Discussion In this study, we found that A2AR control the exacerbation of glutamate induced excitotoxicity exerted by IL 1B, this effect mainly involves namely the control of the direct effect of IL 1B on neurons, as gauged by the prevention of IL 1B induced Inhibitors,Modulators,Libraries acti vation of MAPKs and of IL 1B induced exacerbation of glutamate induced calcium deregulation and neuronal damage. The first finding of this study is that IL 1B type I recep Inhibitors,Modulators,Libraries tors are mainly localized at synaptic regions in the hippo campus of adult rats. The comparison of total membranes, which have a high content of glial and endothelial mem branes, with membranes from purified nerve terminals showed that IL 1B type I receptors are in deed located in synapses, although they are more abundant in total membranes, in agreement with the well established predominant expression and localization of IL 1B type I receptors in endothelial cells in the brain parenchyma.

However, IL 1B type I receptors have also been found to be expressed and present in neurons, especially in the context of brain diseases. 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 Inhibitors,Modulators,Libraries receptor mediated currents both in vitro and in vivo. Addition ally, 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. Inhibitors,Modulators,Libraries This localization of IL 1B type I receptors in neurons, Inhibitors,Modulators,Libraries 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 Nilotinib side effects 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 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.