title: The P38 mitogen-activated protein kinase inhibitor SB203580 antagonizes the inhibitory effects of interleukin-1beta on long-term potentiation in the rat dentate gyrus in vitro.
abstract: Levels of the pro-inflammatory cytokine interleukin-1beta are known to be elevated in patients with chronic disorders such as Alzheimer's disease. We have investigated the effects of interleukin-1beta on long-term potentiation and N-methyl-D-aspartate receptor-mediated field potentials in the rat dentate gyrus in vitro utilizing field extracellular recordings obtained from the middle third of the molecular layer of the dentate gyrus. Presynaptic stimulation was applied to the commissural/association pathway at a frequency of 0.05 Hz and at a distance of 50 microm from the granule cell body layer. As previously reported, interleukin-1beta (1 ng/ml) caused an inhibition of long-term potentiation (108+/-2% of baseline 1 h following application of tetanic stimulation compared with 145+/-5% in vehicle control slices). This action of interleukin-1beta on long-term potentiation, as well as an inhibition of N-methyl-D aspartate receptor-mediated field potentials, was attenuated by pre-treatment of slices with the p38 mitogen-associated protein kinase inhibitor SB203580 (1 microM). SB203580 alone had no significant affect on long-term potentiation, but did cause an increase in baseline synaptic transmission [107+/-2% of baseline, 1 h after SB203580 (1 microM) treatment]. The p42/44 mitogen-activated protein kinase cascade inhibitor PD98059 (50 microM) did not inhibit the interleukin-1beta-induced inhibition of N-methyl-D-aspartate receptor-mediated field potentials. The cyclooxygenase inhibitor indomethacin (50 microM) was found to attenuate the interleukin-1beta-induced effects on both long-term potentiation and N-methyl-D-aspartate receptor-mediated field potentials. The lipid second messenger analogue C2 ceramide (20 microM) was found to attenuate the expression of long-term potentiation (108+/-3% of baseline 1 h following tetanic stimulation), and this effect was not blocked by pre-treatment with SB203580. To investigate a possible role for interleukin-1beta in the normal expression of long-term potentiation, the interleukin-1 receptor antagonist (25 ng/ml) was applied during the maintenance phase of long-term potentiation. This was found to depress the sustained expression of long-term potentiation (116+/-6% of baseline 1 h following tetanic stimulation). Our results indicate possible signalling mechanisms by which interleukin-1beta at pathophysiological concentrations may serve to inhibit long-term potentiation, and also suggests a role for IL-1beta in the physiological expression of synaptic plasticity in the rat dentate gyrus in vitro.
authors.affiliation: Department of Human Anatomy and Physiology, University College, Dublin, Ireland.
authors.forename: A N
authors.initials: AN
authors.lastname: Coogan
authors.forename: L A
authors.initials: LA
authors.lastname: O'Neill
authors.forename: J J
authors.initials: JJ
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D018891:Dentate Gyrus / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D019580:Perforant Pathway / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007375:Interleukin-1; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D007213:Indomethacin