Chronic Treatment with the IDO1 Inhibitor 1-Methyl-D-Tryptophan Minimizes the Behavioural and Biochemical Abnormalities Induced by Unpredictable Chronic Mild Stress in Mice - Comparison with Fluoxetine.
We demonstrated that confronting mice to the Unpredictable Chronic Mild Stress (UCMS) procedure-a validated model of stress-induced depression-results in behavioural alterations and biochemical changes in the kynurenine pathway (KP), suspected to modify the glutamatergic neurotransmission through the imbalance between downstream metabolites such as 3-hydroxykynurenine, quinolinic and kynurenic acids. We showed that daily treatment with the IDO1 inhibitor 1-methyl-D-tryptophan partially rescues UCMS-induced KP alterations as does the antidepressant fluoxetine. More importantly we demonstrated that 1-methyl-D-tryptophan was able to alleviate most of the behavioural changes resulting from UCMS exposure. We also showed that both fluoxetine and 1-methyl-D-tryptophan robustly reduced peripheral levels of proinflammatory cytokines in UCMS mice suggesting that their therapeutic effects might occur through anti-inflammatory processes. KP inhibition might be involved in the positive effects of fluoxetine on mice behaviour and could be a relevant strategy to counteract depressive-like symptoms.
Molecular and Experimental Immunology and Neurogenetics - UMR7355, CNRS - 3b Rue de Férollerie, Orléans La Source, Cedex 2, France.
Anthony
A
Laugeray
UMRS INSERM U942, Service de Biochimie, Hôpital Lariboisière, Assistance Publique - Hôpitaux de Paris, Paris, France.
Jean-Marie
JM
Launay
UMRS INSERM U942, Service de Biochimie, Hôpital Lariboisière, Assistance Publique - Hôpitaux de Paris, Paris, France.
Jacques
J
Callebert
UMRS INSERM U930, CNRS ERL 3106, Université François Rabelais, Tours, France.|Department of Pharmacology, Faculty of Medicine, Kocaeli University, 41380 Kocaeli, Turkey.
Oguz
O
Mutlu
Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, NSW, Sydney, Australia.
Gilles J
GJ
Guillemin
UMRS INSERM U930, CNRS ERL 3106, Université François Rabelais, Tours, France.
Catherine
C
Belzung
UMRS INSERM U930, CNRS ERL 3106, Université François Rabelais, Tours, France.
Pascal R
PR
Barone
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D003863:Depression / Q000503:physiopathology / Q000517:prevention & control; D005473:Fluoxetine / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
D018687:Antidepressive Agents, Second-Generation; D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators; D005473:Fluoxetine; D007737:Kynurenine; D014364:Tryptophan; C525396:1-methyltryptophan