Our results are in agreement with the previously reported localization of IL 1B type I receptors at the PSD, as expected from the ability of IL 1B to control NMDA receptor mediated currents both in vitro and in vivo. Addition ally, selleck chem we now report that IL 1B type I receptors are also present at the pre synaptic active zone, as would be expected based on the ability of IL 1B to control the release of glutamate from nerve terminals. Thus, IL 1B type I receptors do indeed seem to be present at synapses, pre cisely where glutamatergic receptors are more abundant and where glutamate associated neurodegenerative pro cesses are initiated. This localization of IL 1B type I receptors in neurons, which has also been confirmed to occur in cultured hippo campal neurons, supports our observation that IL 1B can recruit various MAPKs in cultured neurons, in a man ner sensitive to the inhibitor of IL 1B type I receptors, IL 1Ra.

This agrees with previous reports that provided evi dence indicating that certain MAPKs, particularly p38, play a crucial role in the mediating the physiopathological effects of IL 1B Inhibitors,Modulators,Libraries in the hippocampus. Although phosphor ylation of MAPKs can also promote neuroprotection under some conditions, the present study focused only on the po tentially deleterious effects of IL 1B induced phosphoryl ation of p38 and JNK. In fact, we found that this ability of IL 1B to recruit MAPKs, including p38, is by itself insuffi cient to trigger neuronal deregulation and damage. because IL 1B only primes neurons for enhanced susceptibility to neuronal damage, rather than itself directly triggering this damage.

We directly verified that IL 1B alone was in deed devoid of neuronal effects, Inhibitors,Modulators,Libraries but was able to potentiate glutamate induced neurotoxicity in cultured hippocampal neurons, in agreement with the ability of IL 1B to ex acerbate brain damage in conditions involving glutamate induced excitotoxicity and in agreement with the localization of IL 1B type I receptors in synapses, where ionotropic glutamate receptors are located. The present study adds a new mechanistic insight by showing that IL 1B causes a larger glutamate induced entry of calcium into neurons and a late calcium deregulation upon exposure Inhibitors,Modulators,Libraries of cultured hippocampal neurons to glutamate. The later is of particular interest in view of the close association between late calcium deregulation and the irreversible loss of cellu lar, especially neuronal, viability. Inhibitors,Modulators,Libraries This opens new ave nues of research to explore the underlying mechanisms of this IL 1B induced late calcium deregulation, Inhibitors,Modulators,Libraries which may be of key importance in the control of the inflammatory excellent validation mediated amplification loop mediating the propagation of brain damage.