Portal-Systemic Encephalopathy: a Disorder of Multiple Neurotransmitter Systems

Butterworth, Roger F.

doi:10.1007/978-1-4615-1989-8_8

Cited by 9 publications

(6 citation statements)

References 43 publications

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“…Glutamate is the most important cerebral excitatory neurotransmitter in the brain and its concentration at the synaptic level is dependent upon the glutamate-glutamine cycle whereby glutamate is released by the pre-synaptic neurons, reacts with the post-synaptic neurons, and is inactivated to glutamine in the astrocyte. In patients with HE, cerebral glutamate is reduced [66,67], reuptake mechanisms for glutamate are impaired and there is downregulation of glutamate-binding sites on the post-synaptic neurons [67]. All these contribute to reduced neuroexcitation.…”

Section: Alterations In the Blood Brain Barrier (Bbb)mentioning

confidence: 99%

Acute-on-Chronic Liver Failure: Pathophysiological Basis of Therapeutic Options

Jalan

Williams²

2002

Blood Purif

269

237

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The vast majority of patients that are referred to a specialist hepatological centre suffer from acute deterioration of their chronic liver disease. Yet, this entity of acute-on-chronic liver failure remains poorly defined. With the emergence of newer liver support strategies, it has become necessary to define this entity, its pathophysiology and the short- and long-term prognosis. This review focusses upon how a precipitant such as an episode of gastrointestinal bleeding or sepsis may start a cascade of events that culminate in end-organ dysfunction and liver failure. We briefly review the pathophysiological basis of the therapeutic modalities that are available. Our current strategy for the management of liver failure involves supportive therapy for the end-organs with the hope that liver function would recover if sufficient time for such a recovery is allowed. Because liver failure, whether of the acute or acute-on-chronic variety, is potentially reversible, the stage is set for the application of newer liver-support strategies to enhance the recovery process.

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Section: Alterations In the Blood Brain Barrier (Bbb)mentioning

confidence: 99%

Acute-on-Chronic Liver Failure: Pathophysiological Basis of Therapeutic Options

Jalan

Williams²

2002

Blood Purif

269

237

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“…PSE has been described as a disorder of multiple neurotransmitter systems. 13 Specifically, the histaminergic synaptic imbalance, which becomes apparent shortly 14,15 and persists for at least 8 months after surgery, 12,16-18 is among the most interesting consequences of portacaval shunting in the rat.We have previously shown that rats with PCA have profound disturbances in their brain histaminergic functions 6 months after surgery. 12,17,18 These rats have excessively high tissue levels of histamine in brain regions particularly enriched in histaminergic neurons and/or cell bodies.…”

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confidence: 99%

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confidence: 99%

Effects of the histamine H1 receptor blocker, pyrilamine, on spontaneous locomotor activity of rats with long-term portacaval anastomosis

et al. 2000

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To find out whether the changes in the brain histaminergic system are involved in the pathophysiology of portalsystemic encephalopathy, we examined the effects of histamine H 1 receptor blockade on spontaneous locomotor activity, feeding, and circadian rhythmicity in rats with portacaval anastomosis (PCA). Pyrilamine, an H 1 receptor blocker (15 mg/kg/day), was delivered with osmotic minipumps. Spontaneous locomotor activity was recorded for 72 hours in the open-field with an electromagnetic detector. Food intake was monitored twice daily at the end of the light (7 PM) and the dark (7 AM) phases for 3 days. Histamine H 1 receptor density in the suprachiasmatic nucleus (SCN) was examined with receptor autoradiography, employing [ 3 H]pyrilamine. PCA surgery led to decreased movement time and velocity and flattened amplitude of the circadian rhythms of locomotion and feeding. In sham-operated rats, pyrilamine significantly decreased the movement time and velocity, as well as the total food consumption and completely abolished the circadian rhythmicity of locomotion. In contrast, pyrilamine increased the movement time and velocity in PCA-operated rats, particularly in the dark phase, and improved the precision of the circadian rhythms of locomotion and feeding. Histamine H 1 receptor density was not altered by PCA surgery, whereas pyrilamine treatment led to the complete blockade of H 1 receptors in both sham-and PCA-operated rats. We suggest that histaminergic imbalance has contributed to the generation and maintenance of the decreased spontaneous locomotor activity and altered circadian rhythmicity following PCA surgery in the rat, probably via an H 1 receptor-mediated mechanism. (HEPATOL-OGY 2000;31:336-344.)Animal models of human disease provide the means of studying the pathological condition in a way that is not always possible in human patients. The rat with an end-toside portacaval anastomosis (PCA) represents an attractive model of portal-systemic encephalopathy (PSE) 1,2 because many of the behavioral abnormalities that occur in this model correspond to the subclinical forms of PSE. Among these abnormalities are the significantly reduced spontaneous locomotor activity and exploration, 3 as well as the reduced or completely abolished differences between day time and night time activity, suggesting a disruption of their circadian rhythmicity. 4-10 These rats also have disturbances in their food intake 11 and show marked growth retardation. 12 Although much research has been performed to elucidate the pathophysiological background of PSE, the exact mechanisms that underlie this condition are still largely unclear. PSE has been described as a disorder of multiple neurotransmitter systems. 13 Specifically, the histaminergic synaptic imbalance, which becomes apparent shortly 14,15 and persists for at least 8 months after surgery, 12,16-18 is among the most interesting consequences of portacaval shunting in the rat.We have previously shown that rats with PCA have profound disturbances in their brain histaminergi...

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“…Both the animal models and human cirrhotics manifest a reproducible sequence of neurological impairment, starting with altered daynight rhythms (Therrien et al, 1995), progressing through altered reflexes (Giguère & Butterworth, 1984) to stupor and coma. (Butterworth, 1994). The experimental models chosen result in sustained hyperammonemia (Butterworth, 1994) and in modifications of astrocytic function including reduced expression of key astrocytic proteins (Giguère et al, 1992) similar to those reported in chronic liver failure in humans.…”

Section: Rationale For the Choice Of Animal Modelmentioning

confidence: 93%

“…(Butterworth, 1994). The experimental models chosen result in sustained hyperammonemia (Butterworth, 1994) and in modifications of astrocytic function including reduced expression of key astrocytic proteins (Giguère et al, 1992) similar to those reported in chronic liver failure in humans. Moreover, of direct pertinence to the present work, both the experimental animal models and human chronic liver failure result in the selective accumulation of Mn in pallidum Butterworth et al, 1995;Rose et al, 1999).…”

Section: Rationale For the Choice Of Animal Modelmentioning

confidence: 93%

Assessment of Bioaccumulation and Neurotoxicity in Rats With Portacaval Anastomosis and Exposed to Manganese Phosphate: A Pilot Study

Salehi¹,

Carrier²,

Normandin³

et al. 2001

Inhalation Toxicology

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The use of the additive methylcyclopentadienyl manganese tricarbonyl in unleaded gasoline has resulted in increased attention to the potential toxic effects of manganese (Mn). Hypothetically, people with chronic liver disease may be more sensitive to the adverse neurotoxic effects of Mn. In this work, bioaccumulation of Mn, as well as histopathology and neurobehavioral damage, in end-to-side portacaval anastomosis (PCA) rats exposed to Mn phosphate via inhalation was investigated. During the week before the PCA operation, 4 wk after the PCA operation, and at the end of exposure, the rats were subjected to a locomotor evaluation (day-night activities) using a computerized autotrack system. Then a group of 6 PCA rats (EXP) was exposed to 3050 microg m(-3) (Mn phosphate) for 8 h/day, 5 days/wk for 4 consecutive weeks and compared to a control group (CON), 7 PCA rats exposed to 0.03 microg m(-3). After exposure, the rats were euthanized and Mn content in tissues and organs was determined by neutron activation analysis. The manganese concentrations in blood (0.05 microg/g vs. 0.02 microg/g), lung (1.32 microg/g vs. 0.24 microg/g), cerebellum (0.85 microg/g vs. 0.64 microg/g), frontal cortex (0.87 microg/g vs. 0.61 microg/g), and globus pallidus (3.56 microg/g vs. 1.33 microg/g) were significantly higher in the exposed group compared to the control group (p <.05). No difference was observed in liver, kidney, testes, and caudate putamen between the two groups. Neuronal cell loss was assessed by neuronal cell counts. The loss of cells in globus pallidus and caudate putamen as well as in frontal cortex was significantly higher (p <.05) for the EXP group. Assessment of the locomotor activities did not reveal any significant difference. This study constitutes a first step toward our understanding of the potential adverse effects of Mn in sensitive populations.

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Portal-Systemic Encephalopathy: a Disorder of Multiple Neurotransmitter Systems

Cited by 9 publications

References 43 publications

Acute-on-Chronic Liver Failure: Pathophysiological Basis of Therapeutic Options

Acute-on-Chronic Liver Failure: Pathophysiological Basis of Therapeutic Options

Effects of the histamine H1 receptor blocker, pyrilamine, on spontaneous locomotor activity of rats with long-term portacaval anastomosis

Assessment of Bioaccumulation and Neurotoxicity in Rats With Portacaval Anastomosis and Exposed to Manganese Phosphate: A Pilot Study

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