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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.
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PMID:Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. 1065 3

Glutamate excitotoxicity, oxidative stress, and acidosis are primary mediators of neuronal death during ischemia and reperfusion. Astrocytes influence these processes in several ways. Glutamate uptake by astrocytes normally prevents excitotoxic glutamate elevations in brain extracellular space, and this process appears to be a critical determinant of neuronal survival in the ischemic penumbra. Conversely, glutamate efflux from astrocytes by reversal of glutamate uptake, volume sensitive organic ion channels, and other routes may contribute to extracellular glutamate elevations. Glutamate activation of neuronal N-methyl-D-aspartate (NMDA) receptors is modulated by glycine and D-serine: both of these neuromodulators are transported by astrocytes, and D-serine production is localized exclusively to astrocytes. Astrocytes influence neuronal antioxidant status through release of ascorbate and uptake of its oxidized form, dehydroascorbate, and by indirectly supporting neuronal glutathione metabolism. In addition, glutathione in astrocytes can serve as a sink for nitric oxide and thereby reduce neuronal oxidant stress during ischemia. Astrocytes probably also influence neuronal survival in the post-ischemic period. Reactive astrocytes secrete nitric oxide, TNFalpha, matrix metalloproteinases, and other factors that can contribute to delayed neuronal death, and facilitate brain edema via aquaporin-4 channels localized to the astrocyte endfoot-endothelial interface. On the other hand erythropoietin, a paracrine messenger in brain, is produced by astrocytes and upregulated after ischemia. Erythropoietin stimulates the Janus kinase-2 (JAK-2) and nuclear factor-kappaB (NF-kB) signaling pathways in neurons to prevent programmed cell death after ischemic or excitotoxic stress. Astrocytes also secrete several angiogenic and neurotrophic factors that are important for vascular and neuronal regeneration after stroke.
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PMID:Astrocyte influences on ischemic neuronal death. 1503 13

Aquaporin-4 (AQP4) is the major water channel in the brain, expressed predominantly in astroglial cell membranes. Initial studies in AQP4-deficient mice showed reduced cellular brain edema following water intoxication and ischemic stroke. We hypothesized that AQP4 deletion would have the opposite effect (increased brain swelling) in vasogenic (noncellular) edema because of impaired removal of excess brain water through glial limitans and ependymal barriers. In support of this hypothesis, we found higher intracranial pressure (ICP, 52+/-6 vs. 26+/-3 cm H2O) and brain water content (81.2+/-0.1 vs. 80.4+/-0.1%) in AQP4-deficient mice after continuous intraparenchymal fluid infusion. In a freeze-injury model of vasogenic brain edema, AQP4-deficient mice had remarkably worse clinical outcome, higher ICP (22+/-4 vs. 9+/-1 cm H2O), and greater brain water content (80.9+/-0.1 vs. 79.4+/-0.1%). In a brain tumor edema model involving stereotactic implantation of melanoma cells, tumor growth was comparable in wild-type and AQP4-deficient mice. However, AQP4-deficient mice had higher ICP (39+/-4 vs. 19+/-5 cm H2O at seven days postimplantation) and corresponding accelerated neurological deterioration. Thus, AQP4-mediated transcellular water movement is crucial for fluid clearance in vasogenic brain edema, suggesting AQP4 activation and/or up-regulation as a novel therapeutic option in vasogenic brain edema.
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PMID:Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. 1520 68

Aquaporin-4 (AQP4) is the major water channel in the CNS. Its expression at fluid-tissue barriers (blood-brain and brain-cerebrospinal fluid barriers) throughout the brain and spinal cord suggests a role in water transport under normal and pathological conditions. Phenotype studies of transgenic mice lacking AQP4 have provided evidence for a role of AQP4 in cerebral water balance and neural signal transduction. Primary cultures of astrocytes from AQP4-null mice have greatly reduced osmotic water permeability compared with wild-type astrocytes, indicating that AQP4 is the principal water channel in these cells. AQP4-null mice have reduced brain swelling and improved neurological outcome following water intoxication and focal cerebral ischemia, establishing a role of AQP4 in the development of cytotoxic (cellular) cerebral edema. In contrast, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema caused by freeze-injury and brain tumor, probably due to impaired AQP4-dependent brain water clearance. AQP4-null mice also have markedly reduced acoustic brainstem response potentials and significantly increased seizure threshold in response to chemical convulsants, implicating AQP4 in modulation of neural signal transduction. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the CNS associated with altered brain water balance.
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PMID:New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice. 1556 13

Brain edema accounts for significant morbidity and mortality in many neurologic conditions such as head trauma, stroke, meningitis, and brain tumor. The water channel aquaporin-4 (AQP4) has been found to be an important determinant of brain water accumulation and clearance of excess brain water. We report the development of a noninvasive near-infrared (NIR) light-scattering method to compare the early kinetics of brain swelling in normal and AQP4-deficient mice. Brain tissue was illuminated through the intact skull with NIR light at 850 nm, and steady-state scattered light intensity was monitored at an angle of 90 degrees at a position on the skull approximately 10 mm from the illuminated site. NIR light scattering reversibly increased with brain swelling (DeltaI/Io approximately 25% per 1% increase in brain water content), but was insensitive to changes in cerebral blood flow, blood oxygenation, or blood flow-related changes in intracranial pressure (ICP). DeltaI/Io increased approximately linearly with brain water content as measured by wet-to-dry weight ratios. Acute water intoxication (intraperitoneal water, 20% body weight) produced a gradual increase in DeltaI/Io of 12 +/- 4% in wild-type mice at 5 min, much greater than that of 2 +/- 1% in AQP4-null mice. Correlation of the NIR signal with ICP showed that increased DeltaI/Io preceded measurable increases in ICP, indicating the ability of the NIR method to detect early brain edema before ICP elevation. NIR light scattering provides a simple noninvasive method to monitor brain edema in mice, with potential clinical applications.
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PMID:Noninvasive early detection of brain edema in mice by near-infrared light scattering. 1576 20

Strong evidence involves aquaporin-4 (AQP4) in the physiopathology of brain edema. Two major points remain unsolved: (1) the capacity of perivascular glial cells to regulate AQP4 in response to disruption of the blood-brain barrier (BBB); and (2) the potential beneficial role of AQP4 in the clearance of brain edema. We used intraparenchymal injection of lipopolysaccharide (LPS) as an efficient model to induce BBB disruption. This was monitored by IgG extravasation and AQP4 was studied at the mRNA and protein level. The first signs of BBB disruption coincided with strong induction of AQP4 mRNA in perivascular glial cells. At the early phase, estradiol treatment highly prevented the LPS-induced disruption of the BBB and the induction of AQP4. Efficient clearance of vasogenic edema is supposed to occur once BBB is restored. This phase coincided with high induction of AQP4 mRNA in parenchymal reactive astrocytes and perivascular glial processes. High levels of AQP4 mRNA may be beneficial under these conditions. Our data may clarify why estradiol treatment reduces mortality in conditions typically associated with edema formation, like stroke.
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PMID:Blood-brain barrier disruption highly induces aquaporin-4 mRNA and protein in perivascular and parenchymal astrocytes: protective effect by estradiol treatment in ovariectomized animals. 1577 82

Aquaporin-4, the major water-selective channel in astroglia throughout the central nervous system, facilitates water movement into and out of the brain. Here, we identify a novel role for aquaporin-4 in astroglial cell migration, as occurs during glial scar formation. Astroglia cultured from the neocortex of aquaporin-4-null mice had similar morphology, proliferation and adhesion, but markedly impaired migration determined by Transwell migration efficiency (18+/-2 vs 58+/-4% of cells migrated towards 10% serum in 8 hours; P<0.001) and wound healing rate (4.6 vs 7.0 microm/hour speed of wound edge; P<0.001) compared with wild-type mice. Transwell migration was similarly impaired (25+/-4% migrated cells) in wild-type astroglia after approximately 90% reduction in aquaporin-4 protein expression by RNA inhibition. Aquaporin-4 was polarized to the leading edge of the plasma membrane in migrating wild-type astroglia, where rapid shape changes were seen by video microscopy. Astroglial cell migration was enhanced by a small extracellular osmotic gradient, suggesting that aquaporin-4 facilitates water influx across the leading edge of a migrating cell. In an in vivo model of reactive gliosis and astroglial cell migration produced by cortical stab injury, glial scar formation was remarkably impaired in aquaporin-4-null mice, with reduced migration of reactive astroglia towards the site of injury. Our findings provide evidence for the involvement of aquaporin-4 in astroglial cell migration, which occurs during glial scar formation in brain injury, stroke, tumor and focal abscess.
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PMID:Involvement of aquaporin-4 in astroglial cell migration and glial scar formation. 1630 50

Aquaporin-4 (AQP4) is expressed in astrocytes throughout the central nervous system, particularly at the blood-brain and brain-cerebrospinal fluid barriers. Phenotype analysis of transgenic mice lacking AQP4 has provided compelling evidence for involvement of AQP4 in cerebral water balance, astrocyte migration, and neural signal transduction. AQP4-null mice have reduced brain swelling and improved neurological outcome in models of (cellular) cytotoxic cerebral edema including water intoxication, focal cerebral ischemia, and bacterial meningitis. However, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema including cortical freeze-injury, brain tumor, brain abscess and hydrocephalus, probably due to impaired AQP4-dependent brain water clearance. AQP4 deficiency or knock-down slows astrocyte migration in response to a chemotactic stimulus in vitro, and AQP4 deletion impairs glial scar progression following injury in vivo. AQP4-null mice also manifest reduced sound- and light-evoked potentials, and increased threshold and prolonged duration of induced seizures. Impaired K+ reuptake by astrocytes in AQP4 deficiency may account for the neural signal transduction phenotype. Based on these findings, we propose modulation of AQP4 expression or function as a novel therapeutic strategy for a variety of cerebral disorders including stroke, tumor, infection, hydrocephalus, epilepsy, and traumatic brain injury.
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PMID:Three distinct roles of aquaporin-4 in brain function revealed by knockout mice. 1656 96

The aquaporin-4 (AQP4) pool in the perivascular astrocyte membranes has been shown to be critically involved in the formation and dissolution of brain edema. Cerebral edema is a major cause of morbidity and mortality in stroke. It is therefore essential to know whether the perivascular pool of AQP4 is up- or down-regulated after an ischemic insult, because such changes would determine the time course of edema formation. Here we demonstrate by quantitative immunogold cytochemistry that the ischemic striatum and neocortex show distinct patterns of AQP4 expression in the reperfusion phase after 90 min of middle cerebral artery occlusion. The striatal core displays a loss of perivascular AQP4 at 24 hr of reperfusion with no sign of subsequent recovery. The most affected part of the cortex also exhibits loss of perivascular AQP4. This loss is of magnitude similar to that of the striatal core, but it shows a partial recovery toward 72 hr of reperfusion. By freeze fracture we show that the loss of perivascular AQP4 is associated with the disappearance of the square lattices of particles that normally are distinct features of the perivascular astrocyte membrane. The cortical border zone differs from the central part of the ischemic lesion by showing no loss of perivascular AQP4 at 24 hr of reperfusion but rather a slight increase. These data indicate that the size of the AQP4 pool that controls the exchange of fluid between brain and blood during edema formation and dissolution is subject to large and region-specific changes in the reperfusion phase.
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PMID:Temporary loss of perivascular aquaporin-4 in neocortex after transient middle cerebral artery occlusion in mice. 1693 71

Aquaporin-4 (AQP4) is a water-channel protein expressed strongly in the brain, predominantly in astrocyte foot processes at the borders between the brain parenchyma and major fluid compartments, including cerebrospinal fluid (CSF) and blood. This distribution suggests that AQP4 controls water fluxes into and out of the brain parenchyma. Experiments using AQP4-null mice provide strong evidence for AQP4 involvement in cerebral water balance. AQP4-null mice are protected from cellular (cytotoxic) brain edema produced by water intoxication, brain ischemia, or meningitis. However, AQP4 deletion aggravates vasogenic (fluid leak) brain edema produced by tumor, cortical freeze, intraparenchymal fluid infusion, or brain abscess. In cytotoxic edema, AQP4 deletion slows the rate of water entry into brain, whereas in vasogenic edema, AQP4 deletion reduces the rate of water outflow from brain parenchyma. AQP4 deletion also worsens obstructive hydrocephalus. Recently, AQP4 was also found to play a major role in processes unrelated to brain edema, including astrocyte migration and neuronal excitability. These findings suggest that modulation of AQP4 expression or function may be beneficial in several cerebral disorders, including hyponatremic brain edema, hydrocephalus, stroke, tumor, infection, epilepsy, and traumatic brain injury.
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PMID:Aquaporin-4 and brain edema. 1734 37


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