This apparently contra useful handbook dictory ability of SCH58261 to increase slightly the glutamate induced intracellular calcium dynamics and to abrogate the e acerbating effect of IL 1B on glutamate induced effects probably results from the pleiotropic nature of A2AR mediated signaling and its plasticity under different e perimental conditions. As a final attempt to link calcium deregulation upon e posure to glutamate and IL 1B with the A2AR mediated control of the e acerbation by IL 1B of glutamate induced neuroto icity, we tested whether inhibition of either p38 or JNK might also prevent the e acerbation by IL 1B of the glutamate induced dynamics of intracellular calcium in cul tured neurons. The p38 inhibitor SB203580, attenuated the e acerbation by IL 1B of glutamate induced initial calcium entry and prevented the calcium deregulation.

The JNK inhibitor SP600125 also attenuated the effect of IL 1B with glutam ate, although this was not significant, and neither of these inhibitors alone displayed any evident effects. The striking parallel between the effects of SCH58261 and SB203580 is an additional finding suggesting that the blockade of A2AR is indeed selectively preventing the e acerbation by IL 1B of glutamate induced calcium transients, although the pleio tropic nature of A2AR may mean there are additional effects of SCH58261 on glutamate induced calcium transients in the absence of IL 1B. Discussion In this study, we found that A2AR control the e acerbation of glutamate induced e citoto icity e erted by IL 1B.

this effect mainly involves the control of the direct effect of IL 1B on neurons, as gauged by the prevention of IL 1B induced acti vation of MAPKs and of IL 1B induced e acerbation of glutamate induced calcium deregulation and neuronal damage. The first finding of this study is that IL 1B type I recep 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 e pression 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 e pressed and present in neurons, especially in the conte t of brain diseases. Our results are in agreement with the previously reported localization of IL 1B type I receptors at the PSD, as e pected from the ability of IL 1B to control NMDA receptor Dacomitinib 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 e pected based on the ability of IL 1B to control the release of glutamate from nerve terminals.