Increased density of catalytic sites and expression of brain monoamine oxidase A in humans with hepatic encephalopathy.
Altered biogenic amine metabolism and function are believed to underlie certain of the neuropsychiatric symptoms, e.g., depression, mania, and anxiety, encountered in clinical hepatic encephalopathy (HE). We therefore investigated the activity of the degradative enzyme monoamine oxidase (MAO) and its binding parameters using [3H]Ro 41-1049 (defining MAO-A) and [3H]Ro 19-6327 (Lazabemide; defining MAO-B) in autopsied brain tissue from male cirrhotic patients with HE. The MAO-B parameters in HE patient tissue were not significantly different from those determined for control tissue. In contrast, increases in MAO-A activities in HE patient frontocortical (by approximately 50%) and cerebellar (by approximately 145%) tissues were observed, confirming our previous findings using comparable tissues. Increases in the abundance of the active MAO-A protein were of the same order of magnitude, e.g., in frontal cortex by approximately 85% and in cerebellum by approximately 225%. Reverse transcriptase-polymerase chain reaction indicated an increase in the level of gene expression (by approximately 155%) and thus offers some of the first evidence of a transcriptional event potentially mediating MAO-A function in human brain tissue. The levels of biogenic amine acid metabolites were increased as expected. As HE patients are most often treated for their hepatic symptoms rather than their neuropsychiatric manifestations, they represent an important "untreated" psychiatric population. The present findings are therefore not only important for our understanding of the pathophysiology of HE but also extremely relevant to our understanding of the pharmacotherapy of other neuropsychiatric disorders in which biogenic amine and MAO-A dysfunction is indicated.
Mousseau
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DD
Neuroscience Research Unit, Hôpital Saint-Luc (University of Montreal), Quebec.
Baker
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GB
Butterworth
R F
RF
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000368:Aged; D001679:Biogenic Amines / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D006501:Hepatic Encephalopathy / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
D001679:Biogenic Amines; D008024:Ligands; D012333:RNA, Messenger; D008995:Monoamine Oxidase; D000251:Adenosine Triphosphatases