Peripheral and cerebral metabolic abnormalities of the tryptophan-kynurenine pathway in a murine model of major depression.
Occurring both peripherally and centrally, the kynurenine pathway (KP) - an alternative pathway to 5-HT synthesis from tryptophan (TRP) - could be of particular value to better understand the link between peripheral changes of circulating levels of glucocorticoids (GC)/proinflammatory cytokines and altered neurotransmission observed in depressed patients. Indeed, it is activated by these mediators of stress and can produce several neuroactive compounds like quinolinic acid (QUIN) and kynurenic acid (KYNA) that can respectively increase and decrease glutamate concentration in brain. In order to characterize the role of both the peripheral and cerebral KP in the pathophysiology of depressive disorders, we used the Unpredictable Chronic Mild Stress (UCMS) to induce a depressive-like syndrome and we then measured the level of relevant TRP-KYN pathway metabolites: KYN, 3-hydroxykynurenine (3HK; precursor of QUIN) and KYNA. We also measured TRP-5HT pathway metabolites: TRP, 5-HT, 5-HIAA. We showed that UCMS increased TRP catabolism along the KP in the periphery. 5-HT and KYN were found to be strongly negatively correlated in all brain structures of control mice and of UCMS mice except in the hippocampus. More importantly we found that KYN was preferentially metabolized along the QUIN pathway at the subcortical level (amygdala/striatum) whereas, at the cortical level (cingulate cortex), the QUIN pathway was reduced. Considering the role of these metabolites on the glutamatergic neurotransmission, we propose that such KP alterations could participate to the cortical/subcortical glutamatergic alterations reported in depressed patients.
Laugeray
Anthony
A
UMRS INSERM U930, CNRS ERL 3106, Université François Rabelais, Tours, France. anthony.laugeray@etu.univ-tours.fr <anthony.laugeray@etu.univ-tours.fr>
Launay
Jean-Marie
JM
Callebert
Jacques
J
Surget
Alexandre
A
Belzung
Catherine
C
Barone
Pascal R
PR
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002908:Chronic Disease; D003865:Major Depressive Disorder / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008807:Mice, Inbred BALB C; D012701:Serotonin / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism*
C005045:3-hydroxykynurenine; D012701:Serotonin; D007737:Kynurenine; D006897:Hydroxyindoleacetic Acid; D014364:Tryptophan