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1.
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.  相似文献   

2.
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.  相似文献   

3.
Aquaporin-4 (AQP4) plays a role in the generation of post-ischemic edema. 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 central nervous system (CNS) associated with altered brain water balance. Edaravone, a free radical scavenger, is used for the treatment of acute ischemic stroke (AIS) in Japan. In this study, edaravone significantly reduced the infarct area and improved the neurological deficit scores at 24 h after reperfusion in a rat transient focal ischemia model. Furthermore, edaravone markedly reduced AQP4 immunoreactivity and protein levels in the cerebral infarct area. In light of observations that edaravone specifically inhibited AQP4 in a rat transient focal ischemia model, we propose that edaravone might reduce cerebral edema through the inhibition of AQP4 expression following cerebral infarction.  相似文献   

4.
Brain abscess is associated with local vasogenic edema, which leads to increased intracranial pressure and significant morbidity. Aquaporin-4 (AQP4) is a water channel expressed in astroglia at the blood-brain and brain-CSF barriers. To investigate the role of AQP4 in brain abscess-associated edema, live Staphylococcus aureus (10(5) colony-forming units) was injected into the striatum to create a focal abscess. Wild-type and AQP4-deficient mice had comparable immune responses as measured by brain abscess volume (approximately 3.7 mm3 at 3 days), bacterial count and cytokine levels in brain homogenates. Blood-brain barrier permeability was increased comparably in both groups as assessed by extravasation of Evans blue dye. However, at 3 days the AQP4 null mice had significantly higher intracranial pressure (mean +/- SEM 27 +/- 2 vs. 17 +/- 2 mmHg; p < 0.001) and brain water content (81.0 +/- 0.3 vs. 79.3 +/- 0.5 % water by weight in the abscess-containing hemisphere; p < 0.01) than wild-type mice. Reactive astrogliosis was found throughout the abscess-containing hemisphere; however, only a subset of astrocytes in the peri-abscess region of wild-type mice had increased AQP4 immunoreactivity. Our findings demonstrate a protective effect of AQP4 on brain swelling in bacterial abscess, suggesting that AQP4 induction may reduce vasogenic edema associated with cerebral infection.  相似文献   

5.
Stroke results in inflammation, brain edema, and neuronal death. However, effective neuroprotectants are not available. Recent studies have shown that high mobility group box-1 (HMGB1), a proinflammatory cytokine, contributes to ischemic brain injury. Aquaporin 4 (AQP4), a water channel protein, is considered to play a pivotal role in ischemia-induced brain edema. More recently, studies have shown that pannexin 1 channels are involved in cerebral ischemic injury and the cellular inflammatory response. Here, we examined whether the pannexin 1 channel inhibitor probenecid could reduce focal ischemic brain injury by inhibiting cerebral inflammation and edema. Transient focal ischemia was induced in C57BL/6J mice by middle cerebral artery occlusion (MCAO) for 1 h. Infarct volume, neurological score and cerebral water content were evaluated 48 h after MCAO. Immunostaining, western blot analysis and ELISA were used to assess the effects of probenecid on the cellular inflammatory response, HMGB1 release and AQP4 expression. Administration of probenecid reduced infarct size, decreased cerebral water content, inhibited neuronal death, and reduced inflammation in the brain 48 h after stroke. In addition, HMGB1 release from neurons was significantly diminished and serum HMGB1 levels were substantially reduced following probenecid treatment. Moreover, AQP4 protein expression was downregulated in the cortical penumbra following post-stroke treatment with probenecid. These results suggest that probenecid, a powerful pannexin 1 channel inhibitor, protects against ischemic brain injury by inhibiting cerebral inflammation and edema.  相似文献   

6.
Aquaporin 4 (AQP4), the most abundant water channel protein in the brain, is involved in brain edema induced by ischemic insults. To evaluate whether the neuroprotective effects of estrogen are associated with AQP4 expression and edema formation, changes in AQP levels and ischemic edema were examined in the brains of male and female mice subjected to transient middle cerebral artery occlusion. Infarct volume and edema formation were markedly less in females than in males. AQP4 expression in the ischemic cortex of females was relatively well preserved, whereas it was significantly decreased in males. These effects disappeared in ovariectomized females but were reversed by estrogen replacement. Furthermore, AQP4 expression was decreased with increased brain edema in females treated with ICI182,780, an estrogen receptor antagonist. These findings suggest that the estrogen effect on the reduction of ischemic brain edema is associated with the preserved level of AQP4 that is partly mediated by estrogen receptors.  相似文献   

7.
Chi Y  Fan Y  He L  Liu W  Wen X  Zhou S  Wang X  Zhang C  Kong H  Sonoda L  Tripathi P  Li CJ  Yu MS  Su C  Hu G 《Aging cell》2011,10(3):368-382
Aquaporin-4 (AQP4) is highly expressed in mammalian brains and is involved in the pathophysiology of cerebral disorders, including stroke, tumors, infections, hydrocephalus, epilepsy, and traumatic brain injury. We found that AQP4-deficient mice were hypersensitive to stimulations such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or lipopolysaccharide compared to wild-type (WT) littermates. In a mouse model of MPTP-induced Parkinson's disease (PD), AQP4-deficient animals show more robust microglial inflammatory responses and more severe loss of dopaminergic neurons (DNs) compared with WT mice. However, a few studies have investigated the association of abnormal AQP4 levels with immune dysfunction. Here, for the first time, we report AQP4 expression in mouse thymus, spleen, and lymph nodes. Furthermore, the significantly lower numbers of CD4(+) CD25(+) regulatory T cells in AQP4-deficient mice compared to WT mice, perhaps resulting from impaired thymic generation, may be responsible for the uncontrolled microglial inflammatory responses and subsequent severe loss of DNs in the substantia nigra pars compacta in the MPTP-induced PD model. These novel findings suggest that AQP4 deficiency may disrupt immunosuppressive regulators, resulting in hyperactive immune responses and potentially contributing to the increased severity of PD or other immune-associated diseases.  相似文献   

8.
Aldehyde dehydrogenase 2 (ALDH2) is a new therapeutic target in the central nervous system. However, the association between ALDH2 and brain edema following ischemic stroke (IS) remains unclear. The present study was investigated to whether active ALDH2 can attenuate brain edema by using a rat model of IS, with the aim of clarifying the underlying mechanisms involved. Rats were administered the ALDH2 agonist Alda-1, vehicle or the ALDH2 inhibitor cyanamide (CYA) 15 min prior to a 1.5 h middle cerebral artery occlusion (MCAO) surgery. The effects of ALDH2 were subsequently investigated 24 h after reperfusion by evaluating neurological function, infarct sizes, brain edema volumes, 4-hydroxy-2-nonenal (4-HNE) levels, and aquaporin 4 (AQP4) protein expression. The results demonstrated that increasing ALDH2 activity significantly improved neurological deficits, reduced infarct sizes, and attenuated brain edema after MCAO. Alda-1 administration led to decreased 4-HNE levels and inhibited AQP4 protein expression in the peri-infarct section of the brain. Whereas, CYA administration increased 4-HNE levels, AQP4 expression, and simultaneously aggravated brain edema following MCAO. In conclusion, increasing ALDH2 activity can improve brain edema, infarct volumes, and reduce neurological impairment in a rat IS model. The therapeutic benefits of ALDH2 are related to 4-HNE clearance and AQP4 down-regulation.  相似文献   

9.
The astroglial water channel aquaporin-4 (AQP4) facilitates water movement into and out of brain parenchyma. To investigate the role of AQP4 in meningitis-induced brain edema, Streptococcus pneumoniae was injected into cerebrospinal fluid (CSF) in wild type and AQP4 null mice. AQP4-deficient mice had remarkably lower intracranial pressure (9 +/- 1 versus 25 +/- 5 cm H2O) and brain water accumulation (2 +/- 1 versus 9 +/- 1 microl) at 30 h, and improved survival (80 versus 0% survival) at 60 h, through comparable CSF bacterial and white cell counts. Meningitis produced marked astrocyte foot process swelling in wild type but not AQP4 null mice, and slowed diffusion of an inert macromolecule in brain extracellular space. AQP4 protein was strongly up-regulated in meningitis, resulting in a approximately 5-fold higher water permeability (P(f)) across the blood-brain barrier compared with non-infected wild type mice. Mathematical modeling using measured P(f) and CSF dynamics accurately simulated the elevated lower intracranial pressure and brain water produced by meningitis and predicted a beneficial effect of prevention of AQP4 upregulation. Our findings provide a novel molecular mechanism for the pathogenesis of brain edema in acute bacterial meningitis, and suggest that inhibition of AQP4 function or up-regulation may dramatically improve clinical outcome.  相似文献   

10.

Aim

Aquaporin-4(AQP4) expression in the brain with relation to edema formation following focal cerebral ischemia was investigated. Studies have shown that brain edema is one of the significant factors in worsening stroke outcomes. While many mechanisms may aggravate brain injury, one such potential system may involve AQP4 up regulation in stroke patients that could result in increased edema formation. Post administration of melatonin following ischemic stroke reduces AQP4 mediated brain edema and confers neuroprotection.

Materials and methods

An in-silico approach was undertaken to confirm effective melatonin-AQP4 binding. Rats were treated with 5 mg/kg, i.p. melatonin or placebo at 30 min prior, 60 min post and 120 min post 60 min of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. Rats were evaluated for battery of neurological and motor function tests just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, apoptosis study and western blot experiments.

Key findings

Melatonin at 60 min post ischemia rendered neuroprotection as evident by reduction in cerebral infarct volume, improvement in motor and neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and malondialdehyde (MDA) were also found to be significantly reduced in ischemic brain regions in treated animals. Melatonin potentiated intrinsic antioxidant status, inhibited acid mediated rise in intracellular calcium levels, decreased apoptotic cell death and also markedly inhibited protein kinase C (PKC) influenced AQP4 expression in the cerebral cortex and dorsal striatum.

Significance

Melatonin confers neuroprotection by protein kinase C mediated AQP4 inhibition in ischemic stroke.  相似文献   

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