Brain Aquaporin-4 in Experimental Acute Liver Failure

Rao, Kakulavarapu V. Rama; Jayakumar, Arumugam R.; Tong, Xiaoying; Curtis, Kevin M.; Norenberg, Michael D.

doi:10.1097/nen.0b013e3181ebe581

Cited by 51 publications

(43 citation statements)

References 81 publications

(84 reference statements)

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“…A study by Wright et al (Wright et al, 2010), found no change in total tissue levels of AQP4 in brain in a rat model of ALF induced by galactosamine, which is in agreement with observations by other investigators (Eefsen et al, 2010; Rama Rao et al, 2010). Based on this finding, these investigators postulated that AQP4 plays no role in the brain edema in ALF.…”

Section: Discussionsupporting

confidence: 88%

“…However, this study, did not examine levels of AQP4 in the plasma membrane, the site where AQP4 facilitates water movement. Such plasma membrane increase in AQP4 was found in brains of rats with ALF (Eefsen et al, 2010; Rama Rao et al, 2010). Complementary to our observations, a recent study also reported increased plasma membrane levels of AQP4 in human postmortem cerebral cortex from patients with ALF (Thumburu et al, 2013).…”

Section: Discussionmentioning

confidence: 66%

“…A similar finding was also reported by Bodega et al (Bodega et al, 2012). More recently, two reports have documented increased brain plasma membrane levels of AQP4 in rats with ALF without any change in total tissue AQP4 protein (Eefsen et al, 2010; Rama Rao et al, 2010). …”

Section: Discussionmentioning

confidence: 99%

“…Additionally, silencing AQP4 in cultured astrocytes prevented the cell swelling following exposure to ammonia (Rama Rao et al, 2010). An increase in brain plasma membrane AQP4 was also documented in experimental ALF (Eefsen et al, 2010; Rama Rao et al, 2010). Together, these studies invoke a major role for AQP4 in the astrocyte swelling/brain edema associated with ALF.…”

Section: Introductionmentioning

confidence: 99%

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Aquaporin-4 deletion in mice reduces encephalopathy and brain edema in experimental acute liver failure

Rao

Curtis

Norenberg

2014

Neurobiology of Disease

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Brain edema and associated astrocyte swelling leading to increased intracranial pressure are hallmarks of acute liver failure (ALF). Elevated blood and brain levels of ammonia have been implicated in the development of brain edema in ALF. Cultured astrocytes treated with ammonia have been shown to undergo cell swelling and such swelling was associated with an increase in the plasma membrane expression of aquaporin-4 (AQP4) protein. Further, silencing the AQP4 gene in cultured astrocytes was shown to prevent the ammonia-induced cell swelling. Here, we examined the evolution of brain edema in AQP4-null mice and their wild type counterparts (WT-mice) in different models of ALF induced by thioacetamide (TAA) or acetaminophen (APAP). Induction of ALF with TAA or APAP significantly increased brain water content in WT mice (by 1.6 ± 0.3 and 2.3 ± 0.4 %, respectively). AQP4 protein was significantly increased in brain plasma membranes of WT mice with ALF induced by either TAA or APAP. In contrast to WT-mice, brain water content did not increase in AQP4-null mice. Additionally, AQP4-null mice treated with either TAA or APAP showed a remarkably lesser degree of neurological deficits as compared to WT mice; the latter displayed an inability to maintain proper gait, and demonstrated a markedly reduced exploratory behavior, with the mice remaining in one corner of the cage with its head tilted downwards. These results support a central role of AQP4 in the brain edema associated with ALF.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aquaporin-4 deletion in mice reduces encephalopathy and brain edema in experimental acute liver failure

Rao

Curtis

Norenberg

2014

Neurobiology of Disease

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“…Aquaporin-4 has been implicated in the development of brain edema in ALF (Eefsen et al, 2010; Rama Rao et al, 2010). However, the role of aquaporin channels in ALF is uncertain (Wright et al, 2010).…”

Section: Increased Bbb Permeability Occurs Without Overt Bbb Breakdowmentioning

confidence: 99%

Blood–brain barrier in acute liver failure

Nguyen

2012

Neurochemistry International

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Brain edema remains a challenging obstacle in the management of acute liver failure (ALF). Cytotoxic mechanisms associated with brain edema have been well recognized, but evidence for vasogenic mechanisms in the pathogenesis of brain edema in ALF has been lacking. Recent reports have not only shown a role of matrix metalloproteinase-9 in the pathogenesis of brain edema in experimental ALF but have also found significant alterations in the tight junction elements including occludin and claudin-5, suggesting a vasogenic injury in the blood-brain barrier (BBB) integrity. This article reviews and explores the role of the paracellular tight junction proteins in the increased selective BBB permeability that leads to brain edema in ALF.

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Hypermagnesemia does not prevent intracranial hypertension and aggravates cerebral hyperperfusion in a rat model of acute hyperammonemia

et al. 2011

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Intravenous infusion of magnesium sulfate prevents seizures in patients with eclampsia and brain edema after traumatic brain injury. Neuroprotection is achieved by controlling cerebral blood flow (CBF), intracranial pressure, neuronal glutamate release, and aquaporin-4 (Aqp4) expression. These factors are also thought to be involved in the development of brain edema in acute liver failure. We wanted to study whether hypermagnesemia prevented development of intracranial hypertension and hyperperfusion in a rat model of portacaval anastomosis (PCA) and acute hyperammonemia. We also studied whether hypermagnesemia had an influence on brain content of glutamate, glutamine, and aquaporin-4 expression. The study consisted of three experiments: The first was a dose-finding study of four different dosing regimens of magnesium sulfate (MgSO 4 ) in healthy rats. The second involved four groups of PCA rats receiving ammonia infusion/vehicle and MgSO 4 /saline. The effect of MgSO 4 on mean arterial pressure (MAP), intracranial pressure (ICP), CBF, cerebral glutamate and glutamine, and aquaporin-4 expression was studied. Finally, the effect of MgSO 4 on MAP, ICP, and CBF was studied, using two supplementary dosing regimens. In the second experiment, we found that hypermagnesemia and hyperammonemia were associated with a significantly higher CBF (P < 0.05, twoway analysis of variance [ANOVA]). Hypermagnesemia did not lead to a reduction in ICP and did not affect the brain content of glutamate, glutamine, or Aqp-4 expression. In the third experiment, we achieved higher P-Mg but this did not lead to a significant reduction in ICP or CBF. Conclusion: Our results demonstrate that hypermagnesemia does not prevent intracranial hypertension and aggravates cerebral hyperperfusion in rats with PCA and hyperammonemia. (HEPATOLOGY 2011;53:1986-1994 A cute liver failure (ALF) is a condition with a substantial mortality rate because of a high risk of multiple organ failure. Of special interest are the cerebral complications in ALF that in the most severe cases can progress to cerebral edema, intracranial hypertension, and ultimately cerebral incarceration. The genesis for these cerebral complications is among other factors related to persistent hyperammonemia, 1,2 systemic inflammation, 2,3 and electrolyte disturbances 4 and is associated with cerebral hyperperfusion and loss of autoregulation of the cerebral blood flow (CBF). 5The complex and multifactorial nature has made the understanding of the pathogenesis of brain edema difficult. Both the therapeutic and prophylactic strategies related to brain edema in ALF are few and limited in efficacy. During surges of high intracranial pressure (ICP), intervention with mannitol, hypertonic saline, hyperventilation, hypothermia, and indomethacin has demonstrated a temporary beneficial effect on intracranial hypertension. 6,7 Recently, ammonia-lowering therapy with the compound of L-ornithine and phenylacetate has shown promising data in animal studies, 8 but no human data have yet been publishe...

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Brain Aquaporin-4 in Experimental Acute Liver Failure

Cited by 51 publications

References 81 publications

Aquaporin-4 deletion in mice reduces encephalopathy and brain edema in experimental acute liver failure

Aquaporin-4 deletion in mice reduces encephalopathy and brain edema in experimental acute liver failure

Blood–brain barrier in acute liver failure

Hypermagnesemia does not prevent intracranial hypertension and aggravates cerebral hyperperfusion in a rat model of acute hyperammonemia

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