MK-801 and 7-Ni attenuate the activation of brain NF-kappa B induced by LPS.
The activation of nuclear factor-kappaB (NF-kappaB) leads to an increase in the expression of genes involved in important events in the central nervous system (CNS), such as development, plasticity and inflammation. It has been shown that inflammatory stimulus in the brain increases excitatory glutamatergic transmission, especially at N-methyl-D-aspartate (NMDA) receptor. These receptors have an important role in glutamate neurotoxicity and are in general coupled with the generation of nitric oxide (NO) through the activation of neuronal nitric oxide synthase (NOS). We have investigated the involvement of NMDA-NO pathway in LPS induction of NF-kappaB in CNS. Our results demonstrate that systemic LPS activates NF-kappaB in several regions of the CNS, which was partially reduced by the NMDA receptor antagonist dizolcipine (MK-801) and by the selective brain NOS inhibitor 7-Nitroindazol (7-Ni). 7-Ni effects were not synergic to MK-801 effects, suggesting that these compounds act through the same pathway. Dexamethasone caused a stronger reduction in LPS induction of NF-kappaB in CNS, demonstrating that MK-801 and 7-Ni act on a pathway that is responsible only by a fraction of the overall NF-kappaB activation. These results suggest that a considerable part of NF-kappaB activation by LPS is linked to the NMDA/NO pathway in CNS.
Glezer
Isaias
I
Molecular Neuropharmacology Laboratory, Department of Pharmacology, Institute of Biomedical Science-ICB-1, Avenida Professor Lineu Prestes, 1524, University of São Paulo, Sao Paulo 05508-900, Brazil.
Munhoz
Carolina Demarchi
CD
Kawamoto
Elisa Mitiko
EM
Marcourakis
Tania
T
Avellar
Maria Christina Werneck
MC
Scavone
Cristoforo
C
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007191:Indazoles / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D007191:Indazoles; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016291:Dizocilpine Maleate; C080122:7-nitroindazole