The IkappaB kinase inhibitor sulfasalazine impairs long-term memory in the crab Chasmagnathus.
Evidence for the participation of Rel/NF-kappaB transcription factors in long-term memory has recently been reported in the context-signal learning paradigm of the crab Chasmagnathus, in which a high correlation between long-term memory formation and NF-kappaB activation was observed. Two components of the NF-kappaB pathway in the crab brain have now been identified by cross-immunoreactivity using mammalian antibodies for IkappaB-alpha and IkappaB kinase alpha. Furthermore, IkappaB kinase-like phosphotransferase activity, which was inhibited by the IkappaB kinase inhibitor sulfasalazine, was detected in brain extracts. We have evaluated the effect of sulfasalazine administration on long-term memory tested at 48 h. Amnesia was found when sulfasalazine was administered pre-training and 5 h after training but not at 0 or 24 h after training. Thus, two periods for sulfasalazine-induced amnesia were found in coincidence with the two phases of NF-kappaB activation previously described (immediately and 6 h after training). The cyclooxygenase inhibitor indomethacin did not induce amnesia when administered pre-training. Thus, the possibility that sulfasalazine induces amnesia by means of cyclooxygenase inhibition is unlikely to be tenable. In vivo sulfasalazine inhibition of basal NF-kappaB activity was found between 30 and 45 min after injection, as assessed by electrophoretic mobility shift assay. On the other hand, in vivo sulfasalazine administration 6 h after training inhibited the second phase of training-induced NF-kappaB activation, providing evidence that the sulfasalazine effect on memory is due to a direct effect of the drug on the NF-kappaB pathway. These results provide the first evidence that IkappaB kinase and NF-kappaB activation are necessary for memory formation.
Merlo
E
E
Laboratorio de Neurobiología de la Memoria, Facultad de Ciencias Exactas y Naturales, Departamento de Ciencias Biológicas, Pabellón II, Universidad de Buenos Aires, (1428), Buenos Aires, Argentina.
Freudenthal
R
R
Romano
A
A
D000647:Amnesia / Q000139:chemically induced; D000818:Animals; D003386:Brachyura / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004924:Escape Reaction / Q000502:physiology; D006185:Habituation, Psychophysiologic / Q000502:physiology; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology*; D013997:Time Factors
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; D012460:Sulfasalazine; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D007213:Indomethacin