Methionine Sulfoximine, a Glutamine Synthetase Inhibitor, Attenuates Increased Extracellular Potassium Activity during Acute Hyperammonemia

Sugimoto, Hideyoshi; Koehler, Raymond C.; Wilson, David A.; Brusilow, Saul W.; Traystman, Richard J.

doi:10.1097/00004647-199701000-00006

Cited by 65 publications

(38 citation statements)

References 47 publications

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“…Downregulation of Kir4.1/Kir5.1, and Cx43 expression could consequently result in reduction of potassium ion siphoning during HA and cause elevated extracellular potassium levels and water accumulation. Consistent with this hypothesis, an elevated extracellular K + concentration was measured in the parietal cortex of healthy rats made hyperammonemic by ammonium acetate infusion (Sugimoto et al, 1997).…”

Section: Discussionsupporting

confidence: 60%

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Lichter‐Konecki

Mangin

Gordish‐Dressman

et al. 2008

Glia

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Acute hyperammonemia (HA) causes cerebral edema and brain damage in children with urea cycle disorders (UCDs) and in patients in acute liver failure. Chronic HA is associated with developmental delay and mental retardation in children with UCDs, and with neuropsychiatric symptoms in patients with chronic liver failure. Astrocytes are a major cellular target of hyperammonemic encephalopathy, and changes occurring in these cells are thought to be causally related to the brain edema of acute HA. To study the effect of HA on astrocytes in vivo, we crossed the Otc spf mouse, a mouse with the X-linked UCD ornithine transcarbamylase (OTC) deficiency, with the hGFAP-EGFP mouse, a mouse selectively expressing green fluorescent protein in astrocytes. We used FACS to purify astrocytes from the brains of hyperammonemic and healthy Otc spf /GFAP-EGFP mice. RNA isolated from these astrocytes was used in microarray expression analyses and qRT-PCR. When compared with healthy littermates, we observed a significant downregulation of the gap-junction channel connexin 43 (Cx43) the water channel aquaporin 4 (Aqp4) genes, and the astrocytic inward-rectifying potassium channel (Kir) genes Kir4.1 and Kir5.1 in hyperammonemic mice. Aqp4, Cx43, and Kir4.1/ Kir5.1 are co-localized to astrocytic end-feet at the brain vasculature, where they regulate potassium and water transport.Since, ions can permeate water and K + -channels, downregulation of these three channels may be a direct effect of elevated blood ammonia levels. Our results suggest that alterations in astrocyte-mediated water and potassium homeostasis in brain may be key to the development of the brain edema.

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Section: Discussionsupporting

confidence: 60%

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Lichter‐Konecki

Mangin

Gordish‐Dressman

et al. 2008

Glia

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“…Alternatively, modifications in the interstitial levels of substances with potential vasoactive effects may occur as a result of glial swelling. Sugimoto et al 23 have shown a marked increase in brain extracellular potassium in hyperammonemic normal rats and have postulated that the uptake of potassium into the end-foot processes may be responsible for alterations in blood flow. 24 The explanation is somewhat unsatisfactory, because in their hands CBF was unchanged despite the marked extracellular potassium increase.…”

Section: Discussionmentioning

confidence: 99%

Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis

1999

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Two mechanisms may account for brain edema in fulminant hepatic failure: the osmotic effects of brain glutamine, a product of ammonia detoxification, and a change of cerebral blood flow (CBF). We have shown brain edema, a marked increase in brain glutamine, and a selective rise in CBF in rats after portacaval anastomosis receiving an ammonia infusion. In this study, we inhibited the activity of glutamine synthetase with methionine-sulfoximine (MSO) and examined ammonia levels, brain water and CBF. A major complication of fulminant hepatic failure (FHF) is the development of brain edema and intracranial hypertension, a leading cause of death in this syndrome. 1 The pathogenesis of the increase in brain water in the setting of a failing liver remains controversial. Over a decade of research in this area, 2 main theories have emerged. In the first, the accumulation of glutamine in glial cells would account for the development of brain edema. 2 Glutamine is the product of detoxification of ammonia, a reaction localized to astrocytes in view of the selective localization of glutamine synthetase to this cell. 3 Glial swelling is a prominent neuropathological feature of experimental 4 and human FHF. 5 Inhibition of glutamine synthesis with methionine-sulfoximine (MSO) prevents the development of ammonia-induced brain edema in normal rats, 6 decreases astrocyte swelling, 7 and ameliorates brain edema in rats after portacaval anastomosis receiving an ammonia infusion. 8 A second view emphasizes a pathogenic role for disturbances in the cerebral circulation. 9 A high cerebral blood flow (CBF) is noted in patients with FHF who develop brain edema. 10,11 In addition, failure of cerebrovascular autoregulation to changes in arterial pressure is also prominent in these subjects. 12 The possibility that this increase in CBF may be linked to brain edema is further supported by reports of selective abnormalities of the blood-brain barrier, a controversial observation in experimental models of FHF. 13,14 The rat after portacaval anastomosis receiving a continuous intravenous ammonia infusion is a well-standardized, controlled paradigm of brain edema, in which cerebral swelling occurs in the absence of acute liver failure. In this preparation, we have recently reported the simultaneous presence of a marked increase in brain glutamine and a selective 3-fold increase in cerebral perfusion at the time of an increase in brain water and intracranial pressure. 15 Furthermore, mild hypothermia (35°C, 33°C) prevented the development of brain edema in spite of a similar increase in brain glutamine as the normothermic animals. The main effect of hypothermia was to prevent the rise in CBF seen in the edematous, normothermic rats.If MSO ameliorates brain edema in this model by inhibiting glutamine synthesis and hypothermia also prevents brain swelling by normalizing CBF, it is of interest to determine the effects of MSO on cerebral perfusion. Normalization of CBF with MSO would suggest that the 2 postulated mechanisms of brain edema may in fac...

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“…They observed that the administration of methionine sulfoximine (MSO), an inhibitor of GS, 41 decreased the death rate of rats following acute ammonia intoxication. Subsequently, a reduction of cerebral glutamine accumulation by MSO was reported to reverse a number of pathophysiologic and metabolic manifestations of experimentally induced HE, including cerebral edema, 42,43 astrocyte swelling in vivo 44 and in cell culture, 45,46 elevated intracranial pressure, 43 increased cerebral blood flow, 16 enhanced extracellular potassium activity, 47 ammonia-induced reactive oxygen species (ROS) production 11,48 and the MPT. 20,21 MSO also reversed ammonia-induced seizures, 40 defects in glucose utilization, 49 and other cerebral metabolic disorders.…”

Section: Glutamine Is Harmfulmentioning

confidence: 99%

Glutamine: A Trojan horse in ammonia neurotoxicity

2006

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Mechanisms involved in hepatic encephalopathy still remain to be defined. Nonetheless, it is well recognized that ammonia is a major factor in its pathogenesis, and that the astrocyte represents a major target of its CNS toxicity. In vivo and in vitro studies have shown that ammonia evokes oxidative/nitrosative stress, mitochondrial abnormalities (the mitochondrial permeability transition, MPT) and astrocyte swelling, a major component of the brain edema associated with fulminant hepatic failure. How ammonia brings about these changes in astrocytes is not well understood. It has long been accepted that the conversion of glutamate to glutamine, catalyzed by glutamine synthetase, a cytoplasmic enzyme largely localized to astrocytes in brain, represented the principal means of cerebral ammonia detoxification. Yet, the "benign" aspect of glutamine synthesis has been questioned. This article highlights evidence that, at elevated levels, glutamine is indeed a noxious agent. We also propose a mechanism by which glutamine executes its toxic effects in astrocytes, the "Trojan horse" hypothesis. Much of the newly synthesized glutamine is subsequently metabolized in mitochondria by phosphate-activated glutaminase, yielding glutamate and ammonia. In this manner, glutamine (the Trojan horse) is transported in excess from the cytoplasm to mitochondria serving as a carrier of ammonia. We propose that it is the glutamine-derived ammonia within mitochondria that interferes with mitochondrial function giving rise to excessive production of free radicals and induction of the MPT, two phenomena known to bring about astrocyte dysfunction, including cell swelling. Future therapeutic approaches might include controlling excessive transport of newly synthesized glutamine to mitochondria and its subsequent hydrolysis. (HEPATOLOGY 2006;44:788-794.)

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Methionine Sulfoximine, a Glutamine Synthetase Inhibitor, Attenuates Increased Extracellular Potassium Activity during Acute Hyperammonemia

Cited by 65 publications

References 47 publications

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis

Glutamine: A Trojan horse in ammonia neurotoxicity

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