title: Brain cholinergic impairment in liver failure.
abstract: The cholinergic system is involved in specific behavioural responses and cognitive processes. Here, we examined potential alterations in the brain levels of key cholinergic enzymes in cirrhotic patients and animal models with liver failure. An increase (~30%) in the activity of the acetylcholine-hydrolyzing enzyme, acetylcholinesterase (AChE) is observed in the brain cortex from patients deceased from hepatic coma, while the activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase, remains unaffected. In agreement with the human data, AChE activity in brain cortical extracts of bile duct ligated (BDL) rats was increased (~20%) compared to controls. A hyperammonemic diet did not result in any further increase of AChE levels in the BDL model, and no change was observed in hyperammonemic diet rats without liver disease. Portacaval shunted rats which display increased levels of cerebral ammonia did not show any brain cholinergic abnormalities, confirming that high ammonia levels do not play a role in brain AChE changes. A selective increase of tetrameric AChE, the major AChE species involved in hydrolysis of acetylcholine in the brain, was detected in both cirrhotic humans and BDL rats. Histological examination of BDL and non-ligated rat brains shows that the subcellular localization of both AChE and choline acetyltransferase, and thus the accessibility to their substrates, appears unaltered by the pathological condition. The BDL-induced increase in AChE activity was not parallelled by an increase in mRNA levels. Increased AChE in BDL cirrhotic rats leads to a pronounced decrease (~50-60%) in the levels of acetylcholine. Finally, we demonstrate that the AChE inhibitor rivastigmine is able to improve memory deficits in BDL rats. One week treatment with rivastigmine (0.6 mg/kg; once a day, orally, for a week) resulted in a 25% of inhibition in the enzymatic activity of AChE with no change in protein composition, as assessed by sucrose density gradient fractionation and western blotting analysis. In conclusion, this study is the first direct evidence of a cholinergic imbalance in the brain as a consequence of liver failure and points to the possible role of the cholinergic system in the pathogenesis of hepatic encephalopathy.
authors.affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain.
authors.forename: María-Salud
authors.initials: MS
authors.lastname: García-Ayllón
authors.forename: Omar
authors.initials: O
authors.lastname: Cauli
authors.forename: María-Ximena
authors.initials: MX
authors.lastname: Silveyra
authors.forename: Regina
authors.initials: R
authors.lastname: Rodrigo
authors.forename: Asunción
authors.initials: A
authors.lastname: Candela
authors.forename: Antonio
authors.initials: A
authors.lastname: Compañ
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jover
authors.forename: Miguel
authors.initials: M
authors.lastname: Pérez-Mateo
authors.forename: Salvador
authors.initials: S
authors.lastname: Martínez
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
authors.forename: Javier
authors.initials: J
authors.lastname: Sáez-Valero
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000201:enzymology* / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006501:Hepatic Encephalopathy / Q000188:drug therapy / Q000201:enzymology* / Q000523:psychology; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000473:pathology / Q000523:psychology; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use; D048448:Phenylcarbamates / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068836:Rivastigmine
chemical_list: D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D012333:RNA, Messenger; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D000109:Acetylcholine; D000068836:Rivastigmine
references.citation: Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2476-80
references.pmid: 8460161
references.citation: Neuroscience. 1996 May;72(2):429-34
references.pmid: 8737413
references.citation: J Hepatol. 2004 May;40(5):742-8
references.pmid: 15094220
references.citation: Acta Biol Hung. 2003;54(2):183-9
references.pmid: 14535624
references.citation: Brain Res. 2007 Jun 11;1153:188-95
references.pmid: 17482580
references.citation: J Neurochem. 1998 Aug;71(2):723-31
references.pmid: 9681463
references.citation: Neurosci Lett. 2001 Aug 17;309(1):21-4
references.pmid: 11489537
references.citation: Science. 1982 Jul 30;217(4558):408-14
references.pmid: 7046051
references.citation: Lancet. 1995 Jul 29;346(8970):270-4
references.pmid: 7630246
references.citation: Metab Brain Dis. 1994 Dec;9(4):401-7
references.pmid: 7898405
references.citation: J Neurochem. 1980 Nov;35(5):1067-79
references.pmid: 7452305
references.citation: Neurochem Res. 1992 May;17(5):489-95
references.pmid: 1528356
references.citation: J Neurochem. 2007 Jun;101(6):1701-11
references.pmid: 17326766
references.citation: Neurotoxicology. 2007 Sep;28(5):1003-14
references.pmid: 17920128
references.citation: Semin Liver Dis. 1996 Aug;16(3):235-44
references.pmid: 8989809
references.citation: Prog Neurobiol. 1993 Jul;41(1):31-91
references.pmid: 8321908
references.citation: Eur J Clin Invest. 2004 Feb;34(2):122-8
references.pmid: 14764075
references.citation: Hepatology. 2006 Jun;43(6):1257-66
references.pmid: 16729306
references.citation: Eur J Biochem. 1999 Sep;264(3):672-86
references.pmid: 10491113
references.citation: Hepatology. 2006 Mar;43(3):444-53
references.pmid: 16496349
references.citation: J Biol Chem. 1981 Apr 25;256(8):3827-30
references.pmid: 7217057
references.citation: Curr Biol. 1995 Sep 1;5(9):1063-71
references.pmid: 8542283
references.citation: Prog Neurobiol. 2002 Jul;67(4):259-79
references.pmid: 12207972
references.citation: J Neurochem. 2006 May;97(3):697-706
references.pmid: 16579834
references.citation: Exp Neurol. 2000 Feb;161(2):704-13
references.pmid: 10686089
references.citation: J Neurosci Res. 1993 Aug 15;35(6):678-89
references.pmid: 8411269
references.citation: Annu Rev Pharmacol Toxicol. 1994;34:281-320
references.pmid: 8042853
references.citation: J Neurochem. 1985 Nov;45(5):1649-52
references.pmid: 4045469
references.citation: J Chem Neuroanat. 2000 Jan;17(4):217-26
references.pmid: 10697248
references.citation: Neuroscience. 2007 Jan 5;144(1):232-8
references.pmid: 17045751
references.citation: Eur J Anaesthesiol. 1999 Feb;16(2):140-2
references.pmid: 10101633
references.citation: Eur J Pharmacol. 2002 Nov 29;455(2-3):101-7
references.pmid: 12445575
references.citation: Mech Ageing Dev. 2006 Feb;127(2):173-9
references.pmid: 16297435
references.citation: Biochem Pharmacol. 1995 Mar 30;49(7):955-63
references.pmid: 7537966
references.citation: World J Surg. 2004 Mar;28(3):283-7
references.pmid: 14961195
references.citation: Nat Med. 1996 Dec;2(12):1382-5
references.pmid: 8946841
references.citation: Hepatology. 1989 Sep;10(3):311-4
references.pmid: 2759549
references.citation: Surgery. 1961 Oct;50:668-72
references.pmid: 14463560
references.citation: Toxicol Lett. 2007 Nov 1;174(1-3):25-30
references.pmid: 17888594
references.citation: J Neural Transm Suppl. 2002;(62):181-7
references.pmid: 12456062
references.citation: J Biol Chem. 1988 Dec 25;263(36):19398-406
references.pmid: 3198632
references.citation: Nature. 1998 May 28;393(6683):373-7
references.pmid: 9620801