Ketamine suppresses endotoxin-induced NF-kappaB expression.
OBJECTIVE
Ketamine reduces endotoxin-induced production of proinflammatory cytokines, including tumour necrosis factor-alpha (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-kappaB). 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-kappaB is likely involved in brain injury and inflammatory neurodegenerative disease, such as multiple sclerosis, we examined whether ketamine inhibits LPS-induced activation of NF-kappaB in human glioma cells in vitro and intact mouse brain cells in vivo.


METHODS
Endotoxin-induced NF-kappaB expression in both the human glioma cells in vitro and the intact mouse brain cells in vivo was determined by electrophoretic mobility shift assays (EMSA) of nuclear extracts and measurement of NF-kappaB expression by densitometry. Endotoxin was injected intracerebroventricularly in vivo and intact brain was harvested. Klenow fragment labeling was used to identify NF-kappaB protein for both the in vivo and vitro experiments.


RESULTS
Endotoxin treatment increased NF-kappaB expression (P < 0.05) both in vivo and vitro compared with control (untreated) cells. Ketamine suppressed endotoxin-induced neuronal NF-kappaB activation in a dose-dependent manner (P < 0.05, except for the 10(-5) M concentration in vitro) both in vivo and vitro.


CONCLUSIONS
Ketamine inhibits endotoxin-induced NF-kappaB expression in brain cells in vivo and vitro and it is suggested that this may have implications in the neuroprotective effects of ketamine reported by other investigators.
Sakai
T
T
Department of Anesthesiology and Pain Management, The University of Texas Southwestern Medical Center at Dallas, 75390-9068, USA.
Ichiyama
T
T
Whitten
C W
CW
Giesecke
A H
AH
Lipton
J M
JM
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D008070:Lipopolysaccharides; D016328:NF-kappa B; D009569:Nitric Oxide; D007649:Ketamine