Aquaporin-4 gene variant independently associated with oedema after intracerebral haemorrhage

Appelboom, Geoff; Bruce, Sam; Duren, Andrew; Piazza, Matt; Monahan, Aimee; Christophe, Brandon R.; Zoller, Stephen D.; LoPresti, Melissa A.; Connolly, E. Sander

doi:10.1179/1743132815y.0000000047

Cited by 21 publications

(16 citation statements)

References 28 publications

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“…This implicates a secondary anti-neuroinflammatory mechanism of action. One interesting hypothesis may be progesterone modulation of aquaporin 4 channels [45], which are known to be associated with edema formation after ICH [46]. Another possibility lies in progesterone's known modulation of the NFκB pathway through TLRs [42,47,48], as supported by the present findings.…”

Section: Discussionsupporting

confidence: 76%

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

Lei

Wang²,

Jeong³

et al. 2015

Neuroendocrinology

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In models of acute brain injury, progesterone improves recovery through several mechanisms including modulation of neuroinflammation. Secondary injury from neuroinflammation is a potential therapeutic target after intracerebral hemorrhage (ICH). For potential translation of progesterone as a clinical acute ICH therapeutic, the present study sought to define efficacy of exogenous progesterone administration in ICH-relevant experimental paradigms. Young and aged C57BL/6 male, female, and ovariectomized (OVX) mice underwent left intrastriatal collagenase (0.05-0.075 U) or autologous whole blood (35 μl) injection. Progesterone at varying doses (4-16 mg/kg) was administered at 2, 5, 24, 48, and 72 h after injury. Rotarod and Morris water maze latencies were measured on days 1-7 and days 28-31 after injury, respectively. Hematoma volume, brain water content (cerebral edema), complementary immunohistochemistry, multiplex cytokine arrays, and inflammatory proteins were assessed at prespecified time points after injury. Progesterone (4 mg/kg) administration improved rotarod and water maze latencies (p < 0.01), and decreased cerebral edema (p < 0.05), microglial proliferation, and neuronal loss (p < 0.01) in young and aged male, young OVX, and aged female mice. Brain concentration of proinflammatory cytokines and Toll-like receptor-associated proteins were also decreased after progesterone (4 mg/kg) treatment (p < 0.01). Progesterone-treated young female mice showed no detectable effects. Exogenous progesterone improved short- and long-term neurobehavioral recovery and modulated neuroinflammation in male and OVX mice after ICH. Future studies should validate these findings, and address timing and length of administration before translation to clinical trial.

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Section: Discussionsupporting

confidence: 76%

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

Lei

Wang²,

Jeong³

et al. 2015

Neuroendocrinology

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“…Nonetheless, AQP4 variants and mutations (including gain of function polymorphisms) have been reported to influence water permeability of cell membranes [126]. In ICH, AQP4 variant rs1054827 has been associated with perihematomal edema formation in a small sample of 128 patients [127].…”

Section: Impact Of Genetic Variation In Abcc8 (Encoding Sur1) and Trpmentioning

confidence: 99%

Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the Evidence

Jha

Bell

Citerio

et al. 2020

IJMS

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Cerebral edema and contusion expansion are major determinants of morbidity and mortality after TBI. Current treatment options are reactive, suboptimal and associated with significant side effects. First discovered in models of focal cerebral ischemia, there is increasing evidence that the sulfonylurea receptor 1 (SUR1)—Transient receptor potential melastatin 4 (TRPM4) channel plays a key role in these critical secondary injury processes after TBI. Targeted SUR1-TRPM4 channel inhibition with glibenclamide has been shown to reduce edema and progression of hemorrhage, particularly in preclinical models of contusional TBI. Results from small clinical trials evaluating glibenclamide in TBI have been encouraging. A Phase-2 study evaluating the safety and efficacy of intravenous glibenclamide (BIIB093) in brain contusion is actively enrolling subjects. In this comprehensive narrative review, we summarize the molecular basis of SUR1-TRPM4 related pathology and discuss TBI-specific expression patterns, biomarker potential, genetic variation, preclinical experiments, and clinical studies evaluating the utility of treatment with glibenclamide in this disease.

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“…Notwithstanding the caveats mentioned above, the available data also support the possibility of identifying and testing transcriptional upregulators of AQP4 to accelerate removal of excess brain water in hydrocephalus. It may be interesting to study whether AQP1 or AQP4 polymorphisms might predispose to hydrocephalus or modulate its severity; AQP4 polymorphisms have been reported with potential functional significance [44] , and possible associations with edema following ischemic stroke [45] , intracranial hemorrhage [46] , and traumatic brain injury [47] . In terms of basic biology, there remain major questions about the magnitude of AQP1-facilitated CSF production in humans and the mechanisms of AQP4-dependent clearance of excess ventricular and parenchymal brain water.…”

Section: Summary and Perspectivementioning

confidence: 99%

Aquaporin Water Channels and Hydrocephalus

Tradtrantip¹,

Smith²,

Yao³

2016

Pediatr Neurosurg

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The aquaporins (AQPs) are a family of water-transporting proteins that are broadly expressed in mammalian cells. Two AQPs in the central nervous system, AQP1 and AQP4, might play a role in hydrocephalus and are thus potential drug targets. AQP1 is expressed in the ventricular-facing membrane of choroid plexus epithelial cells, where it facilitates the secretion of cerebrospinal fluid (CSF). AQP4 is expressed in astrocyte foot processes and ependymal cells lining ventricles, where it appears to facilitate the transport of excess water out of the brain. Altered expression of these AQPs in experimental animal models of hydrocephalus and limited human specimens suggests their involvement in the pathophysiology of hydrocephalus, as do data in knockout mice demonstrating a protective effect of AQP1 deletion and a deleterious effect of AQP4 deletion in hydrocephalus. Though significant questions remain, including the precise contribution of AQP1 to CSF secretion in humans and the mechanisms by which AQP4 facilitates clearance of excess brain water, AQP1 and AQP4 have been proposed as potential drug targets to reduce ventricular enlargement in hydrocephalus.

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Aquaporin-4 gene variant independently associated with oedema after intracerebral haemorrhage

Abstract: The establishment of an independent association between rs1054827 and ICH + PHE volume provides evidence implicating the AQP4 gene in haematoma and oedema formation after ICH. Further investigation is needed to characterise this link.

Cited by 21 publications

References 28 publications

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the Evidence

Aquaporin Water Channels and Hydrocephalus

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