Metabolic Brain Disease

, Volume 24, Issue 2, pp 243–255 | Cite as

Morphological changes of rat astrocytes induced by liver damage but not by manganese chloride exposure

  • Susana Rivera-Mancía
  • Sergio Montes
  • Maricela Méndez-Armenta
  • Pablo Muriel
  • Camilo Ríos
Original Paper


Liver cirrhosis is a common cause of death around the world. One of its more severe complications is hepatic encephalopathy. As a consequence of liver impairment, manganese (Mn) and other substances accumulate in the brain. Astrocytic morphological changes have been found in postmortem brains of cirrhotic patients. In this study we used a model of cirrhosis induced by bile duct ligation and Mn accumulation by exposing rats to MnCl2 (1 mg Mn/ml) in their drinking water. Four experimental groups were used: Sham, Sham plus Mn treatment, BDL (bile duct ligated) and BDL plus Mn treatment. Brain Mn was measured by atomic absorption spectrophotometry in cortex, striatum and globus pallidus. Altered and normal astrocytes were counted in the same brain areas. Brain Mn was highest in rats of the BDLMn group. An increased number of altered astrocytes was found only in BDL groups, Mn did not modify this effect. No changes were found in the total number of astrocytes. According to our results, biliary obstruction induced an increase in the number of altered astrocytes since early stages of cirrhosis and Mn did not affect this effect.


Hepatic encephalopathy Manganese Astrocytes Cirrhosis 



We thank to Biol. Mario Moreno, Mr.Ramón Hernández, and Mr. Benjamín Salinas for their excellent technical assistance.

S. Rivera-Mancía wants to thank to the Biomedical Research Ph D Program, to the Biomedical Research Institute and to the National Autonomous University of Mexico for their support to carry out this work.

This work was supported by CONACYT grant 51541. Susana Rivera-Mancía received a fellowship from CONACYT (203330).


  1. Aschner M, Gannon M (1993) Manganese (Mn) transport across the blood-brain barrier: Saturable and dependent transport mechanisms. Brain Res Bull 33:345–349CrossRefGoogle Scholar
  2. Aschner M, Dorman DC (2006) Manganese: pharmacokinetics and molecular mechanisms of brain uptake. Toxicol Rev 25:147–154PubMedCrossRefGoogle Scholar
  3. Aschner M, Vrana KE, Zheng W (1999) Manganese uptake and distribution in the central nervous system (CNS). Neurotoxicology 20:173–180PubMedGoogle Scholar
  4. Bergmeyer HU, Grabl M, Walter HE (1983) Enzymes. In: Bergmeyer J, Grabl M (eds) Methods of enzymatic analysis. Verlag-Chemie, Weinheim, pp 269–270Google Scholar
  5. Bosetti C, Levi F, Lucchini F, Zatonski WA, Negri E, La Vecchia C (2007) Worldwide mortality from cirrhosis: an update to 2002. J Hepatol 46:827–839PubMedCrossRefGoogle Scholar
  6. Butterworth RF (2000) Complications of cirrhosis III. Hepatic encephalopathy. J Hepatol 32(1 Suppl):171–180PubMedCrossRefGoogle Scholar
  7. Butterworth RF (2001) Neurotransmitter dysfunction in hepatic encephalopathy: new approaches and new findings. Metab Brain Dis 16:55–65PubMedCrossRefGoogle Scholar
  8. Butterworth RF (2002) Pathophysiology of hepatic encephalopathy: a new look to ammonia. Metab Brain Dis 17:221–227PubMedCrossRefGoogle Scholar
  9. Calne DB, Chu NS, Huang CC, Lu CS, Olanow W (1994) Manganism and idiopathic parkinsonism: similarities and differences. Neurology 44:1583–1586PubMedGoogle Scholar
  10. Chia SE, Foo SC, Gan SL, Jeyaratnam J, Tian CS (1993) Neurobehavioral functions among workers exposed to manganese ore. Scand J Work Environ Health 19:264–270PubMedGoogle Scholar
  11. Glossman M, Neville DM (1972) Gamma-Glutamyl transferase in kidney brush border membranes. FEBS Lett 19:340–344CrossRefGoogle Scholar
  12. Hazell AS (2002) Astrocytes and manganese neurotoxicity. Neurochem Int 41:271–277PubMedCrossRefGoogle Scholar
  13. Hazell AS, Normandin L, Norenberg MD, Kennedy G, Jae-Hyuk Y (2006) Alzheimer type II astrocytic changes following sub-acute exposure to manganese and its prevention by antioxidant treatment. Neurosci Lett 396:167–171PubMedCrossRefGoogle Scholar
  14. Hernández-Muñoz R, Díaz-Muñoz M, Suárez-Cuenca J, Trejo-Solís C, López V, Sánchez-Sevilla L, Yáñez L, Chagoya V (2001) Adenosine reverses a preestablished CCl4-induced micronodular cirrhosis through enhancing collagenolytic activity and stimulating hepatocyte cell proliferation in rats. Hepatology 34:677–687PubMedCrossRefGoogle Scholar
  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 inflamatory activation in bile duct ligated rats with diet-induced hyperammonemia: a model of hepatic encephalopathy. Hepatology 43:1257–1266PubMedCrossRefGoogle Scholar
  16. Kountouras J, Billing BH, Scheuer PJ (1984) Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Br J Exp Pathol 65:305–311PubMedGoogle Scholar
  17. Kulisevsky J, Pujol J, Junque C, Deus J, Balanzo J, Capdevila A (1993) MRI pallidal hyperintensity and brain atrophy in cirrhotic patients: two different MRI patterns of clinical deterioration? Neurology 43:2570–2573PubMedGoogle Scholar
  18. Ledig M, Tholey G, Megias-Megias L, Kopp P, Wedler F (1991) Combined effects of ethanol and manganese on cultured neurons and glia. Neurochem Res 16:591–596PubMedCrossRefGoogle Scholar
  19. Levy BS, Nassetta WJ (2003) Neurologic effects of manganese in humans. Int J Occup Environ Health 9:153–163PubMedGoogle Scholar
  20. Montes S, Alcaraz-Zubeldia M, Muriel P, Ríos C (2001) Striatal manganese accumulation induces changes in dopamine metabolism in the cirrhotic rat. Brain Res 891:123–129PubMedCrossRefGoogle Scholar
  21. 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 9:9–15PubMedCrossRefGoogle Scholar
  22. Montes S, Alcaraz-Zubeldia M, Muriel P, Ríos C (2003) Role of Manganese accumulation in increased brain glutamine of the cirrhotic rat. Neurochem Res 28:911–917PubMedCrossRefGoogle Scholar
  23. Muriel P (1998) Nitric oxide protection of rat liver from lipid peroxidation, collagen accumulation, and liver damage induced by carbon tetrachloride. Biochem Pharmacol 56:773–779PubMedCrossRefGoogle Scholar
  24. Norenberg MD (1981) The astrocyte in liver disease. Adv Cell Neurobiol 2:303–352Google Scholar
  25. Norenberg MD, Lapham LW, Nichols FA, May AG (1974) An experimental model for the study of hepatic encephalopathy. Arch Neurol 31:106–109PubMedGoogle Scholar
  26. Normandin L, Hazell A (2002) Manganese neurotoxicity: an update of pathophysiologic mechanisms. Metab Brain Dis 17:375–387PubMedCrossRefGoogle Scholar
  27. Papavasiliou PS, Miller ST, Cotzias GC (1966) Role of liver in regulating distribution and excretion of manganese. Am J Physiol 211:211–216PubMedGoogle Scholar
  28. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic, San DiegoGoogle Scholar
  29. Pentschew A, Ebner F, Kovatch R (1963) Experimental manganese encephalopathy in monkeys. A preliminary report. J Neuropathol Exp Neurol 22:488–489PubMedCrossRefGoogle Scholar
  30. Pomier-Layrargues G, Spahr L, Butterworth RF (1995) Increased manganese concentrations in pallidum of cirrhotic patients. Lancet 345:735PubMedCrossRefGoogle Scholar
  31. Popper H, Zak FG (1958) Pathologic aspects of cirrhosis. Am J Med 24:593–619PubMedCrossRefGoogle Scholar
  32. Quero JC, Schalm SW (1996) Subclinical hepatic encephalopathy. Semin Liver Dis 16:321–328PubMedCrossRefGoogle Scholar
  33. Reitman S, Frankel S (1957) A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol 28:56–63PubMedGoogle Scholar
  34. Rodrigo R, Montoliu C, Chatauret N, Butterworth RF, Behrends S, del Olmo JA, Serra MA, Rodrigo JM, Erceg S, Felipo V (2004) Alterations in soluble guanylate cyclase content and modulation by nitric oxide in liver disease. Neurochem Int 45:947–953PubMedCrossRefGoogle Scholar
  35. Sistrunk SC, Ross MK, Filipov NM (2007) Direct effects of manganese compounds on dopamine and its metabolite Dopac: An in vitro study. Environ Toxicol Pharmacol 23:286–296PubMedCrossRefGoogle Scholar
  36. Sloot WN, Gramsbergen JB (1994) Axonal transport of manganese and its relevance to selective neurotoxicity in the rat basal ganglia. Brain Res 657:124–132PubMedCrossRefGoogle Scholar
  37. vom Dahl S, Kircheis G, Häussinger D (2001) Hepatic encephalopathy as a complication of liver disease. World J Gastroenterol 7:152–156Google Scholar
  38. Weissenborn K, Ehrenheim CH, Hori A, Kubicka S, Manns MP (1995) Pallidal lesions in patients with liver cirrhosis: clinical and MRI evaluation. Metab Brain Dis 10:219–231PubMedCrossRefGoogle Scholar
  39. Yamada M, Ohno S, Okayasu I, Okeda R, Hatakeyama S, Watanabe H, Ushio K, Tsukagoshi H (1986) Chronic manganese poisoning: a neuropathological study with determination of manganese distribution in the brain. Acta Neuropathol 70:273–278PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Susana Rivera-Mancía
    • 1
  • Sergio Montes
    • 1
  • Maricela Méndez-Armenta
    • 2
  • Pablo Muriel
    • 3
  • Camilo Ríos
    • 1
    • 4
  1. 1.Departamento de NeuroquímicaInstituto Nacional de Neurología y Neurocirugía, ‘Manuel Velasco Suárez’México D.FMéxico
  2. 2.Departamento de NeuropatologíaInstituto Nacional de Neurología y Neurocirugía, ‘Manuel Velasco Suárez’México D.FMéxico
  3. 3.Sección Externa de FarmacologíaCentro de Investigación y Estudios Avanzados del I.P.NMéxico D.FMéxico
  4. 4.National Institute of Neurology and Neurosurgery ‘Manuel Velasco Suárez’ Insurgentes Sur 3877México D.FMexico

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