Abstract
Hepatic encephalopathy is a major complication of cirrhosis. Ammonia and manganese have been associated with hepatic encephalopathy underlying mechanisms. Motor impairment and brain edema are common signs of hepatic encephalopathy. In the present study a model of liver damage in rats was combined with ammonia and manganese exposure to evaluate the role of these substances separately and their interactions on brain glutamine, water content and motor coordination. Additionally, we explored brain levels of each substance -Mn and ammonia- in the presence or absence of the other. Liver damage was induced by bile duct ligation. Rats were exposed to MnCl2 in drinking water (1 mg Mn/ml) and to ammonia in chow pellets containing 20% ammonium acetate (w/w). As expected, manganese and ammonia levels increased in the brain of cirrhotic rats exposed to these substances; in these animals, glutamine brain levels also increased and positively correlated with tissue water content in cortex. A three way-ANOVA showed that manganese favored ammonia and glutamine accumulation in brain, and possibly their subsequent deleterious effects, as evidenced by the fact that manganese and ammonia accumulation in the brain of cirrhotic rats severely affected motor function. These results suggest that even when controlling ammonia levels in cirrhotic patients, reduction of manganese intake is also a potential strategy to be considered in clinical practice.
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References
Butterworth RF (2003) Hepatic encephalopathy. Alcohol Res Health 27:240–246
Butterworth RF (2008) Pathophysiology of hepatic encephalopathy: the concept of synergism. Hepatol Res 38(suppl.1):S116–S121
Jones EA, Weissenborn K (1997) Neurology and the liver. J Neurol Neurosurg Psychiatry 63:279–293
Chrzanowska A, Gajewska B, Baranczyk-Kuzma A (2009) Arginase isoenzymes in human cirrhotic liver. Acta Biochim Pol 56:465–469
Schroeter JD, Nong A, Yoon M, Taylor MD, Dorman DC, Andersen ME, Clewell HJ 3rd (2011) Analysis of manganese tracer kinetics and target tissue dosimetry in monkeys and humans with multi-route physiologically-based pharmacokinetic models. Toxicol Sci 120:481–498
Norenberg MD, Martinez-Hernandez A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 161:303–310
Aschner M, Vrana KE, Zheng W (1999) Manganese uptake and distribution in the central nervous system (CNS). Neurotoxicology 20:173–180
Aschner JL, Aschner M (2005) Nutritional aspects of manganese homeostasis. Mol Aspects Med 26:353–362
Watanabe A, Takei N, Higashi T, Shiota T, Nakatsukasa H, Fujiwara M, Sakata T, Nagashima H (1984) Glutamic acid and glutamine levels in serum and cerebrospinal fluid in hepatic encephalopathy. Biochem Med 32:225–231
Jalan R, Shawcross D, Davies N (2003) The molecular pathogenesis of hepatic encephalopathy. Int J Biochem Cell Biol 35:1175–1181
Montes S, Alcaraz-Zubeldia M, Muriel P, Ríos C (2003) Role of manganese accumulation in increased brain glutamine of the cirrhotic rat. Neurochem Res 28:911–917
Bender AS, Norenberg MD (1996) Effects of ammonia on l-glutamate uptake in cultured astrocytes. Neuchem Res 21:567–573
Hazell AS, Norenberg MD (1997) Manganese decreases glutamate uptake in cultured astrocytes. Neuchem Res 22:1443–1447
Panickar KS, Jayakumar AR, Rama Rao KV, Norenberg MD (2007) Downregulation of the 18-kDa translocator protein: effects on the ammonia-induced mitochondrial permeability transition and cell swelling in cultured astrocytes. Glia 55:1720–1727
Rama Rao KV, Reddy PVB, Hazell AS, Norenberg MD (2007) Manganese induces cell swelling in cultured astrocytes. Neurotoxicology 28:807–812
Hazell AS, Normandin L, Norenberg MD, Kennedy G, Ji JH (2006) Alzheimer type II astrocytic changes following sub-acute exposure to manganese and its prevention by antioxidant treatment. Neurosci Lett 396:167–171
Norenberg MD (1987) The role of astrocytes in hepatic encephalopathy. Neurochem Pathol 6:13–33
Jayakumar AR, Rao KVR, Kalaiselvi P, Norenberg MD (2004) Combined effects of ammonia and manganese on astrocytes in culture. Neurochem Res 29:2051–2056
Norenberg M, Rama Rao KV, Jayakumar AR (2004) Ammonia neurotoxicity and the mitochondrial permeability transition. J Bioenerg Biomembr 36:303–307
Rao KV, Norenberg MD (2004) Manganese induces the mitochondrial permeability transition in cultured astrocytes. J Biol Chem 279:32333–32338
Montes S, Alcaraz-Zubeldia M, Ríos C, Muriel P (2002) A method to induce manganese accumulation in the brain of the cirrhotic rat and its evaluation. Brain Res Brain Res Protoc 9:9–15
Jover R, Rodrigo R, Felipo V, Insausti R, Sáez-Valero J, García-Ayllón MS, Suárez I, Candela A, Compañ A, Esteban A, Cauli O, Ausó E, Rodríguez E, Gutiérrez A, Girona E, Erceg S, Berbel P, Pérez-Mateo M (2006) Brain edema and inflammatory activation in bile duct ligated rats with diet-induced hyperammonemia: a model of hepatic encephalopathy in cirrhosis. Hepatology 43:1257–1266
Sponner RJ, Toseland PA, Goldberg DM (1975) The fluorometric determination of ammonia in protein-free filtrates of human blood plasma. Clin Chim Acta 65:47–55
Marmarou A, Poll W, Shulman K, Bhagavan H (1978) A simple gravimetric technique for measurement of cerebral edema. J Neurosurg 49:530–537
Chen SF, Hsu CW, Huang WH, Wang JY (2008) Post-injury baicalein improves histological and functional outcomes and reduces inflammatory cytokines after experimental traumatic brain injury. Br J Pharmacol 155:1279–1296
Montgomery DC (2001) Design and analysis of experiments. Wiley, New York
Peneder TM, Scholze P, Berger ML, Reither H, Heinze G, Bertl J, Bauer J, Richfield EK, Hornykiewicz O, Pifl C (2011) Chronic exposure to manganese decreases striatal dopamine turnover in human alpha-synuclein transgenic mice. Neuroscience 180:280–292
Hennenberg M, Trebicka J, Kohistani Z, Stark C, Nischalke HD, Kramer B, Korner C, Klein S, Granzow M, Fischer HP, Heller J, Sauerbruch T (2010) Hepatic and HSC-specific sorafenib effects in rats with established secondary biliary cirrhosis. Lab Invest 91:241–251
Kountouras J, Billing BH, Scheuer PJ (1984) Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Br J Exp Pathol 65:305–311
Rivera-Mancia S, Montes S, Mendez-Armenta M, Muriel P, Rios C (2009) Morphological changes of rat astrocytes induced by liver damage but not by manganese chloride exposure. Metab Brain Dis 24:243–255
Klos KJ, Ahlskog JE, Kumar N, Cambern S, Butz J, Burritt M, Fealey RD, Cowl CT, Parisi JE, Josephs KA (2006) Brain metal concentrations in chronic liver failure patients with pallidal T1 MRI hyperintensity. Neurology 67:1984–1989
Pomier-Layrargues G, Spahr L, Butterworth RF (1995) Increased manganese concentrations in pallidum of cirrhotic patients. Lancet 345:735
Ott P, Larsen FS (2004) Blood-brain barrier permeability to ammonia in liver failure: a critical reappraisal. Neurochem Int 44:185–198
Nagaraja TN, Brookes N (1998) Intracellular acidification induced by passive and active transport of ammonium ions in astrocytes. Am J Physiol 274:C883–C891
Gagnon KB, England R, Delpire E (2006) Characterization of SPAK and OSR1, regulatory kinases of the Na-K-2Cl cotransporter. Mol Cell Biol 26:689–698
Laubenberger J, Häussinger D, Bayer S, Gufler H, Hennig J, Langer M (1997) Proton magnetic resonance spectroscopy of the brain in symptomatic and asymptomatic patients with liver cirrhosis. Gastroenterology 112:1610–1616
Jayakumar AR, Rao KV, Murthy C, Norenberg MD (2006) Glutamine in the mechanism of ammonia-induced astrocyte swelling. Neurochem Int 48:623–628
Albrecht J, Zielinska M, Norenberg MD (2010) Glutamine as a mediator of ammonia neurotoxicity: a critical appraisal. Biochem Pharmacol 80:1303–1308
Cordoba J, Alonso J, Rovira A, Jacas C, Sanpedro F, Castells L, Vargas V, Margarit C, Kulisewsky J, Esteban R, Guardia J (2001) The development of low-grade cerebral edema in cirrhosis is supported by the evolution of (1)H-magnetic resonance abnormalities after liver transplantation. J Hepatol 35:598–604
Häussinger D, Kircheis G, Fischer R, Schliess F, vom Dahl S (2000) Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema? J Hepatol 32:1035–1038
Poveda MJ, Bernabeu A, Concepcion L, Roa E, de Madaria E, Zapater P, Perez-Mateo M, Jover R (2010) Brain edema dynamics in patients with overt hepatic encephalopathy: a magnetic resonance imaging study. Neuroimage 52:481–487
Yadav SK, Srivastava A, Srivastava A, Thomas MA, Agarwal J, Pandey CM, Lal R, Yachha SK, Saraswat VA, Gupta RK (2010) Encephalopathy assessment in children with extra-hepatic portal vein obstruction with MR, psychometry and critical flicker frequency. J Hepatol 52:348–354
Spahr L, Vingerhoets F, Lazeyras F, Delavelle J, DuPasquier R, Giostra E, Mentha G, Terrier F, Hadengue A (2000) Magnetic resonance imaging and proton spectroscopic alterations correlate with parkinsonian signs in patients with cirrhosis. Gastroenterology 119:774–781
Guilarte TR, Chen MK, McGlothan JL, Verina T, Wong DF, Zhou Y, Alexander M, Rohde CA, Syversen T, Decamp E, Koser AJ, Fritz S, Gonczi H, Anderson DW, Schneider JS (2006) Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates. Exp Neurol 202:381–390
Rodrigo R, Cauli O, Gomez-Pinedo U, Agusti A, Hernandez-Rabaza V, Garcia-Verdugo JM, Felipo V (2010) Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology 139:675–684
Pentschew A, Ebner FF, Kovatch RM (1963) Experimental manganese encephalopathy in monkeys. J Neuropathol Exp Neurol 22:488–499
Ponzoni S, Guimarães FS, Del Bel EA, Garcia-Cairasco N (2000) Behavioral effects of intra-nigral microinjections of manganese chloride: interaction with nitric oxide. Prog Neuropsychopharmacol Biol Psychiatry 24:307–325
Witholt R, Gwiazda RH, Smith DR (2000) The neurobehavioral effects of subchronic manganese exposure in the presence and absence of pre-parkinsonism. Neurotoxicol Teratol 22:851–861
Acknowledgments
This work was financially supported by Consejo Nacional de Ciencia y Tecnología (CONACYT) grant No. 51541. S. Rivera-Mancía wants to thank the Biomedical Research Graduate Program, the Biomedical Research Institute and the National Autonomous University of Mexico for their support to carry out this work. Authors wish to thank Marisela Méndez-Armenta for liver histological preparations, Yessica Heras ans Rodolfo Pérez-Madrigal for their assistance in animal care and Elena Rivera-Mancía for reviewing this manuscript. S Rivera-Mancía receives a fellowship from CONACYT (203330). Instruments acquired with CONACYT grant 61327 were used to carry out this study.
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The authors declare that they have no conflict of interest.
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Rivera-Mancía, S., Ríos, C. & Montes, S. Manganese and Ammonia Interactions in the Brain of Cirrhotic Rats: Effects on Brain Ammonia Metabolism. Neurochem Res 37, 1074–1084 (2012). https://doi.org/10.1007/s11064-012-0710-8
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DOI: https://doi.org/10.1007/s11064-012-0710-8