Protective role of aquaporin‐4 water channels after contusion spinal cord injury

Kimura, Atsushi; Hsu, Mike S.; Seldin, Marcus M.; Verkman, A. S.; Scharfman, Helen E.; Binder, Devin K.

doi:10.1002/ana.22023

Cited by 80 publications

(58 citation statements)

References 35 publications

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“…Oshio et al found that AQP4 was intensely stained throughout the gray matter in spinal cord, especially in the capillary-surrounding astrocytic end-feet 19 . In particular, AQP4 and spinal cord edema are positively correlated 40,41 . AQP4 in spinal cord is expressed in glial cells throughout the gray matter and glial foot processes adjacent to the spinal capillary endothelium 19 .…”

Section: Discussionmentioning

confidence: 95%

Anti-edema effect of melatonin on spinal cord injury in rats

Li¹,

Yu²,

Yang³

et al. 2015

BIOMED PAP

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, Liangbi Xiang aAim. To determine the anti-edema effects of melatonin on spinal cord injury (SCI) in rats. Methods. A total of 150 adult male Sprague-Dawley rats were randomly allocated to the following three groups (n=50): a sham group which underwent laminectomy without dural compression; an SCI group, which underwent laminectomy followed by SCI and received saline i.p. immediately after injury and then daily for 2 days; an MT group, which underwent laminectomy followed by SCI and received a 100 mg/kg dose of melatonin i.p. immediately after SCI and then daily for 2 days. The cords were removed at 12, 24, 48 and 72 h after surgery in every group. Spinal cord edema was evaluated by determining the spinal cord water content. Expressions of AQP4 and GFAP positive cells in injured spinal cord were detected by immunohistochemical staining, and protein expressions of AQP4 and GFAP were detected by Western blotting. Results. Spinal cord water content was obviously increased after SCI, which was maintained almost unchanged by melatonin treatment (100 mg/kg) at 12 h after injury but was significantly reduced from 24 h to 72 h. The expressions of AQP4 and GFAP increased in the injured spinal cord segments, which were decreased by melatonin treatment (100 mg/kg) between 24 h and 72 h after SCI. Conclusions. Melatonin (100 mg/kg) had anti-edema effects after acute SCI probably by down-regulating the expression level of AQP4 protein, and it may eliminate astrocytic swelling after SCI through down-regulating the expression level of GFAP protein.

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Section: Discussionmentioning

confidence: 95%

Anti-edema effect of melatonin on spinal cord injury in rats

Li¹,

Yu²,

Yang³

et al. 2015

BIOMED PAP

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“…For example, Kimura et al 23 have reported that AQP4 has a protective role after contusion SCI in mice. The differences between the study by Kimura et al and ours are likely to be due to the use of different animal species, injury models and severity of injury.…”

Section: Discussionmentioning

confidence: 99%

Myelotomy reduces spinal cord edema and inhibits aquaporin-4 and aquaporin-9 expression in rats with spinal cord injury

Sun

et al. 2014

Spinal Cord

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Objective: Spinal cord edema contributes to the pathophysiological mechanisms underlying spinal cord injury (SCI) and is associated with functional recovery after SCI. Early myelotomy may be a promising surgical intervention for reducing SCI-induced edema. However, it remains unclear whether myelotomy can reduce SCI-induced edema. In addition, aquaporin-4 (AQP4) and aquaporin-9 (AQP9) have important roles in the regulation of water homeostasis. Here, we aimed to determine the effects of myelotomy on AQP4 and AQP9 expression and spinal cord edema in a rat model of moderate SCI. Methods: Rats were randomly assigned to three groups: the sham control group (n = 22) receiving laminectomy alone; the contusion group (n = 44) receiving laminectomy plus contusion; and the myelotomy group (n = 44) receiving laminectomy plus contusion followed by myelotomy at 24 h. Functional recovery was estimated by the open-field and inclined plane tests. Spinal cord edema was determined by measuring the water content. The expression of AQP4 and AQP9 was determined by western blot. Results: Compared with the contusion group, myelotomy significantly improved the Basso, Beattie and Bresnahan scores in the open-field test and resulted in a higher mean angle value in the incline plane test. Myelotomy significantly reduced SCI-induced edema at 4 and 6 days after SCI, which was accompanied by downregulation of AQP4 and AQP9 expression. Conclusion: Myelotomy improves locomotor function, reduces edema in rats with SCI and is associated with decreased expression of AQP4 and AQP9.

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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: 92%

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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Protective role of aquaporin‐4 water channels after contusion spinal cord injury

Abstract: These results suggest that AQP4 plays a protective role after contusion SCI by facilitating the clearance of excess water, and that targeting edema after SCI may be a novel therapeutic strategy.

Cited by 80 publications

References 35 publications

Anti-edema effect of melatonin on spinal cord injury in rats

Anti-edema effect of melatonin on spinal cord injury in rats

Myelotomy reduces spinal cord edema and inhibits aquaporin-4 and aquaporin-9 expression in rats with spinal cord injury

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

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