Increased brain edema in aqp4-null mice in an experimental model of subarachnoid hemorrhage

Tait, Matthew; Saadoun, Samira; Bell, B. Anthony; Verkman, A. S.; Papadopoulos, Marios C.

doi:10.1016/j.neuroscience.2010.01.053

Cited by 72 publications

(39 citation statements)

References 20 publications

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“…For example, the early induction of AQP4 by a low dose of thrombin contributes to limitation of the ischemic infarction and formation of edema in mice [48] , and acute vascular disruption is associated with AQP4 loss after transient MCAO in rats [49] . This protective role is also reported in spinal cord compression injury [50] , subarachnoid hemorrhage [51] , intracerebral hemorrhage [52] and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity [53,54] . These findings demonstrate that AQP4 in astrocytes exerts a beneficial action in pathological conditions.…”

Section: Discussionsupporting

confidence: 60%

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

Shi

Zhao

et al. 2012

Neurosci. Bull.

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Objective Aquaporin-4 (AQP4), the main water channel protein in the brain, plays a critical role in water homeostasis and brain edema. Here, we investigated its role in the inflammatory responses after focal cerebral ischemia. MethodsIn AQP4-knockout (KO) and wild-type mice, focal cerebral ischemia was induced by 30 min of middle cerebral arterial occlusion (MCAO). Ischemic neuronal injury and cellular inflammatory responses, as well as the expression and localization of cysteinyl leukotriene CysLT 2 and CysLT 1 receptors, were determined at 24 and 72 h after MCAO.Results AQP4-KO mice showed more neuronal loss, more severe microglial activation and neutrophil infiltration, but less astrocyte proliferation in the brain after MCAO than wild-type mice. In addition, the protein levels of both CysLT 1 and CysLT 2 receptors were up-regulated in the ischemic brain, and the up-regulation was more pronounced in AQP4-KO mice. The CysLT 1 and CysLT 2 receptors were primarily localized in neurons, microglia and neutrophils; those localized in microglia and neutrophils were enhanced in AQP4-KO mice. Conclusion AQP4 may play an inhibitory role in postischemic inflammation.

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Section: Discussionsupporting

confidence: 60%

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

Shi

Zhao

et al. 2012

Neurosci. Bull.

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“…AQP4 mislocalization partially protects against reperfusion injury after transient middle cerebral artery occlusion in α-syntrophin-null mice (40). AQP4 deficiency in mice appears to worsen the outcome from brain tumor, abscess, cortical freezing, and subarachnoid hemorrhage (41,42). Thus, deficiency or mislocalization of AQP4 protect against cytotoxic (cellular) brain edema with intact blood-brain barrier, whereas AQP4 facilitates clearance of vasogenic (leaky vessel) edema with defective bloodbrain barrier.…”

Section: Discussionmentioning

confidence: 99%

Protective role of brain water channel AQP4 in murine cerebral malaria

Promeneur

Lunde

Amiry-Moghaddam

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Tragically common among children in sub-Saharan Africa, cerebral malaria is characterized by rapid progression to coma and death. In this study, we used a model of cerebral malaria appearing in C57BL/6 WT mice after infection with the rodent malaria parasite Plasmodium berghei ANKA. Expression and cellular localization of the brain water channel aquaporin-4 (AQP4) was investigated during the neurological syndrome. Semiquantitative real-time PCR comparing uninfected and infected mice showed a reduction of brain AQP4 transcript in cerebral malaria, and immunoblots revealed reduction of brain AQP4 protein. Reduction of brain AQP4 protein was confirmed in cerebral malaria by quantitative immunogold EM; however, polarized distribution of AQP4 at the perivascular and subpial astrocyte membranes was not altered. To further examine the role of AQP4 in cerebral malaria, WT mice and littermates genetically deficient in AQP4 were infected with P. berghei. Upon development of cerebral malaria, WT and AQP4-null mice exhibited similar increases in width of perivascular astroglial endfeet in brain. Nevertheless, the AQP4-null mice exhibited more severe signs of cerebral malaria with greater brain edema, although disruption of the blood-brain barrier was similar in both groups. In longitudinal studies, cerebral malaria appeared nearly 1 d earlier in the AQP4-null mice, and reduced survival was noted when chloroquine rescue was attempted. We conclude that the water channel AQP4 confers partial protection against cerebral malaria. C erebral malaria is a dangerous complication of infection with Plasmodium falciparum, especially in children of sub-Saharan Africa, with a mortality rate of 20% (1). If untreated, cerebral malaria often causes coma and death within 24 h (2). Survivors of cerebral malaria often suffer neurological sequelae such as ataxia, hemiplegia, epilepsy, and blindness. The exact pathogenesis of cerebral malaria remains unclear. It is thought that massive sequestration of erythrocytes containing mature stages of P. falciparum within the brain microvasculature (3), as well as an excessive response of the host immune system against the malaria parasite, contribute to the disease (4).Brain edema and intracranial hypertension are common in cerebral malaria. Elevated cerebrospinal fluid pressure has been reported in more than 80% of African children with cerebral malaria (5, 6). Computed tomography of Kenyan children with cerebral malaria revealed that more than 40% had brain edema (7). More recently, increased brain volume in Malawian children with cerebral malaria based on MRI was reported (8). Severe intracranial hypertension in children with cerebral malaria is often fatal (7, 9). Autopsies of African children who died from cerebral malaria revealed brain edema (10, 11).A murine model of cerebral malaria has been established in a susceptible strain of mice (C57BL/6) infected with the rodent malaria parasite P. berghei ANKA (12). Although relevance to human cerebral malaria in adults has been questioned (13), this mo...

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“…9 AQP4 is regarded to have essential roles to maintain BBB integrity in several models of CNS injuries, including spinal cord injury, subarachnoid hemorrhage and ICH. 11,30,31 Our previous study found AQP4 suppressed TJ opening and endothelial cell swelling after ICH when compared with the AQP4 À / À mice group. 11 In addition, AQP4 is believed to be involved in the protective effects of vascular endothelial growth factor (VEGF) and granulocyte colony-stimulating factor on BBB after ICH in our recent work.…”

Section: Erythropoietin Protects Bbb From Disruptionmentioning

confidence: 94%

Erythropoietin protects against hemorrhagic blood–brain barrier disruption through the effects of aquaporin-4

Chu

Ding

Tang

et al. 2014

Laboratory Investigation

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Erythropoietin (EPO) has protective effects against many neurological diseases, including intracerebral hemorrhage (ICH). Here, we aimed to test EPO's effects on blood-brain barrier (BBB) disruption morphologically and functionally following ICH, which has not been well investigated. We also examined whether the effects were dependent on aquaporin-4 (AQP4). We detected the expression of perihematomal AQP4 and EPO receptor (EPOR) induced by EPO injection at 1, 3 and 7 days after ICH. We also examined the effects of EPO on BBB disruption by ICH in wild-type mice, and tested whether such effects were AQP4 dependent by using AQP4 knock-out mice. Furthermore, we assessed the related signal transduction pathways via astrocyte cultures. We found that EPO highly increased perihematomal AQP4 and EPOR expression. Specifically, EPO led to BBB protection in both types of mice by functionally reducing brain edema and BBB permeability, as well as morphologically suppressing tight junction (TJ) opening and endothelial cell swelling, and increasing expression of the TJ proteins occludin and zonula occluden-1 (ZO-1). Statistical analysis indicated that AQP4 was required for these effects. In addition, EPO upregulated phosphorylation of C-Jun amino-terminal kinase (JNK) and p38-mitogenactivated protein kinase (MAPK) as well as EPOR and AQP4 proteins in cultured astrocytes. The latter was inhibited by JNK and p38-MAPK inhibitors. Our data suggest that EPO protects BBB from disruption after ICH and that the main targets are the TJ proteins occludin and ZO-1. The effects of EPO are associated with increased levels of AQP4, and may occur through activation of JNK and p38-MAPK pathways after binding to EPOR. Erythropoietin (EPO) was originally recognized as a humoral mediator involved in the maturation and proliferation of erythroid progenitor cells but is now appreciated for its neuroprotective effects in the central nervous system (CNS) as well. There has been a great deal of research confirming the protective effect of EPO in cerebral ischemic models, the mechanisms of which include apoptosis reduction, inflammation inhibition, angiogenesis enhancement and cerebral blood flow restoration. 1,2 In recent years, studies have been conducted to determine EPO's effects on intracerebral hemorrhage (ICH), another type of stroke. 3,4 However, the mechanisms involved need further investigation.Disruption of the blood-brain barrier (BBB) is an important pathophysiological change after ICH and contributes to vasogenic brain edema formation, which is often serious and leads to poor prognosis. Previous research on EPO and BBB mainly focused on cerebral ischemic models, indicating that BBB disruption induced by middle cerebral artery occlusion can be attenuated by EPO. 5,6 So far, there has only been one study describing how EPO acts on BBB disruption resulting from ICH, and this study reveals that EPO decreased BBB permeability at 3 days after ICH. 7 However, this effect was observed for only one isolated time point without dynamic observation a...

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Increased brain edema in aqp4-null mice in an experimental model of subarachnoid hemorrhage

Cited by 72 publications

References 20 publications

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

Protective role of brain water channel AQP4 in murine cerebral malaria

Erythropoietin protects against hemorrhagic blood–brain barrier disruption through the effects of aquaporin-4

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