Disrupted Tryptophan Metabolism Induced Cognitive Impairment in a Mouse Model of Sepsis-associated Encephalopathy.
Sepsis-associated encephalopathy (SAE) is a common complication in critically ill patients and is associated with a poor prognosis. However, the precise mechanisms underlying sepsis-induced cognitive impairment remain largely to be elucidated. The aim of the present study was to investigate whether indoleamine 2, 3-dioxygenase (IDO) activation-mediated neurotoxicity is involved in the pathophysiology of sepsis-induced cognitive impairment. Sepsis was induced by cecal ligation/perforation (CLP). The animals were randomly divided into the following five groups: Sham + vehicle group; Sham + 1-methyl-D, L-tryptophan group; Sham + L-Kynurenine group; CLP + vehicle group; or CLP + 1-methyl-D, L-tryptophan group. The survival rate was estimated by the Kaplan-Meier method. Behavioral tests were performed by the open field and fear conditioning tests at days 13 and 14 after operation. In the present study, we demonstrated that sepsis induced a deficit in hippocampus-dependent cognitive impairment in a mouse model of SAE. Furthermore, a single peripheral kynurenine administration, the metabolic product of IDO, induced a deficit in the cognitive impairment in the sham mice. However, mice treated with IDO inhibitor 1-methyl-D, L-tryptophan were protected from sepsis-induced cognitive impairment. In conclusion, our study implicates IDO-dependent neurotoxic kynurenine metabolism as a critical factor responsible for the sepsis-induced cognitive impairment and a potential novel target for the treatment of SAE.
Department of Emergency and intensive care medicine, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nanjing University of Chinese Medicine, Nanjing, 210014, China.
Rong
R
Gao
Department of Emergency and intensive care medicine, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nanjing University of Chinese Medicine, Nanjing, 210014, China.
Ming-qiang
MQ
Kan
Department of Emergency and intensive care medicine, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nanjing University of Chinese Medicine, Nanjing, 210014, China.
Shi-gang
SG
Wang
Department of Emergency and intensive care medicine, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nanjing University of Chinese Medicine, Nanjing, 210014, China. yangrunhua1975@163.com.
Run-hua
RH
Yang
Department of Anesthesiology, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nanjing University of Chinese Medicine, Nanjing, 210014, China.
Shao-gang
SG
Zhang
D000818:Animals; D002432:Cecum / Q000601:surgery; D060825:Cognitive Dysfunction / Q000473:pathology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000473:pathology*; D065166:Sepsis-Associated Encephalopathy / Q000473:pathology*; D014364:Tryptophan / Q000378:metabolism* / Q000494:pharmacology
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan
cognitive impairment; indoleamine 2, 3-dioxygenase; kynurenine; sepsis