhaupl KM. Three-dimensional reconstruction of the rat brain cortical microcirculation in vivo. J Cereb Blood Flow Metab. 1991; 11: 353–360.[Medline] [Order article via Infotrieve]
24. Dirnagl U, Villringer A, Einhaupl KM. In-vivo confocal scanning laser microscopy of the cerebral microcirculation. J Microsc. 1992; 165: 147–157.[Medline] [Order article via Infotrieve]
25.
Hudetz AG, Feher G, Weigle CG, Knuese DE, Kampine JP. Video microscopy of cerebrocortical capillary flow: response to hypotension and intracranial hypertension. Am J Physiol. 1995; 268: H2202–H2210.
26. Hudetz AG. Blood flow in the cerebral capillary network: a review emphasizing observations with intravital microscopy. Microcirculation. 1997; 4: 233–252.[Medline] [Order article via Infotrieve]
27. Morris DC, Zhang Z, Davies K, Fenstermacher J, Chopp M. High resolution quantitation of microvascular plasma perfusion in non-ischemic and ischemic rat brain by laser-scanning confocal microscopy. Brain Res Brain Res Protoc. 1999; 4: 185–191.[CrossRef][Medline] [Order article via Infotrieve]
28. Zhang Z, Davies K, Prostak J, Fenstermacher J, Chopp M. Quantitation of microvascular plasma perfusion and neuronal microtubule-associated protein in ischemic mouse brain by laser-scanning confocal microscopy. J Cereb Blood Flow Metab. 1999; 19: 68–78.[CrossRef][Medline] [Order article via Infotrieve]
29. Pinard E, Engrand N, Seylaz J. Dynamic cerebral microcirculatory changes in transient forebrain ischemia in rats: involvement of type I nitric oxide synthase. J Cereb Blood Flow Metab. 2000; 20: 1648–1658.[CrossRef][Medline] [Order article via Infotrieve]
30.
Hallenbeck JM, Dutka AJ, Tanishima T, Kochanek PM, Kumaroo KK, Thompson CB, Obrenovitch TP, Contreras TJ. Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke. 1986; 17: 246–253.
31. Villringer A, Dirnagl U, Them A, Schurer L, Krombach F, Einhaupl KM. Imaging of leukocytes within the rat brain cortex in vivo. Microvasc Res. 1991; 42: 305–315.[CrossRef][Medline] [Order article via Infotrieve]
32. Hudetz AG, Oliver JA, Wood JD, Newman PJ, Kampine JP. Leukocyte adhesion in pial cerebral venules after PMA stimulation and ischemia/reperfusion in vivo. Adv Exp Med Biol. 1997; 411: 513–518.[Medline] [Order article via Infotrieve]
33.
Ritter LS, Orozco JA, Coull BM, McDonagh PF, Rosenblum WI. Leukocyte accumulation and hemodynamic changes in the cerebral microcirculation during early reperfusion after stroke. Stroke. 2000; 31: 1153–1161.
34.
Ishikawa M, Sekizuka E, Sato S, Yamaguchi N, Inamasu J, Bertalanffy H, Kawase T, Iadecola C. Effects of moderate hypothermia on leukocyte-endothelium interaction in the rat pial microvasculature after transient middle cerebral artery occlusion. Stroke. 1999; 30: 1679–1686.
35. Uhl E, Beck J, Stummer W, Lehmberg J, Baethmann A. Leukocyte-endothelium interactions in pial venules during the early and late reperfusion period after global cerebral ischemia in gerbils. J Cereb Blood Flow Metab. 2000; 20: 979–987.[CrossRef][Medline] [Order article via Infotrieve]
36. Barone FC, Hillegass LM, Price WJ, White RF, Lee EV, Feuerstein GZ, Sarau HM, Clark RK, Griswold DE. Polymorphonuclear leukocyte infiltration into cerebral focal ischemic tissue: myeloperoxidase activity assay and histologic verification. J Neurosci Res. 1991; 29: 336–345.[CrossRef][Medline] [Order article via Infotrieve]
37. Clark RK, Lee EV, White RF, Jonak ZL, Feuerstein GZ, Barone FC. Reperfusion following focal stroke hastens inflammation and resolution of ischemic injured tissue. Brain Res Bull. 1994; 35: 387–392.[CrossRef][Medline] [Order article via Infotrieve]
38. Dirnagl U, Niwa K, Sixt G, Villringer A. Cortical hypoperfusion after global forebrain ischemia in rats is not caused by microvascular leukocyte plugging. Stroke. 1994; 25: 1028–1038.[Abstract]
39. Garcia JH, Liu KF, Yoshida Y, Lian J, Chen S, del Zoppo GJ. Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol. 1994; 144: 188–199.[Abstract]
40. Korthuis RJ, Anderson DC, Granger DN. Role of neutrophil-endothelial cell adhesion in inflammatory disorders. J Crit Care. 1994; 9: 47–71.[CrossRef][Medline] [Order article via Infotrieve]
41. Hartl R, Schurer L, Schmid-Schonbein GW, del Zoppo GJ. Experimental antileukocyte interventions in cerebral ischemia. J Cereb Blood Flow Metab. 1996; 16: 1108–1119.[CrossRef][Medline] [Order article via Infotrieve]
42. Jean WC, Spellman SR, Nussbaum ES, Low WC. Reperfusion injury after focal cerebral ischemia: the role of inflammation and the therapeutic horizon. Neurosurgery. 1998; 43: 1382–1396.[Medline] [Order article via Infotrieve]
43. Barone FC, Feuerstein GZ. Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab. 1999; 19: 819–834.[Medline] [Order article via Infotrieve]
44. Ishikawa M, Sekizuka E, Sato S, Yamaguchi N, Inamasu J, Kawase T. Glycerol attenuates the adherence of leukocytes in rat pial venules after transient middle cerebral artery occlusion. Neurol Res. 1999; 21: 785–790.[Medline] [Order article via Infotrieve]
45.
Kaplan SS, Park TS, Gonzales ER, Gidday JM. Hydroxyethyl starch reduces leukocyte adherence and vascular injury in the newborn pig cerebral circulation after asphyxia. Stroke. 2000; 31: 2218–2223.
46. Hudetz AG, Wood JD, Kampine JP. Nitric oxide synthase inhibitor augments post-ischemic leukocyte adhesion in the cerebral microcirculation in vivo. Neurol Res. 1999; 21: 378–384.[Medline] [Order article via Infotrieve]
47.
Gidday JM, Park TS, Shah AR, Gonzales ER. Modulation of basal and postischemic leukocyte-endothelial adherence by nitric oxide. Stroke. 1998; 29: 1423–1429.
48. Keaney JF, Jr, Simon DI, Stamler JS, Jaraki O, Scharfstein J, Vita JA, Loscalzo J. NO forms an adduct with serum albumin that has endothelium-derived relaxing factor-like properties. J Clin Invest. 1993; 91: 1582–1589.
49.
Kaufmann MA, Castelli I, Pargger H, Drop LJ. Nitric oxide dose-response study in the isolated perfused rat kidney after inhibition of endothelium-derived relaxing factor synthesis: the role of serum albumin. J Pharmacol Exp Ther. 1995; 273: 855–862.
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