AQP4 Tag Single Nucleotide Polymorphisms in Patients with Traumatic Brain Injury

Dardiotis, Efthimios; Paterakis, Konstantinos; Tsivgoulis, Georgios; Tsintou, Magdalini; Hadjigeorgiou, Georgios F.; Dardioti, Maria; Grigoriadis, Savas; Simeonidou, Constantina; Komnos, Apostolos; Kapsalaki, Eftychia; Fountas, Kostas N.; Hadjigeorgiou, Georgios M.

doi:10.1089/neu.2014.3347

Cited by 57 publications

(53 citation statements)

References 43 publications

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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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Section: Summary and Perspectivementioning

confidence: 99%

Aquaporin Water Channels and Hydrocephalus

Tradtrantip¹,

Smith²,

Yao³

2016

Pediatr Neurosurg

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“…This impaired clearance was exacerbated by genetic deletion of aquaporin-4, one of the major water channels in brain astrocytes. A logical hypothesis arising from this observation in mice would be that genetic polymorphisms in Acquaporin-4 (Dardiotis et al, 2014; Kleffner et al, 2008; Opdal et al, 2010; Sorani et al, 2008), other water channels, or regulatory pathways could affect the susceptibility or resilience to tau accumulation following concussive TBI in humans.…”

Section: Tau Pathologymentioning

confidence: 99%

The pathophysiology of repetitive concussive traumatic brain injury in experimental models; new developments and open questions

Brody

Benetatos

Bennett

et al. 2015

Molecular and Cellular Neuroscience

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In recent years, there has been an increasing interest in the pathophysiology of repetitive concussive traumatic brain injury (rcTBI) in large part due to the association with dramatic cases of progressive neurological deterioration in professional athletes, military personnel, and others. However, our understanding of the pathophysiology of rcTBI is less advanced than for more severe brain injuries. Most prominently, the mechanisms underlying traumatic axonal injury, microglial activation, amyloid-beta accumulation, and progressive tau pathology are not yet known. In addition, the role of injury to dendritic spine cytoskeletal structures, vascular reactivity impairments, and microthrombi are intriguing and subjects of ongoing inquiry. Methods for quantitative analysis of axonal injury, dendritic injury, and synaptic loss need to be refined for the field to move forward in a rigorous fashion. We and others are attempting to develop translational approaches to assess these specific pathophysiological events in both animals and humans to facilitate clinically relevant pharmacodynamic assessments of candidate therapeutics. In this article, we review and discuss several of the recent experimental results from our lab and others. We include new initial data describing the difficulty in modeling progressive tau pathology in experimental rcTBI, and results demonstrating that sertraline can alleviate social interaction deficits and depressive-like behaviors following experimental rcTBI plus foot shock stress. Furthermore, we propose a discrete set of open, experimentally tractable questions that may serve as a framework for future investigations. In addition, we also raise several important questions that are less experimentally tractable at this time, in hopes that they may stimulate future methodological developments to address them.

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“…cerebral edema(CE), tissue hypoxia, seizures), treatment response, and outcomes. Genetic variability has been increasingly implicated in contributing to observed clinical variability after TBI[1,2]. …”

Section: Introductionmentioning

confidence: 99%

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

et al. 2016

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Objective Cerebral Edema (CE) in TBI is the consequence of multiple underlying mechanisms, and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for Sulfonylurea-receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNP) are predictive of CE. Methods DNA was extracted from 385 patients. SNPs in ABCC8 were genotyped using the Human Core Exome v1.2 (Illumina). CE measurements included acute CT edema, mean and peak intracranial pressure (ICP), and need for decompressive craniotomy. Results 14 SNPs with minor-allele frequency>0.2 were identified. 4 SNPS rs2283261, rs3819521, rs2283258 and rs1799857 were associated with CE measures. In multiple regression models, homozygote-variant genotypes in rs2283261, rs3819521, and rs2283258 had increased odds of CT edema (OR=2.45, p=0.007; OR=2.95, p=0.025; OR=3.00, p=0.013), had higher mean (β=3.13,p=0.000; β=2.95,p=0.005; β=3.20,p=0.008) and peak (β=8.00,p=0.001; β=7.64,p=0.007; β=6.89,p=0.034) ICP. The homozygote wild-type genotype of rs1799857 had decreased odds of decompressive craniotomy (OR=0.47, p=0.004). Conclusions This is the first report assessing the impact of ABCC8 genetic variability on CE development in TBI. Minor allele ABCC8 SNP genotypes had increased risk of CE, while major SNP alleles were protective—potentially suggesting an evolutionary advantage. These findings could guide risk stratification, treatment responders, and the development of novel targeted or gene-based therapies against CE in TBI and other neurological disorders.

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AQP4 Tag Single Nucleotide Polymorphisms in Patients with Traumatic Brain Injury

Cited by 57 publications

References 43 publications

Aquaporin Water Channels and Hydrocephalus

Aquaporin Water Channels and Hydrocephalus

The pathophysiology of repetitive concussive traumatic brain injury in experimental models; new developments and open questions

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

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