Kynurenine pathway of tryptophan metabolism in pathophysiology and therapy of major depressive disorder  

作　　者：Abdulla A-B Badawy Shazia Dawood Samina Bano 

机构地区：[1]Formerly School of Health Sciences,Cardiff Metropolitan University,Cardiff CF52YB,United Kingdom [2]Pharmacy and Allied Health Sciences,Iqra University,Karachi 7580,Pakistan [3]Biochemistry,Karachi University,Karachi 75270,Pakistan

出　　处：《World Journal of Psychiatry》2023年第4期141-148,共8页世界精神病学杂志

摘　　要：Serotonin deficiency in major depressive disorder(MDD)has formed the basis of antidepressant drug development and was originally attributed to induction of the major tryptophan(Trp)-degrading enzyme,liver Trp 2,3-dioxygenase(TDO),by cortisol,leading to decreased Trp availability to the brain for serotonin synthesis.Subsequently,the serotonin deficiency was proposed to involve induction of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase(IDO)by proinflammatory cytokines,with inflammation being the underlying cause.Recent evidence,however,challenges this latter concept,as not all MDD patients are immune-activated and,when present,inflammation is mild and/or transient.A wide range of antidepressant drugs inhibit the activity of liver TDO and bind specifically to the enzyme,but not to IDO.IDO induction is not a major event in MDD,but,when it occurs,its metabolic consequences may be masked and overridden by upregulation of kynurenine monooxygenase(KMO),the gateway to production of modulators of immune and neuronal functions.KMO appears to be activated in MDD by certain proinflammatory cytokines and antidepressants with anti-inflammatory properties may block this activation.We demonstrate the ability of the antidepressant ketamine to dock(bind)to KMO.The pathophysiology of MDD may be underpinned by both the serotonin deficiency and glutamatergic activation mediated respectively by TDO induction and N-methyl-D-aspartate receptor activation.Inhibition of TDO and KMO should be the focus of MDD pharmacotherapy.

关 键 词：Major depressive disorder Indoleamine 2 3-dioxygenase Kynurenine monooxygenase Proinflammatory cytokines Serotonin deficiency Tryptophan 2 3-dioxygenase 

分 类 号：R749.4[医药卫生—神经病学与精神病学]