Advertisement

Canadian Journal of Anesthesia

, Volume 47, Issue 10, pp 1019–1024 | Cite as

Ketamine suppresses endotoxin-induced NF-κB expression

  • Tetsuhiro Sakai
  • Takashi Ichiyama
  • Charles W. WhittenEmail author
  • Adolph H. Giesecke
  • James M. Lipton
Laboratory Investigations

Abstract

Purpose: Ketamine reduces endotoxin-induced production of proinflammatory cytokines, including tumour necrosis factor- α (TNF), in several types of inflammatory cells, including monocytes and macrophages. Transcription of the genes that encode production of these proinflammatory cytokines is regulated by nuclear factor-kappa B (NF-κB). Cytoplasmic B protein is activated by endotoxin (LPS) as well as by TNF, allowing B protein to migrate into the cell nucleus to activate gene transcription for these inflammatory mediators. Because NF-κB is likely involved in brain injury and inflammatory neurodegenerative disease, such as multiple sclerosis, we examined whether ketamine inhibits LPS-induced activation of NF-κB in human glioma cellsin vitro and intact mouse brain cellsin vivo.

Methods: Endotoxin-induced NF-κB expression in both the human glioma cellsin vitro and the intact mouse brain cellsin vivo was determined by electrophoretic mobility shift assays (EMSA) of nuclear extracts and measurement of NF-κB expression by densitometry. Endotoxin was injected intracerebroventricularlyin vivo and intact brain was harvested. Klenow fragment labeling was used to identify NF-κB protein for both thein vivo andvitro experiments.

Results: Endotoxin treatment increased NF-κB expression (P<0.05) bothin vivo andvitro compared with control (untretaed) cells. Ketamine suppressed endotoxin-induced neuronal NF-κB activation in a dose-dependent manner (P<0.05, except for the 10−5M concentrationin vitro) bothin vivo andvitro.

Conclusion: Ketamine inhibits endotoxin-induced NF-κB expression in brain cellsin vivo andvitro and it is suggested that this may have implications in the neuroprotective effects of ketamine reported by other investigators.

Keywords

Ketamine Nuclear Extract Electrophoretic Mobility Shift Assay Human Glioma Cell Traumatic Spinal Cord Injury 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Résumé

Objectif: La kétamine réduit la production de cytokines pro-inflammatoires induite par endotoxine, y compris le facteur nécrosant des tumeurs (TNF), dans certains types de cellules inflammatoires comprenant les monocytes et les macrophages. La transcription des gènes qui encodent la production de ces cytokines pro-inflammatoires est réglée par le facteur-kappa B nucléaire (NF-6B). La protéine cytoplasmique 6B est activée par l’endotoxine (LPS) et par le TNF et peut ainsi migrer dans le noyau cellulaire et activer la transcription génique pour ces médiateurs de l’inflammation. Comme le NF-6B participe probablement aux lésions cérébrales et aux maladies inflammatoires neurodégénératives, dont la sclérose en plaques, notre but était de savoir si la kétamine inhibe l’activation de NF-6B induit par LPS dans des cellules de gliome humainin vitro et dans des cellules cérébrales intactes de sourisin vivo.

Méthode: L’expression du NF-6B induite par endotoxine dans les cellules humainesin vitro et dans les cellules de sourisin vivo a été déterminée par une étude de retardement de la mobilité électrophorétique (ERME) d’extraits nucléaires et la mesure de l’expression du NF-6B a été faite par densitométrie. L’endotoxine a été injectée dans les ventricules cérébrauxin vivo et du tissu cérébral intact a été prélevé. Le marquage de fragments de Klenow a été utilisé pour identifier la protéine du NF-6B des deux expériencesin vivo etvitro.

Résultats: Le traitement avec l’endotoxine a augmenté l’expression du NF-6B (P<0,05) des cellulesin vivo etin vitro comparées aux cellules témoin (non traitées). La kétamine a supprimé l’activation neuronale de NF-6B induite par endotoxine d’une façon dose-dépendante (P<0,05, sauf pour une concentration de 10−5Min vitro) des cellulesin vivo etin vitro.

Conclusion: La kétamine inhibe l’expression de NF-6B induite par endotoxine dans des cellules cérébralesin vivo etin vitro et on croit que cela pourrait contribuer aux effets neuroprotecteurs de la kétamine dont parlent d’autres chercheurs.

References

  1. 1.
    Baldwin AS Jr. The NF-κB and IκB proteins: new discoveries and insights. Ann Rev Immunol 1996; 14: 649–81.CrossRefGoogle Scholar
  2. 2.
    Larsen B, Hoff G, Wilhelm W, Buchinger H, Wanner GA, Bauer M. Effect of intravenous anesthetics on spontaneous and endotoxin-stimulated cytokine response in cultured human whole blood. Anesthesiology 1998; 89: 1218–27.PubMedCrossRefGoogle Scholar
  3. 3.
    Kawasaki T, Ogata M, Kawasaki C, Ogata J, Inoue Y, Shigematsu A. Ketamine suppresses proinflammatory cytokine production in human whole bloodin vitro. Anesth Analg 1999; 89: 665–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Takenaka I, Ogata M, Koga K, Matsumoto T, Shigematsu A. Ketamine suppresses endotoxin-induced tumor necrosis factor alpha production in mice. Anesthesiology 1994; 80: 402–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Jimi N, Segawa K, Minami K, Sata T, Shigematsu A. Inhibitory effect of the intravenous anesthetic, ketamine, on rat mesangial cell proliferation. Anesth Analg 1997; 84: 190–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Roythlat L, Talmor D, Rachinsky M, et al. Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth Analg 1998; 87: 266–71.CrossRefGoogle Scholar
  7. 7.
    Bethea JR, Castro M, Keane RW, Lee TT, Dietrich WD, Yezierski RP. Traumatic spinal cord injury induces nuclear factor-B activation. J Neuroscience 1998; 18; 3251–60.Google Scholar
  8. 8.
    Guerrini L, Blasi F, Denis-Donini S. Synaptic activation of NF-κB by glutamate in cerebellar granule neuronsin vitro. Proc Natl Acad Sci USA1995; 92: 9077–81.PubMedCrossRefGoogle Scholar
  9. 9.
    Moynagh PN, Williams DC, O’Neill LA Interelukin-1 activates transcription factor NF-κB in glial cells. Biochem J 1993; 294: 343–7.PubMedGoogle Scholar
  10. 10.
    O’Neill LAJ, Kaltschmidt C NF-κB: a crucial transcription factor for glial and neuronal function. Trends Neurosci 1997; 20: 252–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Himmelseher S, Pfenninger E, Georgieff M. The effects of ketamine-isomers on neuronal injury and regeneration in rat hippocampal neurons. Anesth Analg 1996; 83: 505–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Kahn RA, Panah M, Weinberger J. Modulation of ischemic excitatory neurotransmitter and -aminobutyric acid release during global temporary cerebral ischemia by selective neuronal nitric oxide synthase inhibition. Anesth Analg 1997; 84: 997–1003.PubMedCrossRefGoogle Scholar
  13. 13.
    Ichiyama T, Zhao H, Catania A, Furukawa A, Lipton JM. -melanocyte-stimulating hormone inhibits NF-κB activation and IkB degradation in human astrocytes and in experimental brain inflammation. Exp Neurol 1999; 157: 359–65.PubMedCrossRefGoogle Scholar
  14. 14.
    Haley TJ, McCormick WG. Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. Br J Pharmacol 1957; 12: 12–5.Google Scholar
  15. 15.
    Lipton JM, Macaluso A, Hiltz ME, Catania A. Central administration of the peptide -MSH inhibits inflammation in the skin. Peptides 1991; 12: 795–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Deryckere F, Gannon F. A one-hour minipreparation technique for extraction of DNA-binding proteins from animal tissues. Biotechniques 1994; 16: 405.PubMedGoogle Scholar
  17. 17.
    Unlap T, Jope RS. Dexamethasone attenuates kainate-induced AP-1 activation in rat brain. Mol Brain Res 1994; 24: 275–82.PubMedCrossRefGoogle Scholar
  18. 18.
    Rothwell NJ, Hopkins SJ. Cytokines and the nervous system II: actions and mechanisms of action. Trends Neurosci 1995; 18: 130–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Woodroofe MN. Cytokine production in the central nervous system. Neurology 1995; 45(Suppl 6): S6–10.PubMedGoogle Scholar
  20. 20.
    Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg 1998; 87: 1186–93.PubMedCrossRefGoogle Scholar
  21. 21.
    Shapira Y, Artru AA, Lam AM. Ketamine decreases cerebral infarct volume and improves neurological outcome following experimental head trauma in rats. J Neurosurg Anesth 1992; 4: 231–40.CrossRefGoogle Scholar
  22. 22.
    Oddis CV, Finkel MS. NF-B and GTP cyclohydrolase regulate cytokine-induced nitric oxide production by cardiac myocytes. Am J Physiol 1996; 270: H1864–8.PubMedGoogle Scholar
  23. 23.
    Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 1991; 88: 6368–71.PubMedCrossRefGoogle Scholar
  24. 24.
    Tseng EE, Brock MV, Lange MS, et al. Nitric oxide mediates neurologic injury after hypothermic circulatory arrest. Ann Thorac Surg 1999; 67: 65–71.PubMedCrossRefGoogle Scholar
  25. 25.
    Galley HF, Webster NR. Brain nitric oxide synthase activity is decreased by in travenous anesthetics. Anesth Analg 1996; 83: 591–4.PubMedCrossRefGoogle Scholar
  26. 26.
    Shimaoka M, Iida T, Ohara A, et al. Ketamine inhibits nitric oxide production in mouse-activated macrophage-like cells. Br J Anaesth 1996; 77: 238–42.PubMedGoogle Scholar
  27. 27.
    Kessler P, Kronemann N, Hecker M, Busse R, Schini-Kerth VB. Effects of barbiturates on the expression of the inducible nitric synthase in vascular smooth muscle. J Cardiovasc Pharmacol 1997; 30: 802–10.PubMedCrossRefGoogle Scholar
  28. 28.
    Wieber J, Gugler R, Hengstmann JH, Dengler HJ. Pharmacokinetics of ketamine in man. Anaesthesist 1975; 24: 260–3.PubMedGoogle Scholar
  29. 29.
    Idvall J, Ahlgren I, Aronsen KF, Stenberg P. Ketamine infusions: pharmacokinetics and clinical effects. Br J Anaesth 1979; 51: 1167–72.PubMedCrossRefGoogle Scholar

Copyright information

© Canadian Anesthesiologists 2000

Authors and Affiliations

  • Tetsuhiro Sakai
    • 1
  • Takashi Ichiyama
    • 1
  • Charles W. Whitten
    • 1
    Email author
  • Adolph H. Giesecke
    • 1
  • James M. Lipton
    • 1
  1. 1.From the Departments of Anesthesiology and Pain Management and PhysiologyThe University of Texas Southwestern Medical Center at DallasDallasUSA

Personalised recommendations