title: Activation of brain indoleamine 2,3-dioxygenase contributes to epilepsy-associated depressive-like behavior in rats with chronic temporal lobe epilepsy.
abstract: BACKGROUND
  Depression has most often been diagnosed in patients with temporal lobe epilepsy (TLE), but the mechanism underlying this association remains unclear. In this study, we report that indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in tryptophan metabolism, plays a key role in epilepsy-associated depressive-like behavior.
  
  
  METHODS
  Rats which develop chronic epilepsy following pilocarpine status epilepticus exhibited a set of interictal disorders consistent with depressive-like behavior. Changes of depressive behavior were examined by taste preference test and forced swim test; brain IL-1β, IL-6 and IDO1 expression were quantified using real-time reverse transcriptase PCR; brain kynurenine/tryptophan and serotonin/tryptophan ratios were analyzed by liquid chromatography-mass spectrometry. Oral gavage of minocycline or subcutaneous injection of 1-methyltryptophan (1-MT) were used to inhibite IDO1 expression.
  
  
  RESULTS
  We observed the induction of IL-1β and IL-6 expression in rats with chronic TLE, which further induced the upregulation of IDO1 expression in the hippocampus. The upregulation of IDO1 subsequently increased the kynurenine/tryptophan ratio and decreased the serotonin/tryptophan ratio in the hippocampus, which contributed to epilepsy-associated depressive-like behavior. The blockade of IDO1 activation prevented the development of depressive-like behavior but failed to influence spontaneous seizures. This effect was achieved either indirectly, through the anti-inflammatory tetracycline derivative minocycline, or directly, through the IDO antagonist 1-MT, which normalizes kynurenine/tryptophan and serotonin/tryptophan ratios.
  
  
  CONCLUSIONS
  Brain IDO1 activity plays a key role in epileptic rats with epilepsy-associated depressive-like behavior.
authors.affiliation: Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China. xieweizn@fimmu.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.forename: Lun
authors.initials: L
authors.lastname: Cai
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Yu
authors.forename: Liang
authors.initials: L
authors.lastname: Gao
authors.forename: Limin
authors.initials: L
authors.lastname: Xiao
authors.forename: Qianchao
authors.initials: Q
authors.lastname: He
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Ren
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D016207:Cytokines / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy; D005518:Food Preferences; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D018021:Lithium Chloride / Q000633:toxicity; D008297:Male; D013058:Mass Spectrometry; D008911:Minocycline / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D013997:Time Factors; D014364:Tryptophan / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; D008911:Minocycline; D018021:Lithium Chloride; C525396:1-methyltryptophan