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.

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

“…Improvement of motor manifestations of TAA-induced HE, prevention of coma, and induction of EEG changes that correspond to milder forms of HE strongly suggest that FIN exerts neuroprotective effect in TAA-induced HE and may be a potential device for the improvement of the course of type A HE. FIN did not enable a complete recovery of motor functions, since the pathogenesis of motor disturbances in HE is complex and involves changes in various neurotransmitters, including glutamate, dopamine, acetylcholine, and catecholamines (17,22,37). This possibly indicates that FIN in combination with modulators of other neurotransmitters could exert even better protective effects in HE.…”

Randomized, Placebo-Controlled Trial of Transdermal Rivastigmine for the Treatment of Encephalopathy in Liver Cirrhosis (TREC Trial)

“…Alterations in the cholinergic neurotransmitter system have also been observed in both animal models of HE [8]- [12] and in postmortem brain tissue samples from patients with HE [7] [8] [13]. For example, the level of acetylcholine (ACh) and the neurotransmitter of the cholinergic system, were reduced, and the activity of acetylcholinesterase (AChE), the enzyme that hydrolyzes ACh, was increased in brain extracts from rats with experimentally induced HE [8]. Similarly, the activity of AChE was higher in postmortem brain samples from patients with HE compared with controls without cirrhosis [8].…”

“…While the changes in neurotransmitter systems may be complex and heterogenous, [7] upregulation of the inhibitory GABAergic and serotonergic pathways and impairment of the excitatory glutamatergic and catecholaminergic pathways have been hypothesized to be involved in the pathogenesis of HE [6]. Alterations in the cholinergic neurotransmitter system have also been observed in both animal models of HE [8]- [12] and in postmortem brain tissue samples from patients with HE [7] [8] [13]. For example, the level of acetylcholine (ACh) and the neurotransmitter of the cholinergic system, were reduced, and the activity of acetylcholinesterase (AChE), the enzyme that hydrolyzes ACh, was increased in brain extracts from rats with experimentally induced HE [8].…”

“…For example, the level of acetylcholine (ACh) and the neurotransmitter of the cholinergic system, were reduced, and the activity of acetylcholinesterase (AChE), the enzyme that hydrolyzes ACh, was increased in brain extracts from rats with experimentally induced HE [8]. Similarly, the activity of AChE was higher in postmortem brain samples from patients with HE compared with controls without cirrhosis [8]. Given the importance of cholinergic neurotransmission in cognitive function and consciousness [14] alterations such as those, which disrupt cholinergic signaling, may explain the deficits in cognitive function and consciousness observed in patients with HE.…”

Research progress on hepatic encephalopathy: animal models and disease mechanisms

“…Interestingly, this phenomenon was not found in the animals with type A or B HE. Since acetylcholine is the inhibitor of HE, and such change is independent of the inducetion of circulating ammonia level, it is considered to be a new molecular mechanism for type C HE progression [38][39][40] . Type C model is often established by inducing chronic liver cirrhosis using CCl 4 , ethanol or other liver toxic substances, in association with portacaval anastomosis [9] .…”