Increased activities of MAOA and MAOB in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy

Rao, Venkat K.; Giguère, Jean-François; Layrargues, Gilles Pomier; Butterworth, Roger F.

doi:10.1016/0006-8993(93)90126-8

Cited by 65 publications

(33 citation statements)

References 18 publications

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“…MAO A has been reported to be relatively high in thalamus (29,30) and in occipital cortex (31), with intermediate values in basal ganglia, frontal, and temporal cortices (29,32) and a low concentration in cerebellum (31), though this comparison is limited by the lack of a single postmortem study measuring the same regions sampled by PET.…”

Section: Discussionmentioning

confidence: 98%

Brain monoamine oxidase A inhibition in cigarette smokers

Fowler

Volkow

Wang

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

388

219

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Several studies have documented a strong association between smoking and depression. Because cigarette smoke has been reported to inhibit monoamine oxidase (MAO) A in vitro and in animals and because MAO A inhibitors are effective antidepressants, we tested the hypothesis that MAO A would be reduced in the brain of cigarette smokers. We compared brain MAO A in 15 nonsmokers and 16 current smokers with [ 11 C]clorgyline and positron emission tomography (PET). Four of the nonsmokers were also treated with the antidepressant MAO inhibitor drug, tranylcypromine (10 mg͞day for 3 days) after the baseline PET scan and then rescanned to assess the sensitivity of [ 11 C]clorgyline binding to MAO inhibition. MAO A levels were quantified by using the model term k 3 which is a function of brain MAO A concentration. Smokers had significantly lower brain MAO A than nonsmokers in all brain regions examined (average reduction, 28%). The mean k 3 values for the whole brain were 0.18 ؎ 0.04 and 0.13 ؎ 0.03 cc brain (ml plasma )؊1 min ؊1 for nonsmokers and smokers, respectively; P < 0.0003). Tranylcypromine treatment reduced k 3 by an average of 58% for the different brain regions. Our results show that tobacco smoke exposure is associated with a marked reduction in brain MAO A, and this reduction is about half of that produced by a brief treatment with tranylcypromine. This suggests that MAO A inhibition needs to be considered as a potential contributing variable in the high rate of smoking in depression and in the development of more effective strategies for smoking cessation.There are approximately 1 billion cigarette smokers in the world today and about 3 million die each year from smokingassociated illnesses (1). This places a sense of urgency on understanding the neuropharmacological properties of tobacco smoke and their relationship to smoking behavior and epidemiology. For example, it is not understood why smoking is more prevalent in depression and why smoking cessation is less successful in depressed patients (2, 3). Though it is unlikely that any one factor accounts for the strong association between smoking and depression, it is possible that tobacco smoke may have antidepressant properties. One of the molecular targets proposed to link smoking and depression is monoamine oxidase (MAO) (4, 5), an enzyme which was first associated with mood over 40 years ago when it was discovered that MAO inhibitors had antidepressant properties (6, 7).MAO exists in two subtypes (MAO A and B) that are different gene products (8, 9). In the brain, MAO A oxidizes serotonin and norepinephrine and is found primarily in catecholaminergic neurons, whereas MAO B oxidizes benzylamine and phenethylamine and is localized in serotonergic neurons and in glial cells (10). Both forms oxidize dopamine (11). The antidepressant effects of the nonselective MAO inhibitors are generally attributed to the inhibition of MAO A (12).We recently reported that smokers have reduced brain MAO B relative to nonsmokers and former smokers (13).Others have fo...

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Section: Discussionmentioning

confidence: 98%

Brain monoamine oxidase A inhibition in cigarette smokers

Fowler

Volkow

Wang

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

388

219

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“…A significant elevation of blood manganese was recently reported in three patients mine-degrading enzyme monoamine oxidase, and of postsynaptic dopamine D 1 binding sites in basal ganglia. 24,25 Studies with biopsy-proven cirrhosis who exhibited characteristic pallidal MRI changes, 19 and studies in autopsied brain tissue from in autopsied brain tissue from cirrhotic patients who died in hepatic coma reveal a selective loss of postsynaptic dopamine cirrhotic patients who died in hepatic coma have consistently revealed selective increases of pallidal manganese. 6,15 Results D 2 binding sites in pallidum, 26 coincident with two-to fivefold increases of manganese in this brain structure.…”

Section: Portacaval Shuntmentioning

confidence: 99%

Increased blood manganese in cirrhotic patients: Relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms

et al. 1996

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1 long-term parenteral nutrition, 3 and after occupational manIncreasing evidence suggests that manganese deposiganese exposure sufficient to cause Parkinson's-like extrapytion is responsible for the T 1 -weighted magnetic resoramidal symptoms. 4 MRI signal hyperintensities may disapnance imaging (MRI) signal hyperintensity consistently pear after the cessation of manganese administration during observed in pallidum of cirrhotic patients. However, the parenteral nutrition 5 or after liver transplantation. 1 More relationship between blood manganese and the etiology recently, we demonstrated that pallidal manganese concenor severity of liver disease, as well as the neurological trations were markedly elevated in cirrhotic patients who symptomatology in these patients, has not been well esdied in hepatic coma. tablished. In the present study, blood manganese conHepatic encephalopathy (HE) is a spectrum of neuropsychicentrations were measured by atomic absorption specatric disturbances occurring in patients with chronic liver trometry together with MRI and neurological evaluation disease. Variable degrees of impairment of mental function in 57 cirrhotic patients with various etiologies and seare observed, and close clinical examination may disclose exverity of liver disease. Blood manganese concentrations trapyramidal signs. Recent reports evaluating the relationwere elevated in 67% of cirrhotic patients and were sigship between pallidal hyperintensity and neurological sympnificantly higher in patients with previous portacaval toms provide conflicting results. 7-12 Because manganese anastomoses or transjugular intrahepatic portosystemic toxicity may result in both pallidal hyperintensity and in shunt (TIPS). Pallidal signal hyperintensity was ob-Parkinson's-like extrapyramidal symptoms, and because served in 88% of patients, and significant correlations similar symptoms have been described in patients with were demonstrated between blood manganese and palchronic liver disease, we evaluated and attempted to correlidal index (PI) (a measure of pallidal signal hyperintenlate, in the same cirrhotic patients, neurological status, T 1 -sity), as well as Child-Pugh score. Assessment of extrapyweighted pallidal MRI signal intensity, and blood manganese ramidal symptoms using the Columbia rating scale concentrations. revealed a significant incidence of tremor, rigidity, or akinesia in up to 89% of cirrhotic patients. However, PATIENTS AND METHODSthere was no significant correlation between blood manPatients. Fifty-seven patients with biopsy-proven cirrhosis were ganese and extrapyramidal symptoms, although severincluded in the present study. None of them had clinically overt ity of akinesia was significantly greater in Child-Pugh encephalopathy. Clinical and biochemical characteristics are shown C patients. Extrapyramidal symptoms could result from in Table 1. a toxic effect of manganese on basal ganglia dopaminerNeurological evaluation was performed by the same neurologist gic function. These findings further support a rol...

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“…Chronic manganese administration causes increased activity of the monoamine-degrading enzyme monoamine oxidase (MAO) in brain (Subhash andPadmashree, 1990, Leung et al, 1986). Increased activities of both MAOA and MAOB isoforms have been described in autopsied brain tissue from cirrhotic patients who died in hepatic coma (Raghavendra Rao et al, 1993) and a selective loss of binding sites for the dopamine D2 receptor ligand 3H spiperone has been observed in pallidum of cirrhotic patients (Bergeron et al, 1989).…”

Section: Relationship Between Brain Manganese Accumulation and Neurolmentioning

confidence: 99%

Untitled

Layrargues

Rose

Spahr

et al. 1998

Metabolic Brain Disease

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Amongst the potential neurotoxins implicated in the pathogenesis of hepatic encephalopathy, manganese emerges as a new candidate. In patients with chronic liver diseases, manganese accumulates in blood and brain leading to pallidal signal hyperintensity on T1-weighted Magnetic Resonance (MR) Imaging. Direct measurements in globus pallidus obtained at autopsy from cirrhotic patients who died in hepatic coma reveal 2 to 7-fold increases of manganese concentration. The intensity of pallidal MR images correlates with blood manganese and with the presence of extrapyramidal symptoms occurring in a majority of cirrhotic patients. Liver transplantation results in normalization of pallidal MR signals and disappearance of extrapyramidal symptoms whereas transjugular intrahepatic portosystemic shunting induces an increase in pallidal hyperintensity with a concomitant deterioration of neurological dysfunction. These findings suggest that the toxic effects of manganese contribute to extrapyramidal symptoms in patients with chronic liver disease. The mechanisms of manganese neurotoxicity are still speculative, but there is evidence to suggest that manganese deposition in the pallidum may lead to dopaminergic dysfunction. Future studies should be aimed at evaluating the effects of manganese chelation and/or of treatment of the dopaminergic deficit on neurological symptomatology in these patients.

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Increased activities of MAOA and MAOB in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy

Cited by 65 publications

References 18 publications

Brain monoamine oxidase A inhibition in cigarette smokers

Brain monoamine oxidase A inhibition in cigarette smokers

Increased blood manganese in cirrhotic patients: Relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms

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