EFFECT OF METHIONINE AND METHIONINE SULPHOXIMINE ON RAT BRAIN <i>S</i>‐ADENOSYL METHIONINE LEVELS

Schatz, Robert A.; Sellinger, Otto Z.

doi:10.1111/j.1471-4159.1975.tb07628.x

Cited by 40 publications

(21 citation statements)

References 13 publications

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“…Seizures associated with MSO have been attributed to altered methylation because coadministration of L-methionine prevented the decrease in S-adenosylmethionine (26) and in the occurrence of seizures (10) without decreasing glutamine synthetase activity (27). In our experiments, L-methionine was coadministered with MSO to avoid the potential confounding influence of seizure activity.…”

Section: Discussionmentioning

confidence: 99%

Glutamine-dependent inhibition of pial arteriolar dilation to acetylcholine with and without hyperammonemia in the rat

Kawaguchi¹,

Brusilow²,

Traystman³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Glutamine has been shown to influence endothelial-dependent relaxation and nitric oxide production in vitro, possibly by limiting arginine availability, but its effects in vivo have not been well studied. Hyperammonemia is a pathophysiological condition in which glutamine is elevated and contributes to depressed CO 2 reactivity of cerebral arterioles. We tested thehypothesis that acute hyperammonemia decreases pial arteriolar dilation to acetylcholine in vivo and that this decrease could be prevented by inhibiting glutamine synthetase with L-methionine-S-sulfoximine (MSO) or by intravenous infusion of L-arginine. Pial arteriolar diameter responses to topical superfusion of acetylcholine were measured in anesthetized rats before and at 6 h of infusion of either sodium or ammonium acetate. Ammonium acetate infusion increased plasma ammonia concentration from 3 0 to ~ 600 μM and increased cerebral glutamine concentration fourfold. Arteriolar dilation to acetylcholine was intact after infusion of sodium acetate in groups pretreated with vehicle or with MSO plus methionine, which was coadministered to prevent MSO-induced seizures. In contrast, dilation in response to acetylcholine was completely blocked in hyperammonemic groups pretreated with vehicle or methionine alone. However, MSO plus methionine administration before hyperammonemia, which maintained cerebral glutamine concentration at control values, preserved acetylcholine dilation. Intravenous infusion of L-arginine during the last 2 h of the ammonium acetate infusion partially restored dilation to acetylcholine without reducing cerebral glutamine accumulation. Superfusion of 1 or 2 mM L-glutamine through the cranial window for 1 h in the absence of hyperammonemia attenuated acetylcholine dilation but had no effect on endothelialindependent dilation to nitroprusside. We conclude that 1) hyperammonemia reduces acetylcholineevoked dilation in cerebral arterioles, 2) this reduction depends on increased glutamine rather than ammonium ions, and 3) increasing arginine partially overcomes the inhibitory effect of glutamine. Keywordsarginine; cerebral circulation; endothelial-dependent dilation; hepatic encephalopathy; hyperammonemia; nitric oxide Patients with hepatic failure have been reported to have a depressed cerebrovascular response to hypercapnia (9). Depressed cerebral vasodilation to hypercapnia also has been observed in experimental models of acute hyperammonemia in a variety of species, including monkey, dog, cat, and rat (2,6,15,16,33 Hyperammonemia produces substantial increases in brain glutamine concentration (7). Inhibition of glutamine synthetase preserves cerebrovascular reactivity to hypercapnia and hypocapnia during acute hyperammonemia (13,15). Thus the loss of CO 2 reactivity is related to glutamine accumulation rather than to direct vascular effects of ammonium ions. Moreover, intravenous infusion of glutamine in the absence of hyperammonemia decreases hypercapnic vasodilation, although not to the same extent as hyperammonemia (22). The...

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Section: Discussionmentioning

confidence: 99%

Glutamine-dependent inhibition of pial arteriolar dilation to acetylcholine with and without hyperammonemia in the rat

Kawaguchi¹,

Brusilow²,

Traystman³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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“…To avoid the potential confounding influence of seizures, we co-administered L-methionine with MSO in an 8:1 molar ratio. Work by Sellinger et al (1968;Schatz and Sellinger, 1975;Sellinger et al, 1984) demonstrated that methionine coadministration at this ratio prevented MSO-induced seizures and associated reductions in Sadenosyl methionine without reducing the potency of GS inhibition by MSO.…”

Section: Astrocyte Swellingmentioning

confidence: 99%

“…injection of either 0.83 mmol/kg of MSO (Sigma-Aldrich, St. Louis, MO, USA) or sterile saline vehicle (2.5 ml/kg). L-Methionine (6.7 mmol/kg) was co-injected with MSO at a molar ratio of 8:1 to prevent seizures associated with high doses of MSO (Sellinger et al, 1968(Sellinger et al, , 1984Schatz and Sellinger, 1975). L-Methionine was dissolved in 100 mmol/l NaOH and titrated to a pH of 7.6 with HCl.…”

Section: Experimental Procedures Experimental Protocolmentioning

confidence: 99%

Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats

et al. 2005

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Inhibition of glutamine synthesis reduces astrocyte swelling and associated physiological abnormalities during acute ammonium acetate infusion in anesthetized rats. We tested the hypothesis that inhibition of glutamine accumulation during more prolonged ammonium acetate infusion in unanesthetized rats reduces cortical astrocyte swelling and immunohistochemical changes in astrocytic proteins. Rats received a continuous i.v. infusion of either sodium acetate or ammonium acetate for 24 h to increase plasma ammonia from about 30-400 μmol/l. Cohorts were pretreated with vehicle or L-methionine-S-sulfoximine (MSO; 0.83 mmol/kg). MSO reduced glutamine synthetase activity by 57% and glutamine synthetase immunopositive cell number by 69%, and attenuated cortical glutamine accumulation by 71%. Hyperammonemia increased the number of swollen astrocytes in cortex and MSO reduced this increase to control values. The number of glial fibrillary acidic protein immunopositive cells in cortex was greater in hyperammonemic rats and the increase in superficial cortical layers was attenuated by MSO. Immunoreactivity for the gap junction protein connexin-43 in the neuropil, assessed by optical density, was greater in the hyperammonemic group compared with controls, but this increase was not attenuated by MSO. No changes in the optical density of GLT1 glutamate transporter immunoreactivity in cortex were detected in any group. We conclude that glutamine synthetase inhibition reduces astrocyte swelling and ameliorates some of the reactive astroglial cytoskeletal alterations seen at 24 h of hyperammonemia, but that gap junction changes in astrocytes occur independently of glutamine accumulation and swelling. Keywords ammonia; astrocyte; connexin; cerebral edema; glial fibrillary acidic protein; glutamine Astrocyte swelling is a distinctive feature of the histological finding in humans who die from severe liver disease or urea cycle disorders. Experimental models of liver dysfunction and hyperammonemia are also marked by watery swelling of astrocytes and cellular hypertrophy of astrocyte cell bodies without necessarily presenting with overt neuronal pathology. Thus, hyperammonemia is considered to be a major factor contributing to the cellular changes seen in severe hepatic encephalopathy (Norenberg, 1998 Tracer studies reveal that blood-borne ammonia is rapidly incorporated into brain glutamine, and that this process is markedly slowed in vivo by inhibiting glutamine synthetase (GS) with methionine sulfoximine (MSO), thereby disrupting compartmentation of nitrogen metabolism (Cooper et al., 1979). Based on the observations 1) that increased brain glutamine concentration is one of the most consistent biochemical change seen both clinically and experimentally with liver disease, urea cycle disorders or pure hyperammonemia (Cooper, 2001), and 2) that GS is enriched in astrocytes (Norenberg and Martinez-Hernandez, 1979), we postulated that glutamine accumulated in astrocytes may act as an osmolyte that contributes to astrocyte swelli...

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“…These have included studies on the effect of MSO on the cerebral metabolism of amino acids and ammonia (1-8), brain amines (9, 10), glycogen ( cortical slices (19), rat brain S-adenosyl-L-methionine levels (20), mouse cerebellar ammonia (7), and rat brain glutamine synthetase (3). MSO and methionine have also been shown to be uptake antagonists (21,22).…”

Section: Introductionmentioning

confidence: 99%

The effect of methionine on the uptake, distribution, and binding of the convulsant methionine sulfoximine in the rat

1976

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The effect of methionine on the uptake, distribution, and binding of the convulsant methionine sulfoximine (MSO) in 7 rat brain regions, the spinal cord, the liver, and the kidney was investigated. The administration of methionine decreased the uptake of MSO in all brain regions. The uptake of MSO by and its distribution in the nervous tissue was uniform and failed to result in any preferential accumulation of the drug. Methionine decreased the amount of MSO bound to cerebral structures and to the spinal cord. MSO bound to the spinal cord was less susceptible to release by Triton X-100 than was brain-bound MSO.

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EFFECT OF METHIONINE AND METHIONINE SULPHOXIMINE ON RAT BRAIN S‐ADENOSYL METHIONINE LEVELS

Cited by 40 publications

References 13 publications

Glutamine-dependent inhibition of pial arteriolar dilation to acetylcholine with and without hyperammonemia in the rat

Glutamine-dependent inhibition of pial arteriolar dilation to acetylcholine with and without hyperammonemia in the rat

Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats

The effect of methionine on the uptake, distribution, and binding of the convulsant methionine sulfoximine in the rat

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