Greatly improved survival and neuroprotection in aquaporin‐4‐knockout mice following global cerebral ischemia

Katada, Ryuichi; Akdemir, Gökhan; Asavapanumas, Nithi; Ratelade, Julien; Zhou, Hua; Verkman, A. S.

doi:10.1096/fj.13-231274

Cited by 74 publications

(52 citation statements)

References 50 publications

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“…We previously reported greatly improved outcome in AQP4 knockout mice following focal ischemia produced by permanent MCAO [16], and more recently, improved outcome in AQP4 knockout mice following global ischemia produced by transient carotid artery occlusion [1, 10]. Also, several correlative studies reported reduced cerebral edema following ischemia with reduced AQP4 expression, including propofol and edaravone administration, protein kinase C activation [4], hypertonic saline administration [30], and endothelin-1 overexpression [13].…”

Section: Introductionmentioning

confidence: 99%

Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia

Yao

Derugin

Manley

et al. 2015

Neuroscience Letters

103

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Aquaporin-4 (AQP4) is a water channel expressed in astrocyte end-feet lining the blood-brain barrier. AQP4 deletion in mice is associated with improved outcomes in global cerebral ischemia produced by transient carotid artery occlusion, and focal cerebral ischemia produced by permanent middle cerebral artery occlusion (MCAO). Here, we investigated the consequences of 1-hour transient MCAO produced by intraluminal suture blockade followed by 23 hours of reperfusion. In nine AQP4+/+ and nine AQP4−/− mice, infarct volume was significantly reduced by an average of 39 ± 4 % at 24 hours in AQP4−/− mice, cerebral hemispheric edema was reduced by 23 ± 3 %, and Evans blue extravasation was reduced by 31 ± 2 % (mean ± SEM). Diffusion-weighted magnetic resonance imaging showed greatest reduction in apparent diffusion coefficient around the occlusion site after reperfusion, with remarkably lesser reduction in AQP4−/− mice. The reduced infarct volume in AQP4−/− mice following transient MCAO supports the potential utility of therapeutic AQP4 inhibition in stroke.

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Section: Introductionmentioning

confidence: 99%

Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia

Yao

Derugin

Manley

et al. 2015

Neuroscience Letters

103

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“…This suggests that AQP4 may be important in the chronic phase of the post-ischemic recovery process. Research conducted by Katada et al [37] and Shi et al [40] may yield different conclusions, and several factors may explain this discrepancy. First and foremost, different models used may have caused these inconsistencies.…”

Section: Current Research Investigating the Effects Of Aqp4 On Neuroimentioning

confidence: 95%

“…The BCAO model has been widely used to study the mechanisms of neuronal death and cognitive impairments after ischemia. Katada et al [37] suggested that there was strong neuroprotection in mice lacking AQP4 in a model of global cerebral ischemia produced by transient BCAO, and the neuroprotective effects of AQP4 deletion in global cerebral ischemia involved reduced astrocyte swelling and brain water accumulation, resulting in reduced blood-brain barrier (BBB) disruption, inflammation, and neuron death. Similarly, Fukuda et al [38] observed that siAQP4 treatment after TBI resulted in a decrease in AQP4 associated with less BBB disruption, less edema, and better behavioral outcomes compared to the control group at up to 2 months post-injury.…”

Section: Current Research Investigating the Effects Of Aqp4 On Neuroimentioning

confidence: 99%

A research update on the potential roles of aquaporin 4 in neuroinflammation

et al. 2015

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The presence of aquaporins (AQPs) in the brain has led to intense research on the underlying roles of this family of proteins under both normal and pathological conditions. Aquaporin 4 (AQP4) is the major water-channel membrane protein expressed in the central nervous system (CNS), primarily in astrocytes. Emerging evidence suggests that AQP4 could play an important role in water and ion homeostasis in the brain, and it has been studied in various brain pathological conditions. However, far less is known about the potential for AQP4 to influence neuroinflammation and, furthermore, its potential role in neurodegenerative disorders such as Alzheimer's disease (AD). It has been suggested that the pathogenesis of many clinical diseases, such as neuromyelitis optica (NMO), multiple sclerosis (MS) and brain injuries, is related to the regulation of AQP4 expression. Investigating the effects of AQP4 on microglia and astrocytes could be important to understand its role in the pathogenesis of neuroinflammation. Although the exact roles of non-steroidal anti-inflammatory drugs (NSAIDs) in protection against the detrimental effects of neuroinflammation remain unclear, research into the possible neuroprotective effects of AQP4 against neuroinflammation regulation seems to be important for future investigations.

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“…Notwithstanding the complexities of cytotoxic and vasogenic mechanisms, the main finding of this study was a small beneficial effect of AQP4 deletion in TBI. The beneficial effect was very small compared with the robust beneficial effects of AQP4 deletion in water intoxication, a model of pure cytotoxic edema 4 , or in focal 32 or global33,34 cerebral ischemia, where cytotoxic edema predominates. The small beneficial effect of AQP4 deletion in the CCI model here may be the consequence of mixed cytotoxic/vasogenic edema mechanisms in which AQP4 has opposing actions.…”

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confidence: 90%

Mildly Reduced Brain Swelling and Improved Neurological Outcome in Aquaporin-4 Knockout Mice following Controlled Cortical Impact Brain Injury

Yao

Uchida

Papadopoulos

et al. 2015

Journal of Neurotrauma

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Brain edema following traumatic brain injury (TBI) is associated with considerable morbidity and mortality. Prior indirect evidence has suggested the involvement of astrocyte water channel aquaporin-4 (AQP4) in the pathogenesis of TBI. Here, focal TBI was produced in wild type (AQP4(+/+)) and knockout (AQP4(-/-)) mice by controlled cortical impact injury (CCI) following craniotomy with dura intact (parameters: velocity 4.5 m/sec, depth 1.7 mm, dwell time 150 msec). AQP4-deficient mice showed a small but significant reduction in injury volume in the first week after CCI, with a small improvement in neurological outcome. Mechanistic studies showed reduced intracranial pressure at 6 h after CCI in AQP4(-/-) mice, compared with AQP4(+/+) control mice (11 vs. 19 mm Hg), with reduced local brain water accumulation as assessed gravimetrically. Transmission electron microscopy showed reduced astrocyte foot-process area in AQP4(-/-) mice at 24 h after CCI, with greater capillary lumen area. Blood-brain barrier disruption assessed by Evans blue dye extravasation was similar in AQP4(+/+) and AQP4(-/-) mice. We conclude that the mildly improved outcome in AQP4(-/-) mice following CCI results from reduced cytotoxic brain water accumulation, though concurrent cytotoxic and vasogenic mechanisms in TBI make the differences small compared to those seen in disorders where cytotoxic edema predominates.

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Greatly improved survival and neuroprotection in aquaporin‐4‐knockout mice following global cerebral ischemia

Cited by 74 publications

References 50 publications

Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia

Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia

A research update on the potential roles of aquaporin 4 in neuroinflammation

Mildly Reduced Brain Swelling and Improved Neurological Outcome in Aquaporin-4 Knockout Mice following Controlled Cortical Impact Brain Injury

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