title: Effects of pentoxifylline, 7-nitroindazole, and imipramine on tumor necrosis factor-α and indoleamine 2,3-dioxygenase enzyme activity in the hippocampus and frontal cortex of chronic mild-stress-exposed rats.
abstract: OBJECTIVE
  This study aimed to investigate the role of tumor necrosis factor (TNF)-α and the neuronal nitric oxide synthase enzyme in dysregulation of indoleamine 2,3-dioxygenase (IDO) enzyme, and hence serotonin availability in chronic mild stress (CMS), an animal model of depression.
  
  
  METHODS
  RATS WERE DIVIDED INTO FIVE GROUPS: two control and CMS-exposed for 6 weeks, and another three groups exposed to CMS and administered pentoxifylline 50 mg/kg/day intraperitoneally, 7-nitroindazole 40 mg/kg/day subcutaneously, or imipramine 20 mg/kg/day intraperitoneally for the previous 3 CMS weeks. Rats were assessed for neurochemical and immunohistochemical abnormalities.
  
  
  RESULTS
  Pentoxifylline-, 7-nitroindazole-, and imipramine-treated rats showed amelioration of CMS-induced behavioral deficits that was accompanied by significant reduction in kynurenine/serotonin molar ratio and nitrates/nitrites in frontal cortex and hippocampus. In the pentoxifylline and 7-nitroindazole groups, serum TNF-α was reduced relative to the CMS group (18.54 ± 0.85 and 19.16 ± 1.54 vs 26.20 ± 1.83 pg/mL, respectively; P < 0.05). Exposure to CMS increased TNF-α and IDO immunohistochemical staining scores in both hippocampus and midbrain raphe nuclei. 7-Nitroindazole and pentoxifylline significantly (P < 0.05) reduced TNF-α immunostaining in hippocampus and raphe nuclei, with significant (P < 0.01) reduction of IDO immunostaining in raphe nuclei. Likewise, imipramine reduced TNF-α immunostaining (P < 0.05) in hippocampus.
  
  
  CONCLUSIONS
  Neuronal nitric oxide synthase and TNF-α may play a concerted role in modulating IDO enzyme activity in CMS-exposed rats and provide additional evidence for possible alternative approaches to switch the neurobiological processes in depression.
authors.affiliation: Department of Pharmacology, National Research Centre, Cairo, Egypt; ; Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, Canada.
authors.forename: Bassim Msa
authors.initials: BM
authors.lastname: Mohamed
authors.forename: Sawsan
authors.initials: S
authors.lastname: Aboul-Fotouh
authors.forename: Eman A
authors.initials: EA
authors.lastname: Ibrahim
authors.forename: Hanan
authors.initials: H
authors.lastname: Shehata
authors.forename: Amal A
authors.initials: AA
authors.lastname: Mansour
authors.forename: Nemat Az
authors.initials: NA
authors.lastname: Yassin
authors.forename: Wafaa
authors.initials: W
authors.lastname: El-Eraky
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Abdel-Tawab
keywords: TNF-α; chronic mild stress; immunohistochemistry; kynurenine; nNOS; serotonin