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Vasopressin V1a Receptors Regulate Cerebral Aquaporin 1 after Traumatic Brain Injury.

ABSTRACT: Brain edema formation contributes to secondary brain damage and unfavorable outcome after traumatic brain injury (TBI). Aquaporins (AQP), highly selective water channels, are involved in the formation of post-trauma brain edema; however, their regulation is largely unknown. Because vasopressin receptors are involved in AQP-mediated water transport in the kidney and inhibition of V1a receptors reduces post-trauma brain edema formation, we hypothesize that cerebral AQPs may be regulated by V1a receptors. Cerebral Aqp1 and Aqp4 messenger ribonucleic acid (mRNA) and AQP1 and AQP4 protein levels were quantified in wild-type and V1a receptor knockout (V1a-/-) mice before and 15?min, 1, 3, 6, 12, or 24?h after experimental TBI by controlled cortical impact. In non-traumatized mice, we found AQP1 and AQP4 expression in cortical neurons and astrocytes, respectively. Experimental TBI had no effect on Aqp4 mRNA or AQP4 protein expression, but increased Aqp1 mRNA (p?

SUBMITTER: Rauen K

PROVIDER: S-EPMC7045352 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Vasopressin V<sub>1a</sub> Receptors Regulate Cerebral Aquaporin 1 after Traumatic Brain Injury.

Rauen Katrin K Pop Viorela V Trabold Raimund R Badaut Jerome J Plesnila Nikolaus N

Journal of neurotrauma 20191204 4

Brain edema formation contributes to secondary brain damage and unfavorable outcome after traumatic brain injury (TBI). Aquaporins (AQP), highly selective water channels, are involved in the formation of post-trauma brain edema; however, their regulation is largely unknown. Because vasopressin receptors are involved in AQP-mediated water transport in the kidney and inhibition of V<sub>1a</sub> receptors reduces post-trauma brain edema formation, we hypothesize that cerebral AQPs may be regulated ...[more]

PMID: 31547764

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Project description:BackgroundTraumatic brain injury (TBI) initiates a complex sequence of destructive and neuroprotective cellular responses. The initial mechanical injury is followed by an extended time period of secondary brain damage. Due to the complicated pathological picture a better understanding of the molecular events occurring during this secondary phase of injury is needed. This study was aimed at analysing gene expression patterns following cerebral cortical contusion in rat using high throughput microarray technology with the goal of identifying genes involved in an early and in a more delayed phase of trauma, as genomic responses behind secondary mechanisms likely are time-dependent.ResultsAmong the upregulated genes 1 day post injury, were transcription factors and genes involved in metabolism, e.g. STAT-3, C/EBP-delta and cytochrome p450. At 4 days post injury we observed increased gene expression of inflammatory factors, proteases and their inhibitors, like cathepsins, alpha-2-macroglobulin and C1q. Notably, genes with biological function clustered to immune response were significantly upregulated 4 days after injury, which was not found following 1 day. Osteopontin and one of its receptors, CD-44, were both upregulated showing a local mRNA- and immunoreactivity pattern in and around the injury site. Fewer genes had decreased expression both 1 and 4 days post injury and included genes implicated in transport, metabolism, signalling, and extra cellular matrix formation, e.g. vitronectin, neuroserpin and angiotensinogen.ConclusionThe different patterns of gene expression, with little overlap in genes, 1 and 4 days post injury showed time dependence in genomic responses to trauma. An early induction of factors involved in transcription could lead to the later inflammatory response with strongly upregulated CD-44 and osteopontin expression. An increased knowledge of genes regulating the pathological mechanisms in trauma will help to find future treatment targets. Since trauma is a risk factor for development of neurodegenerative disease, this knowledge may also reduce late negative effects.

Project description:Background: A major contributor to unfavorable outcome after traumatic brain injury (TBI) is secondary brain injury. Low brain tissue oxygen tension (PbtO2) has shown to be an independent predictor of unfavorable outcome. Although PbtO2 provides clinicians with an understanding of the ischemic and non-ischemic derangements of brain physiology, its value does not take into consideration systemic oxygenation that can influence patients' outcomes. This study analyses brain and systemic oxygenation and a number of related indices in TBI patients: PbtO2, partial arterial oxygenation pressure (PaO2), PbtO2/PaO2, ratio of PbtO2 to fraction of inspired oxygen (FiO2), and PaO2/FiO2. The primary aim of this study was to identify independent risk factors for cerebral hypoxia. Secondary goal was to determine whether any of these indices are predictors of mortality outcome in TBI patients. Materials and Methods: A single-centre retrospective cohort study of 70 TBI patients admitted to the Neurocritical Care Unit (NCCU) at Cambridge University Hospital in 2014-2018 and undergoing advanced neuromonitoring including invasive PbtO2 was conducted. Three hundred and three simultaneous measurements of PbtO2, PaO2, PbtO2/PaO2, PbtO2/FiO2, PaO2/FiO2 were collected and mortality at discharge from NCCU was considered as outcome. Generalized estimating equations were used to analyse the longitudinal data. Results: Our results showed PbtO2 of 28 mmHg as threshold to define cerebral hypoxia. PaO2/FiO2 found to be a strong and independent risk factor for cerebral hypoxia when adjusting for confounding factor of intracranial pressure (ICP) with adjusted odds ratio of 1.78, 95% confidence interval of (1.10-2.87) and p-value = 0.019. With respect to TBI outcome, compromised values of PbtO2, PbtO2/PaO2, PbtO2/FiO2, and PaO2/FiO2 were all independent predictors of mortality while considered individually and adjusting for confounding factors of ICP, age, gender, and cerebral perfusion pressure (CPP). However, when considering all the compromised values together, only PaO2/FiO2 became an independent predictor of mortality with adjusted odds ratio of 3.47 (1.20-10.04) and p-value = 0.022. Conclusions: Brain and Lung interaction in TBI patients is a complex interrelationship. PaO2/FiO2 seems to be a major determinant of cerebral hypoxia and mortality. These results confirm the importance of employing ventilator strategies to prevent cerebral hypoxia and improve the outcome in TBI patients.

Dataset Information

Vasopressin V1a Receptors Regulate Cerebral Aquaporin 1 after Traumatic Brain Injury.

Publications

Vasopressin V<sub>1a</sub> Receptors Regulate Cerebral Aquaporin 1 after Traumatic Brain Injury.

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