A glutamine synthetase inhibitor increases survival and decreases cytokine response in a mouse model of acute liver failure

Jambekar, Amruta; Palma, Elena; Nicolosi, Luca; Rasola, Andrea; Petronilli, Valeria; Chiara, Federica; Bernardi, Paolo; Needleman, Richard; Brusilow, William S.A.

doi:10.1111/j.1478-3231.2011.02553.x

Cited by 20 publications

(14 citation statements)

References 54 publications

(57 reference statements)

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“…38 Furthermore, inhibition of this enzyme has recently been shown to increase survival and decrease cytokine response in a mouse model of acute liver failure. 39 In summary, we find that inhibition of GS during an acute ammonia load in rats enhances incorporation of 15 N into alanine mediated through the concerted action of GDH and ALAT. The increased ammonia fixation in alanine was in co-culture experiments demonstrated to occur in a dose-dependent manner, which is probably a direct result of the GS inhibition.…”

Section: Nhmentioning

confidence: 58%

Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

Dadsetan

Kukolj

Bak

et al. 2013

J Cereb Blood Flow Metab

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Hyperammonemia is a major etiological toxic factor in the development of hepatic encephalopathy. Brain ammonia detoxification occurs primarily in astrocytes by glutamine synthetase (GS), and it has been proposed that elevated glutamine levels during hyperammonemia lead to astrocyte swelling and cerebral edema. However, ammonia may also be detoxified by the concerted action of glutamate dehydrogenase (GDH) and alanine aminotransferase (ALAT) leading to trapping of ammonia in alanine, which in vivo likely leaves the brain. Our aim was to investigate whether the GS inhibitor methionine sulfoximine (MSO) enhances incorporation of 15 NH 4 þ in alanine during acute hyperammonemia. We observed a fourfold increased amount of 15 NH 4 incorporation in brain alanine in rats treated with MSO. Furthermore, co-cultures of neurons and astrocytes exposed to 15 NH 4 Cl in the absence or presence of MSO demonstrated a dose-dependent incorporation of 15 NH 4 into alanine together with increased 15 N incorporation in glutamate. These findings provide evidence that ammonia is detoxified by the concerted action of GDH and ALAT both in vivo and in vitro, a mechanism that is accelerated in the presence of MSO thereby reducing the glutamine level in brain. Thus, GS could be a potential drug target in the treatment of hyperammonemia in patients with hepatic encephalopathy.

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Section: Nhmentioning

confidence: 58%

Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

Dadsetan

Kukolj

Bak

et al. 2013

J Cereb Blood Flow Metab

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“…The neurotoxicity due to hyperammonemia is likely to be due at least in part to the excess production of glutamine and MSO decreases the amounts of this amino acid in vivo (Ghoddoussi et al 2010). Indeed, MSO protects against acute ammonia toxicity in rodents (Warren and Schenker 1964) and acute liver failure in rodents (Jambekar et al 2011). Thus, MSO may by extension be of use in the treatment of hyperammonemia in human patients.…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies indicate that MSO is therapeutic in the treatment of hyperammonemia and glutamate excitotoxicity. For example, in an acute murine model of liver disease, the animals were protected by prior administration of MSO (Warren and Schenker 1964, Jambekar et al 2011). Similarly, the chronic administration of MSO in a murine model of amyotrophic lateral sclerosis (ALS) increased the survival time of the affected animals (Ghoddoussi et al 2010, Bame et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine—relevance to the treatment of neurological diseases

Jeitner

Cooper

2013

Metab Brain Dis

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At high concentrations, the glutamine synthetase inhibitor L-methionine-S,R-sulfoximine is a convulsant, especially in dogs. Nevertheless, sub-convulsive doses of MSO are neuroprotective in rodent models of hyperammonemia, acute liver disease, and amyotrophic lateral sclerosis and suggest MSO may be clinically useful. Previous work has also shown that much lower doses of MSO are required to produce convulsions in dogs than in primates. Evidence from the mid-20th century suggests that humans are also less sensitive. In the present work, the inhibition of recombinant human glutamine synthetase with MSO is shown to be biphasic – an initial reversible competitive inhibition (Ki 1.19 mM) is followed by rapid irreversible inactivation. This Ki value for the human enzyme accounts, in part, for relative insensitivity of primates to MSO and suggests that this inhibitor could be used to safely inhibit glutamine synthetase activity in humans.

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“…Because MSO and NMDA-receptor antagonists protect the brain from ammonia toxicity by different mechanisms [15,39,44,45,51], we tested whether the combination of MSO and MK-801 is more effective in prolonging the survival of 4 dpf zebrafish in 4 mM NH 4 Ac than either drug alone. Only the lower dose of MSO was tested because 30 μM MSO appeared to be less effective than 10 μM MSO in protecting zebrafish from ammonia toxicity.…”

Section: Resultsmentioning

confidence: 99%

“…Methionine sulfoximine (MSO) is a suicide inhibitor of GS that could prevent the accumulation of glutamine in astrocytes [43]. Although MSO extended the survival of rats with hepatic encephalopathy [44,45], it may not be suitable for use as a drug because it also provoked seizures presumably due to interference with methionine metabolism in the brain [46–48]. MSO may also have undesirable side effects due to production of toxic metabolites since it could be a substrate for the cystathionine γ-lyase, L-amino acid oxidase and glutamate cysteine ligase [49,50].…”

Section: Introductionmentioning

confidence: 99%

A zebrafish model of hyperammonemia

Feldman¹,

Tuchman²,

Caldovic³

2014

Molecular Genetics and Metabolism

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Hyperammonemia is the principal consequence of urea cycle defects and liver failure, and the exposure of the brain to elevated ammonia concentrations leads to a wide range of neurocognitive deficits, intellectual disabilities, coma and death. Current treatments focus almost exclusively on either reducing ammonia levels through the activation of alternative pathways for ammonia disposal or on liver transplantation. Ammonia is toxic to most fish and its pathophysiology appears to be similar to that in mammals. Since hyperammonemia can be induced in fish simply by immersing them in water with elevated concentration of ammonia, we sought to develop a zebrafish (Danio rerio) model of hyperammonemia. When exposed to 3 mM ammonium acetate (NH4Ac), 50% of 4-day old (dpf) fish died within 3 hours and 4 mM NH4Ac was 100% lethal. We used 4 dpf zebrafish exposed to 4 mM NH4Ac to test whether the glutamine synthetase inhibitor methionine sulfoximine (MSO) and/or NMDA receptor antagonists MK-801, memantine and ketamine, which are known to protect the mammalian brain from hyperammonemia, prolong survival of hyperammonemic fish. MSO, MK-801, memantine and ketamine all prolonged the lives of the ammonia-treated fish. Treatment with the combination of MSO and an NMDA receptor antagonist was more effective than either drug alone. These results suggest that zebrafish can be used to screen for ammonia-neuroprotective agents. If successful, drugs that are discovered in this screen could complement current treatment approaches to improve the outcome of patients with hyperammonemia.

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A glutamine synthetase inhibitor increases survival and decreases cytokine response in a mouse model of acute liver failure

Abstract: These results demonstrate that the MSO target glutamine synthetase is required for the early steps of the cytokine response to endotoxins, and that its pharmacological inhibition may be exploited to treat inflammation.

Cited by 20 publications

References 54 publications

Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine—relevance to the treatment of neurological diseases

A zebrafish model of hyperammonemia

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