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Brain cholinergic impairment in liver failure.

García-Ayllón MS, Cauli O, Silveyra MX, Rodrigo R, Candela A, Compañ A, Jover R, Pérez-Mateo M, Martínez S, Felipo V, Sáez-Valero J - Brain (2008)

Bottom Line: Here, we examined potential alterations in the brain levels of key cholinergic enzymes in cirrhotic patients and animal models with liver failure.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.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.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain.

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.

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AChE and ChAT detection in the cerebral cortex of control and experimental rats. (A–I) AChE immunoreactivity in brain frontal cortex in normal (NL) rats (A–C), BDL rats, (D–F) and BDL + HD rats (G–I). The immunopositive staining is mainly localized in the perinuclear area of layer V pyramidal neurons in both control and experimental samples. Inserts show the progressive higher power pictures in the localized areas for each rat model. Scale bar: 250 microns in (A), (D) and (G); 100 microns in (B), (E) and (H); and 30 microns in (C), (F) and (I). (J–O) ChAT immunoreactivity of frontal cortex in normal (NL) rats (J and M), BDL rats (K and N) and BDL + HD rats (L and O). Immunopositive staining is mainly localized in the perinuclear area of layer V pyramidal neurons in control and experimental samples. Inserts show progressive higher power pictures in localized areas for each rat model. Scale bar: 250 microns in (J), (K) and (L); 100 microns in (M), (N) and (O). No significant staining was found in cortical superficial layers in pyramidal cells or interneurons, only apical processes of pyramidal neurons could be followed from layer V. Not staining was observed in the white matter.
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Figure 4: AChE and ChAT detection in the cerebral cortex of control and experimental rats. (A–I) AChE immunoreactivity in brain frontal cortex in normal (NL) rats (A–C), BDL rats, (D–F) and BDL + HD rats (G–I). The immunopositive staining is mainly localized in the perinuclear area of layer V pyramidal neurons in both control and experimental samples. Inserts show the progressive higher power pictures in the localized areas for each rat model. Scale bar: 250 microns in (A), (D) and (G); 100 microns in (B), (E) and (H); and 30 microns in (C), (F) and (I). (J–O) ChAT immunoreactivity of frontal cortex in normal (NL) rats (J and M), BDL rats (K and N) and BDL + HD rats (L and O). Immunopositive staining is mainly localized in the perinuclear area of layer V pyramidal neurons in control and experimental samples. Inserts show progressive higher power pictures in localized areas for each rat model. Scale bar: 250 microns in (J), (K) and (L); 100 microns in (M), (N) and (O). No significant staining was found in cortical superficial layers in pyramidal cells or interneurons, only apical processes of pyramidal neurons could be followed from layer V. Not staining was observed in the white matter.

Mentions: We also assessed whether the subcellular location of both, AChE and ChAT were modified by the BDL condition (Fig. 4). Immunoreactivity to AChE and ChAT showed consistent and similar expression in both experimental and control animals. While strong immunoreactive signal was observed in the perinuclear area of pyramidal cells in frontal cortex layer V, a weak reaction was localized in the cytoplasm of these cells, staining within basal and apical dendrites. Some small cells around the pyramidal neurons also show perinuclear labelling with very weak cellular signal. No difference observed in the localization and intensity of the AChE and ChAT immunoreactivity in all the analysed coronal sections of control NL (n = 3), BDL (n = 3) and BDL + HD (n = 3) rats.Fig. 4


Brain cholinergic impairment in liver failure.

García-Ayllón MS, Cauli O, Silveyra MX, Rodrigo R, Candela A, Compañ A, Jover R, Pérez-Mateo M, Martínez S, Felipo V, Sáez-Valero J - Brain (2008)

AChE and ChAT detection in the cerebral cortex of control and experimental rats. (A–I) AChE immunoreactivity in brain frontal cortex in normal (NL) rats (A–C), BDL rats, (D–F) and BDL + HD rats (G–I). The immunopositive staining is mainly localized in the perinuclear area of layer V pyramidal neurons in both control and experimental samples. Inserts show the progressive higher power pictures in the localized areas for each rat model. Scale bar: 250 microns in (A), (D) and (G); 100 microns in (B), (E) and (H); and 30 microns in (C), (F) and (I). (J–O) ChAT immunoreactivity of frontal cortex in normal (NL) rats (J and M), BDL rats (K and N) and BDL + HD rats (L and O). Immunopositive staining is mainly localized in the perinuclear area of layer V pyramidal neurons in control and experimental samples. Inserts show progressive higher power pictures in localized areas for each rat model. Scale bar: 250 microns in (J), (K) and (L); 100 microns in (M), (N) and (O). No significant staining was found in cortical superficial layers in pyramidal cells or interneurons, only apical processes of pyramidal neurons could be followed from layer V. Not staining was observed in the white matter.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
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Figure 4: AChE and ChAT detection in the cerebral cortex of control and experimental rats. (A–I) AChE immunoreactivity in brain frontal cortex in normal (NL) rats (A–C), BDL rats, (D–F) and BDL + HD rats (G–I). The immunopositive staining is mainly localized in the perinuclear area of layer V pyramidal neurons in both control and experimental samples. Inserts show the progressive higher power pictures in the localized areas for each rat model. Scale bar: 250 microns in (A), (D) and (G); 100 microns in (B), (E) and (H); and 30 microns in (C), (F) and (I). (J–O) ChAT immunoreactivity of frontal cortex in normal (NL) rats (J and M), BDL rats (K and N) and BDL + HD rats (L and O). Immunopositive staining is mainly localized in the perinuclear area of layer V pyramidal neurons in control and experimental samples. Inserts show progressive higher power pictures in localized areas for each rat model. Scale bar: 250 microns in (J), (K) and (L); 100 microns in (M), (N) and (O). No significant staining was found in cortical superficial layers in pyramidal cells or interneurons, only apical processes of pyramidal neurons could be followed from layer V. Not staining was observed in the white matter.
Mentions: We also assessed whether the subcellular location of both, AChE and ChAT were modified by the BDL condition (Fig. 4). Immunoreactivity to AChE and ChAT showed consistent and similar expression in both experimental and control animals. While strong immunoreactive signal was observed in the perinuclear area of pyramidal cells in frontal cortex layer V, a weak reaction was localized in the cytoplasm of these cells, staining within basal and apical dendrites. Some small cells around the pyramidal neurons also show perinuclear labelling with very weak cellular signal. No difference observed in the localization and intensity of the AChE and ChAT immunoreactivity in all the analysed coronal sections of control NL (n = 3), BDL (n = 3) and BDL + HD (n = 3) rats.Fig. 4

Bottom Line: Here, we examined potential alterations in the brain levels of key cholinergic enzymes in cirrhotic patients and animal models with liver failure.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.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.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain.

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.

Show MeSH
Related in: MedlinePlus