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Acetylcholinesterase activity in an experimental rat model ofType C hepatic encephalopathy

Marta Mendez a,n, Magdalena Mendez-Lopez a, Laudino Lopez a, Mara A. Aller b, Jaime Ariasb, Jorge L. Arias a

a Laboratorio de Neurociencias, Departamento de Psicologa, Universidad de Oviedo, Plaza Feijoo s/n, 33003 Oviedo, Spainb Department of Surgery, Faculty of Medicine, Complutense University of Madrid, 28040 Madrid, Spain

a r t i c l e i n f o

Article history:

Received 26 November 2009

Received in revised form

15 January 2010

Accepted 18 January 2010

Keywords:

Hepatic encephalopathy

Acetylcholinesterase

Cirrhosis

Thioacetamide

Rat

a b s t r a c t

Patients with liver malfunction often suffer from hepatic encephalopathy, a neurological complication

which can affect attention and cognition. Diverse experimental models have been used to study brain

alterations that may be responsible for hepatic encephalopathy symptoms. The aim of the study was to

determine whether cognitive impairment found in cirrhosis could be due to disturbance of

acetylcholinesterase activity. Acetylcholinesterase activity was assessed in the brains of Wistar rats

with thioacetamide-induced cirrhosis. The cirrhotic group displayed up-regulation of acetylcholines-

terase levels in the entorrhinal cortex, anterodorsal and anteroventral thalamus and accumbens,

whereas down-regulation was found in the CA1, CA3 and dentate gyrus of the hippocampus. Our results

indicate that the experimental model of hepatic encephalopathy by chronic administration of

thioacetamide presents alterations of acetylcholinesterase activity in brain limbic system regions,

which play a role in attention and memory.

& 2010 Elsevier GmbH. All rights reserved.

Introduction

Hepatic encephalopathy (HE) is a neuropsychological disorder

observed in patients with acute or chronic hepatic failure. This

disorder exists in three major types, depending on its origin or

cause: Type A HE, associated with acute liver failure, Type B HE,

associated with portal-systemic bypass and no intrinsic hepatocel-

lular disease and Type C HE, associated with cirrhosis and portal

hypertension or portal-systemic shunts (Ferenci et al., 2002). Type

C HE is the most common because hepatic cirrhosis, as well as

other types of acute or chronic hepatic diseases, is one of the main

clinical conditions affecting the Western World. This disease

requires costly treatment and has high mortality rates. More than

950,000 individuals die every year from liver diseases all over theWorld (WHO, 2003). Therefore, it is necessary to resort to animal

experimentation in order to clarify both the behavioral and the

brain dysfunction that occurs in HE (Blei et al., 1992; Chamuleau,

1996). The models proposed to study HE due to chronic cirrhosis

mimic the clinical characteristics of cirrhosis and portal hyperten-

sion and require obstruction of the bile duct (Kountouras et al.,

1984; Jover et al., 2005) or the administration of hepatotoxins, such

as intoxication with carbon tetrachloride or with thioacetamide

(TAA) (Dashti et al., 1989; Laleman et al., 2006).

The clinical stages of HE range from subtle psychiatric and

behavioral changes in the early stages, to deep coma. As HE

progresses, motor function and intellectual abilities deteriorate and

patients show deficits in attention and arousal (Weissenborn et al.,

2005), disturbances of learning, memory and recognition (Ortiz

et al., 2006) and impaired motor performance, visual perception and

visuo-constructive abilities (Weissenborn et al., 2003). The factor or

factors that determine the development of these alterations found

in patients with HE are still unknown and, in spite of advances in

recent years, there are many unanswered questions concerning HE,

with regard to its etiopathogeny (Butterworth, 2003), diagnosis

(Montagnese et al., 2004) or treatment (Blei and Cordoba, 2001).Several factors have been implicated in the etiology of HE,

such as morphological cell changes, which mainly affect astrocytes

(Butterworth, 2002) and alterations of neurotransmitter systems

(Butterworth, 2000), hyperammonemia and other factors such as

inflammation, electrolyte alterations and altered blood flow (Hazell

and Butterworth, 1999; Vaquero et al., 2003). All these alterations

have been regarded as possible mechanisms responsible for the

neuropsychological deficits frequently seen in patients with liver

disease. Also, some mechanisms of the pathophysiology of HE are

associated with changes in brain cell membranes (Swapna et al.,

2006a, b) and neurotransmitter uptake, particularly of glutamate

(Felipo and Butterworth, 2002).

Contents lists available at ScienceDirect

journal homepage: www.elsevier.de/acthis

acta histochemica

0065-1281/$- see front matter& 2010 Elsevier GmbH. All rights reserved.

doi:10.1016/j.acthis.2010.01.009

n Corresponding author.

E-mail address: [email protected] (M. Mendez).

acta histochemica 113 (2011) 358362
http://-/?-http://www.elsevier.de/acthishttp://dx.doi.org/10.1016/j.acthis.2010.01.009mailto:[email protected]:[email protected]:[email protected]://dx.doi.org/10.1016/j.acthis.2010.01.009http://dx.doi.org/10.1016/j.acthis.2010.01.009mailto:[email protected]://dx.doi.org/10.1016/j.acthis.2010.01.009http://www.elsevier.de/acthishttp://-/?-


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Acetylcholinesterase (AChE) is a membrane-bound enzyme

involved in cholinergic neurotransmission, which hydrolyzes

acetylcholine released from presynaptic terminals obstructing

acetylcholine transmission (Silman and Sussman, 2008). Recently,

it has been demonstrated that AChE was severely decreased in the

brain cortex of an experimental model of acute liver failure by

TAA (Swapna et al., 2007), whereas in bile duct ligated rats, it was

increased and no changes were observed in the portal-systemic

HE (Garca-Ayllon et al., 2008).Cholinergic neurotransmission is one of the most important

means of neurotransmission in the mammalian brain. Cortical

acetylcholine mediates sustained and selective attention, arousal,

alertness, wakefulness and electroencephalographic desynchro-

nization (Sarter et al., 2003). The activity of AChE is altered in

neuropsychological disorders such as Alzheimers disease and

dementia (Mesulam, 2004), which show disturbance of learning

and memory processes.

Considering that impaired spatial learning and active avoidance

behavior have been described in rats with chronic liver failure

by TAA administration (Mendez et al., 2008, 2009a, 2009b), we

hypothesized that this model of chronic hepatic cirrhosis may

show alterations in the level of AChE. For this reason, the aim of

this study was to analyse the AChE activity of different brain limbic

system regions considered to be implicated in memory processes.

Material and methods

Animals

A total of 16 male Wistar rats were used from the animal

house of Oviedo University. All the animals had ad libitum access

to food and tapwater and were maintained at constant room

temperature (21 1C), with a relative humidity of 6570% and

artificial lightdark cycle of 12 h (08:0020:00/20:0008:00 h).

The procedures and manipulation of the animals used in this

study were carried out according to the Directive 86/609/EEC (The

Council Directive of the European Community) concerning the

protection of animals used for experimental and other scientific

purposes. The national legislation, in agreement with this

Directive, is defined in Royal Decree no. 1201/2005. The study

was approved by the local committee for animal studies (Oviedo

University).

Fig. 1. Acetylcholinesterase (AChE) histochemistry. Acetylcholinesterase (AChE) histochemistry in control (CO) and cirrhotic (TAA) rats and schematic drawings illustrating

areas of analysis (indicated by the boxes) of AChE activity (A, D, G, J). AChE activity in accumbens core (ACc) and shell (ACs) (B, C), anterior thalamic nuclei (E, F)

anterodorsal (TAD), anteroventral (TAV), anteromedial (TAM), hippocampal CA1, CA3 and dentate gyrus (DG) (H, I) and entorhinal cortex (EntC) (K, L). Scale bar: 500 mm.

M. Mendez et al. / acta histochemica 113 (2011) 358362 359


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The experimental model

The animals were initially split into two groups. The experimental

group (TAA) (n=8) was composed of cirrhotic rats. The method used

to produce cirrhosis was administration of TAA (Sigma-Aldrich,

Germany) in drinking water (Xiangnong et al., 2002). The animals

received continuous administration of TAA for 12 weeks and its

concentration was modified weekly, depending on the animals

weight gain or weight loss. Only TAA solution was used as drinkingwater for this group. The initial concentration of TAA was 0.03%. The

control group (CO) (n=8) was isolated in the same way as the TAA

group during 12 weeks and received normal tapwater. Experimental

and control animals received commercial chow ad libitum and their

body weights and fluid intake were recorded weekly.

Acetylcholinesterase (AChE) histochemistry

Rats were decapitated, brains were removed intact, frozen

rapidly in isopentane (Sigma-Aldrich, Germany) and stored at

40 1C. Coronal sections (30 mm) of the brain were cut in a

cryostat (Leica CM1900, Leica Microsystems, Wetzlar, Germany)

and mounted on gelatinized slides. The sections were stored at80 1C until required for processing. The sections were thawed

at room temperature for 1 h before histochemistry staining.

Acetylcholinesterase incubating medium (800 ml 0.05 M sodium

acetate buffer at pH 5.0, 0.256 g cupric sulfate, 3.2 mg ethopro-

pazine, 0.92 g acetylthiocholine iodide and 0.6 g glycine) was

prepared immediately before use and slides were incubated for

2 h at 37 1C in the dark and then washed 8 times in distilled water

for 1 min. To visualize the sites of acetylcholinesterase activity,

the sections were subjected to a 1.25% ammonium sulfide

solution (in distilled H2O) for 1 min. The slides were then rinsed

in several distilled water incubations and fixed in buffered 10%formalin (0.1 M, pH 7.4) overnight, then dehydrated and mounted

in DPX. This method was adapted from Slattery et al. (2005).

AChE densitometry

Measurements were taken by using a computer-controlled

image analysis workstation (MCID, InterFocus Imaging Ltd.,

Linton, England) and expressed as arbitrary units of optical

density (OD). In order to establish comparisons between different

staining baths, measurements were taken from AChE-stained

brain standards of different thicknesses. Regression curves and

coefficients between section thickness and AChE activity mea-

sured from each set of standards were calculated for eachincubation bath. Optical density values measured for the brain

regions selected were set at the same level using the optical

Fig. 2. Acetylcholinesterase (AChE) optical density values. Acetylcholinesterase (AChE) optical density values (+ SEM) of control (CO) and cirrhotic (TAA) group in

accumbens core (ACc) and shell (ACs) (A), anterior thalamic nuclei (B) anterodorsal (TAD), anteroventral (TAV), anteromedial (TAM), hippocampal CA1, CA3 and dentate

gyrus (DG) (C) and entorhinal cortex (EntC) (D). Asterisk (n) shows significant difference (po0.05) in the AChE optical density values between control group and cirrhotic

group.

M. Mendez et al. / acta histochemica 113 (2011) 358362360


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density differences calculated from the regression plots of the

brain standards. The OD of each structure was measured on the

right side of bilateral structures using three consecutive sections

in each animal. In each section, four, non-overlapping readings

were taken using a square-shaped sampling window that was

adjusted for each region size. A total of twelve measurements

were taken per region. These twelve measurements were

averaged to obtain one mean per region for each subject.

Measurements were performed by an investigator using codedsamples without knowledge of the groups. The selected brain

regions that were analysed were anatomically defined according

to Paxinos and Watsons atlas (2005). The stained coronal sections,

from anterior to posterior, corresponded to Bregma levels

1.44 mm (accumbens core (ACc) and accumbens shell (ACs)),

1.92 mm (anterodorsal thalamic nucleus (TAD), anteroventral

thalamic nucleus (TAV) and anteromedial thalamic nuleus

(TAM)), 3.84 mm (hippocampal CA1 (CA1), hippocampal CA3

(CA3) and hippocampal dentate gyrus (DG)) and 5.04 mm

(entorhinal cortex (EntC)) (Fig. 1).

Data analysis

A t-test for independent samples was used to compare AChEoptical density values between the TAA and CO groups. Differ-

ences were considered statistically significant if po0.05. The

results are represented in Fig. 2.

Results

AChE optical density levels of the TAA group were lower than

those of the CO in all the hippocampal subfields CA1, CA3 and DG

[t(14)=4.409, po0.001; t(14)=2.281, po0.05 and t(14)=3.361,p=0.005, respectively]. However, TAA had higher AChE levels than

those of CO in the thalamic nuclei TAD and TAV [ t(14)=3.455,

po0.005 and t(14)=4.309, po0.001, respectively] and in the

ACc and ACs [t(14)=3.835, po0.005 and t(14)=5.885,po0.001, respectively]. Also, AChE levels of the TAA group were

increased in the EntC [t(14)=2.305, po0.05] (Fig. 2).

Discussion

Our study demonstrates alteration of AChE activity in an

experimental model of HE by chronic administration of TAA.

This alteration was not uniform in the entire brain. Our analysis

shows that up-regulation of AChE levels was found in the EntC,

TAD, TAV, ACc and ACs, whereas down-regulation was found in the

hippocampus. The impaired areas are related to attention and

memory function and receive extensive innervations from choli-

nergic neurons (Butcher and Woolf, 2004). Therefore, it is possible

that the dysfunction of cholinergic neurotransmission in theselimbic system regions is related to the impairment of cognition

seen both in patients and in the experimental models of HE.

The relationship between cholinergic system alterations and

liver failure has been assessed in previous studies. Alterations in

AChE kinetic properties have been described in TAA-induced

acute liver failure (Swapna et al., 2007) and increased levels of

AChE have been found both in cirrhotic patients and in rats with

bile duct ligation (Garca-Ayllon et al., 2008). Nonetheless, some

of these studies fail to demonstrate changes in the levels of

cholinergic enzymes in human or experimental portal-systemic

encephalopathy or in hyperammonemic conditions (Raghavendra

Rao et al., 1994; Garca-Ayllon et al., 2008), confirming decreased

cholinesterase activity in acute or subacute liver disease, but

not in portal-systemic HE. Chronic liver disease could alter

bloodbrain barrier permeability, increase toxic substances in

brain and produce anomalous metabolic response that may

contribute to neurotransmission deregulation (Hazell and

Butterworth, 1999; Butterworth, 2003).

Cholinergic pathways innervate all cortical and limbic areas

and are associated with the ascending reticular activating system,

influencing cognition and behavior. Increased levels of AChE in

the brain, which obstructs acetylcholine neurotransmission by

hydrolyzing presynaptic acetylcholine, might cause a decrease ofextracellular acetylcholine and affect information processing and

learning acquisition. Increased AChE could lead to a pronounced

decrease in the levels of the neurotransmitter acetylcholine.

Therefore, these data suggests an impairment of the brain

cholinergic system induced by cirrhosis, which may be associated

with failure in learning and attention processes (Hasselmo and

Giocomo, 2006).

This study shows abnormally higher AChE levels in the

entorhinal cortex. Given that cortical acetylcholine mediates detec-

tion and selection of relevant stimuli and both sustained and

selective attention (Sarter et al., 2003), high AChE levels in the

entorhinal cortex could cause deficits in information processing and

encoding of new episodic memories. The effects of high AChE levels

in the entorhinal cortex might provide support for the involvement

of cholinergic transmission in the impairment in divided attention

found in human subjects with HE (Amodio et al., 2005).

A similar increase in AChE levels was found in the anterodorsal

and anteroventral thalamic nuclei. The thalamus is a structure

which influences behavior through its participation in many brain

circuits involved in the processing of new and old information

(Van der Werf et al., 2000). These nuclei contain neurons that

code for direction (Taube, 1995; Blair et al., 1999) and theta

rhythm (Vertes et al., 2001; Albo et al., 2003) and are involved in

complex cognitive skills and memory processes, participating in

selection of stimuli for subsequent memory storage in accordance

with the connections with the hippocampal system. Hence, the

impairment of cholinergic neurotransmission in these thalamic

nuclei could be related to the deterioration of cognition found

in this experimental model (Mendez et al., 2008) and is inaccordance with the reduction of oxidative metabolism of these

nuclei (Mendez et al., 2009b).

Down-regulation of AChE in the accumbens core and shell

nuclei suggests an impairment of reward and learning. The

accumbens receives projections from several limbic regions such

as the hippocampus, the cortex, the thalamic nuclei and the

ventral tegmental area (Fallon and Moore, 1978; Krayniak et al.,

1981; Kelley and Domesick, 1982; Ligorio et al., 2009), and its

primary output is to the ventral pallidum (Zahm and Heimer,

1990). Therefore, its cholinergic interneurons are involved in

motivation and reward and aversive behavior, and are considered

a part of the limbic system (Mogenson et al., 1980; Hoebel et al.,

2007).

Contrary to the results in the previous structures, AChE levelsin the cirrhotic animals were decreased in the dorsal hippocam-

pus. This could imply an increase of acetylcholine in the

hippocampal formation and might correlate with the increase in

the neuronal activity assessed by cytochrome oxidase histochem-

istry found in the hippocampus in this experimental model

(Mendez et al., 2009b). Cholinergic transmission enhancement

could contribute to the impairment of learning found in this

model (Mendez et al., 2008) because, contrary to the idea that

increased hippocampal acetylcholine release will facilitate the

acquisition of a learning task (Givens and Olton, 1994, 1995),

some studies suggest that the increase in hippocampal acetylcho-

line by stimulation of septohippocampal cholinergic cells pro-

duces deficit in spatial learning assessed in the Morris water maze

(Elvander et al., 2004). Also, the consolidation of memory

M. Mendez et al. / acta histochemica 113 (2011) 358362 361


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processes should be impaired by increases in acetylcholine levels

during consolidation (Bunce et al., 2004).

Taking into account these results, further research is necessary

to understand the role of acetylcholine neurotransmission in the

cognitive deficits of HE Type C.

Aknowledgements

We would like to thank Piedad Burgos and Begona Valdes for

their technical assistance, and Virginia Navascues for reviewing

the English text of this manuscript. This research was supported

by grants from the current Spanish Ministry of Science and

Innovation (SEJ2007-63506).

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