Astrocyte Swelling in Liver Failure: Role of Glutamine and Benzodiazepines

Norenberg, Michael D.; Bender, Alex S.

doi:10.1007/978-3-7091-9334-1_6

Cited by 77 publications

(66 citation statements)

References 10 publications

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“…It has been shown that pre-treatment of cultured astrocytes with the irreversible GS inhibitor, methionine sulfoximine (MSO), result in an attenuation in the increase in ammonia-induced glutamine and swelling (Norenberg and Bender, 1994). Similar results have been observed following ammonia-infusion in portacaval shunted rats pre-treated with MSO (Master et al, 1999 andWillard-Mack et al, 1996).…”

Section: Glutamine/glutamatementioning

confidence: 62%

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Bosoi

Rose

2013

Neurochemistry International

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Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that typically develops as a result of acute liver failure or chronic liver disease. Brain edema is a common feature associated with HE. In acute liver failure, brain edema contributes to an increase in intracranial pressure, which can fatally lead to brain stem herniation. In chronic liver disease, intracranial hypertension is rarely observed, even though brain edema may be present. This discrepancy in the development of intracranial hypertension in acute liver failure versus chronic liver disease suggests that brain edema plays a different role in relation to the onset of HE. Furthermore, the pathophysiological mechanisms involved in the development of brain edema in acute liver failure and chronic liver disease are dissimilar. This review explores the types of brain edema, the cells, and pathogenic factors involved in its development, while emphasizing the differences in acute liver failure versus chronic liver disease. The implications of brain edema developing as a neuropathological consequence of HE, or as a cause of HE, are also discussed. HighlightsBrain edema is a common feature in ALF and CLD. HE is inconsistently associated with the presence of brain edema. Fibrous and protoplasmic astrocytes are differentially implicated in the pathogenesis of HE. The pathogenesis of HE is multifactorial causing an array of neurological symptoms.

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Section: Glutamine/glutamatementioning

confidence: 62%

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Bosoi

Rose

2013

Neurochemistry International

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“…Indeed, both biochemical and spectroscopic studies in experimental liver failure [9] and [11] as well as in ammonia-treated cultured astrocytes [23] provide evidence for decreased brain myo-inositol concentrations concomitant with cell swelling. Results of the present study are consistent with these findings.…”

Section: Discussionmentioning

confidence: 99%

Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia

et al. 2004

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Zwingmann, C. et al., 2004. Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia. Brain Research, 999(1), ABSTRACTThe principal cause of mortality in patients with acute liver failure (ALF) is brain herniation resulting from intracranial hypertension caused by a progressive increase of brain water. In the present study, ex vivo highresolution 1 H-NMR spectroscopy was used to investigate the effects of ALF, with or without superimposed hypothermia, on brain organic osmolyte concentrations in relation to the severity of encephalopathy and brain edema in rats with ALF due to hepatic devascularization. In normothermic ALF rats, glutamine concentrations in frontal cortex increased more than fourfold at precoma stages, i.e. prior to the onset of severe encephalopathy, but showed no further increase at coma stages. In parallel with glutamine accumulation, the brain organic osmolytes myo-inositol and taurine were significantly decreased in frontal cortex to 63% and 67% of control values, respectively, at precoma stages (p<0.01), and to 58% and 67%, respectively, at coma stages of encephalopathy (p<0.01). Hypothermia, which prevented brain edema and encephalopathy in ALF rats, significantly attenuated the depletion of myo-inositol and taurine. Brain glutamine concentrations, on the other hand, did not respond to hypothermia. These findings demonstrate that experimental ALF results in selective changes in brain organic osmolytes as a function of the degree of encephalopathy which are associated with brain edema, and provides a further rationale for the continued use of hypothermia in the management of this condition.

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“…One explanation that has been proposed to explain ammonia-induced brain edema in ALF involves alterations in intracellular (astrocytic) osmolarity resulting from glutamine accumulation. In favor of this hypothesis, administration of the glutamine synthetase inhibitor, methionine sulfoximine, reduces ammonia-induced brain edema both in vitro 27 and in vivo. 28,29 However, in the present study, hypothermia-induced reductions in brain-water content in ALF rats were not accompanied by significant reductions of extracellular brain glutamine at time points associated with brain edema.…”

Section: Discussionmentioning

confidence: 99%

Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure

et al. 2000

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Mild hypothermia is effective in the prevention of brain edema associated with cerebral ischemia and traumatic brain injury. Brain edema is also a serious complication of acute liver failure (ALF). To assess the effectiveness of hypothermia in ALF, groups of rats were subjected to hepatic devascularization (portacaval anastomosis, followed 48 hours later by hepatic artery ligation), and body temperatures were maintained at either 35ЊC (hypothermic) or 37ЊC (normothermic). A major cause of death in patients with acute liver failure (ALF) is brain herniation resulting from raised intracranial pressure caused by a progressive increase in brain water content. 1 It has been estimated that up to 40% of patients with ALF die while on the waiting list for liver transplantation, 2 in whom, in almost all cases, death results from brain herniation. Despite several decades of investigation, the pathophysiological mechanisms responsible for the central nervous system consequences of ALF have not been fully elucidated. However, ammonia remains a prime candidate. Hyperammonemia is a consistent finding in experimental animal models of ALF resulting from hepatectomy, 3 hepatic devascularization, 4,5 or toxic liver injury 6 , and, in these cases, brain edema is invariably observed. In ALF, brain ammonia may reach millimolar concentrations, 7 and exposure of various in vitro brain preparations to millimolar concentrations of ammonia results in significant cell swelling. 8,9 Hyperammonemia is a feature of Reye' s Syndrome 10 and congenital urea cycle enzymopathies, 11 conditions in which cerebral edema is also consistently observed.Previous studies showed that hypothermia extended the survival time and prevented the development of brain edema in rats with ALF. 12 Furthermore, mild hypothermia (33°C-35°C) has been shown to be neuroprotective in experimental models of traumatic 13 and ischemic brain injury. 14 In the case of the latter, it was suggested that the beneficial effects of hypothermia were the result of inhibition of the release of neurotransmitters, rather than of an effect on cerebral energy metabolism. 15 The goals of the present investigation, therefore, were to study the effect of hypothermia on the development of hepatic encephalopathy and brain edema in relation to blood and cerebrospinal fluid (CSF) ammonia levels, and to extracellular glutamate and glutamine concentrations in rats with ALF caused by hepatic devascularization. MATERIALS AND METHODSO-phthaldialaldehyde reagent solution, 2-mercaptoethanol, Trisacetate, Ringer' s solution constituents, and amino acid standards were purchased from Sigma Chemical Co. (St. Louis, MO). Sodium phosphate (monobasic), methanol (high-performance liquid chromatography [HPLC]-grade), and tetrahydrofuran (HPLC-grade) were obtained from Anachemia (Montreal, Quebec, Canada). Doubledistilled deionized water was used for preparation of standard amino acid solutions and buffers. The mobile phase used for HPLC was filtered through 0.45-mm-pore-size membrane filters (Millipore Corp., B...

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Astrocyte Swelling in Liver Failure: Role of Glutamine and Benzodiazepines

Cited by 77 publications

References 10 publications

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia

Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure

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