Abstract
Congenital deficiencies of the urea cycle enzyme ornithine transcarbamylase (OTC) result in chronic hyperammonemia and severe neurological dysfunction including seizures and mental retardation. As part of a series of studies to elucidate the pathophysiologic mechanisms responsible for the CNS consequences of OTC deficiency, concentrations of ammonia-related and neurotransmitter amino acids were measured as their o-phthalaldehyde derivatives using high performance liquid chromatography with fluorescence detection in regions of the brains of sparse-fur (spf) mice, a mutant with an X-linked inherited defect of OTC. Compared to CD-1/Y controls, the brains of spf/Y mutant mice contained significant alterations of several amino acids. A generalized, up to 2-fold, increase of brain glutamine was observed, consistent with the exposure of these brains to increased concentrations of ammonia. Significant increases of brain alanine were also observed and, together with previous reports of increased concentrations of α-ketoglutarate, are consistent with ammonia-induced inhibition of α-ketoglutarate dehydrogenase in the brains of spf/Y mice. Increased brain content of the excitatory amino acid aspartate coul be responsible for the seizures frequently encountered in congenital OTC deficiency.
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atshaw, M.L. and Hyman, S.L., Coyle, J.T., Robinson, M.B., Qureshi, I.A., Mellits, E.D and Quaskey, S. (1988). Effect of sodium benzoate and sodium phenylacetate on brain serotonin turnover in the ornithine transcarbamylase-deficient sparse-fur mouse.Pediatr. Res. 23:368–374.
Butterworth, R.F., Merkel, A.D and Landreville, F. (1982). Regional amino acid distribution in relation to function in insulin hypoglycaemia.J. Neurochem. 38:1483–1489.
Butterworth, R.F and Giguère, J.F. (1986). Cerebral amino acids in portal-systemic encephalopathy: Lack of evidence for altered γ-amino butyric acid (GABA) function.Metab. Brain Dis. 1:221–228.
Butterworth, R.F., Giguère, J.F., Michaud, J., Lavoie, J and Pomier Layrargues, G. (1987). Ammonia: Key factor in the pathogenesis of hepatic encephalopathy.Neurochem. Pathol. 6:1–12.
DeMars, R., LeVan, S.L., Trend, B.L and Russell, L.B. (1976). Abnormal ornithine carbamyltransferase in mice having the sparse-fur mutation.Proc. Natl. Acad. Sci. USA.73:1693–1697.
Dolman, C.L., Clasen, R.A and Dorovini-Zis, K. (1988). Severe cerebral damage in ornithine transcarbamylase deficiency.Clin Neuropathol. 7:10–15.
Giguère, J.F and Butterworth, R.F. (1984). Amino acid changes in regions of the CNS in relation to function in experimental portal-systemic encephalopathy.Neurochem. Res. 9:1309–1321.
Harding B.N., Leonard, J.V and Erdohazi, M. (1984). Ornithine carbamyltransferase deficiency. A neuropathological study.Pediatrics.141:215–220.
Hawkins, R.A and Mans, A.M. (1989). Brain energy metabolism in hepatic encephalopathy. In:Hepatic Encephalopathy (R.F. Butterworth and G. Pomier Layrargues, eds.), Humana Press Inc., Clifton, New Jersey, pp. 159–176.
Inoue, I., Gushiken, T., Kobayashi, K and Saheki, T. (1987). Accumulation of large neutral amino acids in the brain of sparse-fur mice at hyperammonemic state.Biochem. Med. Metab. Biol. 38:378–386.
Jessy, J., Mans, A.M., De Joseph, M.R and Hawkins, R.A. (1990). Hyperammonemia causes many of the changes found after portacaval shunting.Biochem. J. 272:311–317.
Lai, J.C.K. and Cooper, A.J.L. (1986). Brain α-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution and effects of inhibitors.J. Neurochem. 47:1376–1386.
Lavoie, J., Giguère, J.F., Pomier Layrargues, G and Butterworth, R.F. (1987). Amino acid changes in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy.J. Neurochem. 49:692–697.
Norenberg, M.D. (1979). The distribution of glutamine synthetase in the rat central nervous system.J. Histochem. Cytochem. 27:756–762.
Qureshi, I.A., Letarte, J and Ouellet, R. (1978). Study of enzyme defect in a case of ornithine transcarbamylase deficiency.Diab. Metab. (Paris) 4:239–241.
Qureshi, I.A., Letarte, J and Ouellet, R. (1979). Ornithine transcarbamylase deficiency in mutant mice. 1. Studies on the characterization of enzyme defect and suitability as animal model of human disease.Pediatr. Res. 13:807–811.
Qureshi, I.A. (1992). Animal models of hereditary hyperammonemia. In:Animal Models of Neurological Disease (A. Boulton, G. Baker and R.F. Butterworth (eds)), Humana Press Inc., Clifton, New Jersey, pp. 329–356.
Qureshi, I.A., Ratnakumari, L and Butterworth, R.F. (1993). Cerebral glutamine synthetase and glutamate dehydrogenase in congenitally hyperammonemic sparse-fur (spf/Y) mice: Effect of acetyl-L-carnitine.Hepato-Gastroenterology.40:XXII (in press).
Ratnakumari, L., Qureshi, I.A. and Butterworth, R.F. (1992). Effects of congenital hyperammonemia on the cerebral and hepatic levels of the intermediates of energy metabolism in spf mice.Biochem. Biophys. Res. Commn. 184:746–751.
Ratnakumari, L., Qureshi, I.A and Butterworth, R.F. (1993). Evidence for a severe cholinergic neuronal deficit in brain in congenital ornithine transcarbamylase (OTC) deficiency. Soc. Neurosci. Abst.19:122.13.
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Ratnakumari, L., Qureshi, I.A. & Butterworth, R.F. Regional amino acid neurotransmitter changes in brains of spf/Y mice with congenital ornithine transcarbamylase deficiency. Metab Brain Dis 9, 43–51 (1994). https://doi.org/10.1007/BF01996073
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DOI: https://doi.org/10.1007/BF01996073