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Volume 23, Issue 12
  • ISSN: 1871-5273
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Abstract

Background

In response to inflammation and other stressors, tryptophan is catalyzed by Tryptophan 2,3-Dioxygenase (TDO), which leads to activation of the kynurenine pathway. Sepsis is a serious condition in which the body responds improperly to an infection, and the brain is the inflammation target in this condition.

Objective

This study aimed to determine if the induction of TDO contributes to the permeability of the Blood-Brain Barrier (BBB), mortality, neuroinflammation, oxidative stress, and mitochondrial dysfunction, besides long-term behavioral alterations in a preclinical model of sepsis.

Methods

Male Wistar rats with two months of age were submitted to the sepsis model using Cecal Ligation and Perforation (CLP). The rats received allopurinol (Allo, 20 mg/kg, gavage), a TDO inhibitor, or a vehicle once a day for seven days.

Results

Sepsis induction increased BBB permeability, IL-6 level, neutrophil infiltrate, nitric oxide formation, and oxidative stress, resulting in energy impairment in 24h after CLP and Allo administration restored these parameters. Regarding memory, Allo restored short-term memory impairment and decreased depressive behavior. However, no change in survival rate was verified.

Conclusion

In summary, TDO inhibition effectively prevented depressive behavior and memory impairment 10 days after CLP by reducing acute BBB permeability, neuroinflammation, oxidative stress, and mitochondrial alteration.

© 2024 Bentham Science Publishers
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2024-12-01
2024-11-15

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References

  1. SingerM. The new sepsis consensus definitions (Sepsis-3): The good, the not-so-bad, and the actually-quite-pretty.Intensive Care Med.201642122027202910.1007/s00134‑016‑4600‑4 27815587
     [Google Scholar]
  2. RuddK.E. JohnsonS.C. AgesaK.M. Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the global burden of disease study.Lancet20203951021920021110.1016/S0140‑6736(19)32989‑7 31954465
     [Google Scholar]
  3. IwashynaT.J. ElyE.W. SmithD.M. LangaK.M. Long-term cognitive impairment and functional disability among survivors of severe sepsis.JAMA2010304161787179410.1001/jama.2010.1553 20978258
     [Google Scholar]
  4. HensleyM.K. PrescottH.C. Bad brains, bad outcomes: Acute neurologic dysfunction and late death after sepsis.Crit. Care Med.20184661001100210.1097/CCM.0000000000003097 29762396
     [Google Scholar]
  5. PrescottH.C. CostaD.K. Improving long-term outcomes after sepsis.Crit. Care Clin.201834117518810.1016/j.ccc.2017.08.013 29149939
     [Google Scholar]
  6. RogersA.J. McGeachieM. BaronR.M. GazourianL. HaspelJ.A. NakahiraK. Metabolomic derangements are associated with mortality in critically ill adult patients.PLoS One201491e8753810.1371/journal.pone.0087538
     [Google Scholar]
  7. MaddisonD.C. GiorginiF. The kynurenine pathway and neurodegenerative disease.Semin. Cell Dev. Biol.20154013414110.1016/j.semcdb.2015.03.002 25773161
     [Google Scholar]
  8. CurzonG. GreenA.R. Regional and subcellular changes in the concentration of 5‐hydroxytryptamine and 5‐hydroxyindoleacetic acid in the rat brain caused by hydrocortisone, DL‐α‐methyltryptophan l‐kynurenine and immobilization.Br. J. Pharmacol.1971431395210.1111/j.1476‑5381.1971.tb07155.x 5136463
     [Google Scholar]
  9. CurzonG. GreenA.R. Effects of immobilization on rat liver tryptophan pyrrolase and brain 5‐hydroxytryptamine metabolism.Br. J. Pharmacol.196937368969710.1111/j.1476‑5381.1969.tb08507.x 5348471
     [Google Scholar]
  10. BadawyA.A.B. DawoodS. BanoS. Kynurenine pathway of tryptophan metabolism in pathophysiology and therapy of major depressive disorder.World J. Psychiatry202313414114810.5498/wjp.v13.i4.141 37123095
     [Google Scholar]
  11. GiustinaA.D. DanielskiL.G. NovochadloM.M. GoldimM.P.S. JoaquimL. MetzkerK.L.L. Vitamin B6 reduces oxidative stress in lungs and liver in experimental sepsis.An. Acad. Bras. Cienc.2019914e2019043410.1590/0001‑3765201920190434
     [Google Scholar]
  12. DanielskiL.G. Della GiustinaA. GoldimM.P. FlorentinoD. MathiasK. GarbossaL. Vitamin b6 reduces neurochemical and long-term cognitive alterations after polymicrobial sepsis: Involvement of the kynurenine pathway modulation.Mol. Neurobiol.20172017114 28879460
     [Google Scholar]
  13. WelchA.N. BadawyA A B. Tryptophan pyrrolase in haem regulation. Experiments with administered haematin and the relationship between the haem saturation of tryptophan pyrrolase and the activity of 5-aminolaevulinate synthase in rat liver.Biochem. J.1980192240341010.1042/bj1920403 7236220
     [Google Scholar]
  14. HubbardW.J. ChoudhryM. SchwachaM.G. Cecal ligation and puncture.Shock200524Suppl. 1525710.1097/01.shk.0000191414.94461.7e 16374373
     [Google Scholar]
  15. RéusG.Z. BeckerI.R.T. ScainiG. The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia.Prog. Neuropsychopharmacol. Biol. Psychiatry201881556310.1016/j.pnpbp.2017.10.009 29030243
     [Google Scholar]
  16. UyamaO. OkamuraN. YanaseM. NaritaM. KawabataK. SugitaM. Quantitative evaluation of vascular permeability in the gerbil brain after transient ischemia using Evans blue fluorescence.J. Cereb. Blood Flow Metab.19888228228410.1038/jcbfm.1988.59 3343300
     [Google Scholar]
  17. CancelierA.C. PetronilhoF. ReinkeA. Inflammatory and oxidative parameters in cord blood as diagnostic of early-onset neonatal sepsis: A case-control study.Pediatr. Crit. Care Med.200910446747110.1097/PCC.0b013e318198b0e3 19307820
     [Google Scholar]
  18. YoungL.M. KheifetsJ.B. BallaronS.J. YoungJ.M. Edema and cell infiltration in the phorbol ester-treated mouse ear are temporally separate and can be differentially modulated by pharmacologic agents.Agents Actions1989263-433534110.1007/BF01967298 2567568
     [Google Scholar]
  19. GreenL.C. WagnerD.A. GlogowskiJ. SkipperP.L. WishnokJ.S. TannenbaumS.R. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids.Anal. Biochem.1982126113113810.1016/0003‑2697(82)90118‑X 7181105
     [Google Scholar]
  20. DraperH.H. HadleyM. Malondialdehyde determination as index of lipid Peroxidation.Methods Enzymol.199018642143110.1016/0076‑6879(90)86135‑I 2233309
     [Google Scholar]
  21. LevineR.L. GarlandD. OliverC.N. Determination of carbonyl content in oxidatively modified proteins.Methods Enzymol.1990186146447810.1016/0076‑6879(90)86141‑H 1978225
     [Google Scholar]
  22. BannisterJ. Assays for superoxide dismutase.Methods Biochem. Anal.198732279312
     [Google Scholar]
  23. AebiH. Catalase in vitro.Methods Enzymol.1984105C12112610.1016/S0076‑6879(84)05016‑3 6727660
     [Google Scholar]
  24. FischerJ.C. RuitenbeekW. BerdenJ.A. Differential investigation of the capacity of succinate oxidation in human skeletal muscle.Clin. Chim. Acta19851531233610.1016/0009‑8981(85)90135‑4 3000647
     [Google Scholar]
  25. CassinaA. RadiR. Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport.Arch. Biochem. Biophys.1996328230931610.1006/abbi.1996.0178 8645009
     [Google Scholar]
  26. RustinP. ChretienD. BourgeronT. Biochemical and molecular investigations in respiratory chain deficiencies.Clin. Chim. Acta19942281355110.1016/0009‑8981(94)90055‑8 7955428
     [Google Scholar]
  27. LowryO. RosebroughN. FarrA.L. RandallR. Protein measurement with the Folin phenol reagent.J. Biol. Chem.1951193126527510.1016/S0021‑9258(19)52451‑6 14907713
     [Google Scholar]
  28. CarvalhoD. PetronilhoF. VuoloF. The nociceptin/orphanin FQ-NOP receptor antagonist effects on an animal model of sepsis.Intensive Care Med.200834122284229010.1007/s00134‑008‑1313‑3 18846364
     [Google Scholar]
  29. TuonL. ComimC.M. PetronilhoF. Time-dependent behavioral recovery after sepsis in rats.Intensive Care Med.20083491724173110.1007/s00134‑008‑1129‑1 18542919
     [Google Scholar]
  30. RéusG.Z. CarlessiA.S. TitusS.E. A single dose of S ‐ketamine induces long‐term antidepressant effects and decreases oxidative stress in adulthood rats following maternal deprivation.Dev. Neurobiol.201575111268128110.1002/dneu.22283 25728399
     [Google Scholar]
  31. MichelsM. VieiraA.S. VuoloF. The role of microglia activation in the development of sepsis-induced long-term cognitive impairment.Brain Behav. Immun.201543545910.1016/j.bbi.2014.07.002 25019583
     [Google Scholar]
  32. ZarbatoG.F. de Souza GoldimM.P. GiustinaA.D. Dimethyl fumarate limits neuroinflammation and oxidative stress and improves cognitive impairment after polymicrobial sepsis.Neurotox. Res.201834341843010.1007/s12640‑018‑9900‑8 29713994
     [Google Scholar]
  33. MichelsM. DanieslkiL.G. VieiraA. CD40-CD40 ligand pathway is a major component of acute neuroinflammation and contributes to long-term cognitive dysfunction after sepsis.Mol. Med.201521121922610.2119/molmed.2015.00070 25822797
     [Google Scholar]
  34. BarichelloT. GenerosoJ.S. SimõesL.R. Role of Microglial Activation in the Pathophysiology of Bacterial Meningitis.Mol. Neurobiol.20165331770178110.1007/s12035‑015‑9107‑4 25744564
     [Google Scholar]
  35. CalabresiP. CastriotoA. Di FilippoM. PicconiB. New experimental and clinical links between the hippocampus and the dopaminergic system in Parkinson’s disease.Lancet Neurol.2013128811821
     [Google Scholar]
  36. PlaschkeK. FichtenkammP. SchrammC. Early postoperative delirium after open-heart cardiac surgery is associated with decreased bispectral EEG and increased cortisol and interleukin-6.Intensive Care Med.201036122081208910.1007/s00134‑010‑2004‑4 20689917
     [Google Scholar]
  37. MaesM. BerkM. GoehlerL. Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways.BMC Med.20121016610.1186/1741‑7015‑10‑66 22747645
     [Google Scholar]
  38. AndersonG. KuberaM. DudaW. LasońW. BerkM. MaesM. Increased IL-6 trans-signaling in depression: Focus on the tryptophan catabolite pathway, melatonin and neuroprogression.Pharmacol. Rep.20136561647165410.1016/S1734‑1140(13)71526‑3 24553013
     [Google Scholar]
  39. SchwarczR. BrunoJ.P. MuchowskiP.J. WuH.Q. Kynurenines in the mammalian brain: When physiology meets pathology.Nat. Rev. Neurosci.201213746547710.1038/nrn3257 22678511
     [Google Scholar]
  40. ChangsirivathanathamrongD. WangY. RajbhandariD. Tryptophan metabolism to kynurenine is a potential novel contributor to hypotension in human sepsis.Crit. Care Med.201139122678268310.1097/CCM.0b013e31822827f2 21765346
     [Google Scholar]
  41. BarichelloT. LemosJ.C. GenerosoJ.S. Oxidative stress, cytokine/chemokine and disruption of blood-brain barrier in neonate rats after meningitis by Streptococcus agalactiae.Neurochem. Res.201136101922193010.1007/s11064‑011‑0514‑2 21633926
     [Google Scholar]
  42. KovachM.A. StandifordT.J. The function of neutrophils in sepsis.Curr. Opin. Infect. Dis.201225332132710.1097/QCO.0b013e3283528c9b 22421753
     [Google Scholar]
  43. AmanzadaA. MalikI.A. NischwitzM. SultanS. NazN. RamadoriG. Myeloperoxidase and elastase are only expressed by neutrophils in normal and in inflammed liver.Histochem. Cell Biol.2011135330531510.1007/s00418‑011‑0787‑1 21327394
     [Google Scholar]
  44. NovochadloM. GoldimM.P. BonfanteS. Folic acid alleviates the blood brain barrier permeability and oxidative stress and prevents cognitive decline in sepsis-surviving rats.Microvasc. Res.202113710419310.1016/j.mvr.2021.104193 34062190
     [Google Scholar]
  45. DanielskiL.G. GiustinaA.D. BadawyM. Brain barrier breakdown as a cause and consequence of neuroinflammation in sepsis.Mol. Neurobiol.20185521045105310.1007/s12035‑016‑0356‑7 28092082
     [Google Scholar]
  46. FialkowL. WangY. DowneyG.P. Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function.Free Radic. Biol. Med.200742215316410.1016/j.freeradbiomed.2006.09.030 17189821
     [Google Scholar]
  47. AyalT.B. Alternative kynurenic acid synthesis routes studied in the rat cerebellum.Front. Cell. Neurosci.20159178
     [Google Scholar]
  48. Prado De CarvalhoL. BochetP. RossierJ. The endogenous agonist quinolinic acid and the non endogenous homoquinolinic acid discriminate between NMDAR2 receptor subunits.Neurochem. Int.199628444545210.1016/0197‑0186(95)00091‑7 8740453
     [Google Scholar]
  49. Della GiustinaA. GoldimM.P. DanielskiL.G. FlorentinoD. GarbossaL. JoaquimL. Fish oil-rich lipid emulsion modulates neuroinflammation and prevents long-term cognitive dysfunction after sepsis.Nutrition201870110417 30867119
     [Google Scholar]
  50. FlorentinoD. Della GiustinaA. de Souza GoldimM.P. Early life neuroimmune challenge protects the brain after sepsis in adult rats.Neurochem. Int.202013510471210.1016/j.neuint.2020.104712
     [Google Scholar]
  51. GiustinaA.D. BonfanteS. ZarbatoG.F. Dimethyl Fumarate Modulates Oxidative Stress and Inflammation in Organs After Sepsis in Rats.Inflammation201841131532710.1007/s10753‑017‑0689‑z 29124567
     [Google Scholar]
  52. SavioL.E.B. P2X7 receptor signaling contributes to sepsis-associated brain dysfunction.Mol. Neurobiol.201754864596470
     [Google Scholar]
  53. Villavicencio TejoF. QuintanillaR.A. Contribution of the Nrf2 Pathway on oxidative damage and mitochondrial failure in Parkinson and Alzheimer’s disease.Antioxidants2021107106910.3390/antiox10071069 34356302
     [Google Scholar]
  54. GanzellaM. JardimF.M. BoeckC.R. VenditeD. Time course of oxidative events in the hippocampus following intracerebroventricular infusion of quinolinic acid in mice.Neurosci. Res.200655439740210.1016/j.neures.2006.05.003 16766071
     [Google Scholar]
  55. ComimC.M. RezinG.T. ScainiG. Mitochondrial respiratory chain and creatine kinase activities in rat brain after sepsis induced by cecal ligation and perforation.Mitochondrion20088431331810.1016/j.mito.2008.07.002 18657632
     [Google Scholar]
  56. SantiagoA.P.S.A. ChavesE.A. OliveiraM.F. GalinaA. Reactive oxygen species generation is modulated by mitochondrial kinases: Correlation with mitochondrial antioxidant peroxidases in rat tissues.Biochimie200890101566157710.1016/j.biochi.2008.06.013 18634844
     [Google Scholar]
  57. Reyes-OcampoJ. Mitochondrial dysfunction related to cell damage induced by 3-hydroxykynurenine and 3-hydroxyanthranilic acid: Non-dependent-effect of early reactive oxygen species production.Neurotoxicology2015508191
     [Google Scholar]
  58. Colín-GonzálezA.L. Maya-LópezM. Pedraza-ChaverríJ. AliS.F. ChavarríaA. SantamaríaA. The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum.Brain Res.2014158911410.1016/j.brainres.2014.09.034 25251594
     [Google Scholar]
  59. DanielskiL.G. GiustinaA.D. BonfanteS. NLRP3 activation contributes to acute brain damage leading to memory impairment in sepsis-surviving rats.Mol. Neurobiol.202057125247526210.1007/s12035‑020‑02089‑9 32870491
     [Google Scholar]
  60. GoldimM.P. DanielskiL.G. RodriguesJ.F. Oxidative stress in the choroid plexus contributes to blood-cerebrospinal fluid barrier disruption during sepsis development.Microvasc. Res.2019123192410.1016/j.mvr.2018.12.001 30552905
     [Google Scholar]
  61. SprungC.L. Impact of encephalopathy on mortality in the sepsis syndrome. The veterans administration systemic sepsis cooperative study group.Crit. Care Med.1990188801806
     [Google Scholar]
  62. DellingerR.P. LevyM.M. RhodesA. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock, 2012.Intensive Care Med.201339216522810.1007/s00134‑012‑2769‑8 23361625
     [Google Scholar]
  63. BarichelloT. SayanaP. GiridharanV.V. Long-term cognitive outcomes after Sepsis: A translational systematic review.Mol. Neurobiol.201956118625110.1007/s12035‑018‑1048‑2 29687346
     [Google Scholar]
  64. KaurJ. SinghiP. SinghiS. MalhiP. SainiA.G. Neurodevelopmental and behavioral outcomes in children with sepsis-associated encephalopathy admitted to pediatric intensive care unit.J. Child Neurol.201631668369010.1177/0883073815610431 26500243
     [Google Scholar]
  65. PetronilhoF. PéricoS.R. VuoloF. Protective effects of guanosine against sepsis-induced damage in rat brain and cognitive impairment.Brain Behav. Immun.201226690491010.1016/j.bbi.2012.03.007 22497789
     [Google Scholar]
  66. GarbossaL. JoaquimL. DanielskiL.G. The effect of modafinil on passive avoidance memory, brain level of BDNF and oxidative stress markers in sepsis survivor rats.Int. J. Neurosci.20221910.1080/00207454.2022.2154076 36448768
     [Google Scholar]
  67. ParrottJ.M. RedusL. O’ConnorJ.C. Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge.J. Neuroinflammation201613112410.1186/s12974‑016‑0590‑y 27233247
     [Google Scholar]
  68. MorA. Tankiewicz-KwedloA. KrupaA. PawlakD. Role of kynurenine pathway in oxidative stress during neurodegenerative disorders.Cells2021107160310.3390/cells10071603 34206739
     [Google Scholar]
  69. SkorobogatovK. De PickerL. VerkerkR. Brain versus blood: A systematic review on the concordance between peripheral and central kynurenine pathway measures in psychiatric disorders.Front. Immunol.20211271698010.3389/fimmu.2021.716980 34630391
     [Google Scholar]
  70. van der VlietA. BastA. Effect of oxidative stress on receptors and signal transmission.Chem. Biol. Interact.1992852-39511610.1016/0009‑2797(92)90055‑P 1493612
     [Google Scholar]
  71. CobleyJ.N. FiorelloM.L. BaileyD.M. 13 reasons why the brain is susceptible to oxidative stress.Redox Biol.20181549050310.1016/j.redox.2018.01.008 29413961
     [Google Scholar]
  72. BlackC.N. BotM. SchefferP.G. CuijpersP. PenninxB.W.J.H. Is depression associated with increased oxidative stress? A systematic review and meta-analysis.Psychoneuroendocrinology20155116417510.1016/j.psyneuen.2014.09.025 25462890
     [Google Scholar]
  73. JonesC. GriffithsR.D. Mental and physical disability after sepsis.Minerva Anestesiol.2013791113061312 23857443
     [Google Scholar]
  74. JacksonK.C.II St OngeE.L. Antidepressant pharmacotherapy: Considerations for the pain clinician.Pain Pract.20033213514310.1046/j.1533‑2500.2003.03020.x 17163912
     [Google Scholar]
  75. ComimCM Cassol- OJJr ConstantinoLC Depressive-like parameters in sepsis survivor rats.Neurotox. Res.201017327928610.1007/s12640‑009‑9101‑6 19705213
     [Google Scholar]
/content/journals/cnsnddt/10.2174/0118715273282363240415045927
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Amelioration of Neurochemical Alteration and Memory and Depressive Behavior in Sepsis by Allopurinol, a Tryptophan 2,3-Dioxygenase Inhibitor
CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 23, 1499 (2024); https://doi.org/10.2174/0118715273282363240415045927
/content/journals/cnsnddt/10.2174/0118715273282363240415045927
/content/journals/cnsnddt/10.2174/0118715273282363240415045927
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  • Article Type:     Research Article
Keyword(s): blood-brain barrier permeability; catalase; cognitive impairment; oxidative stress; Sepsis; tryptophan-2,3-dioxygenase

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