Im portantly, the inhibitory STI 571 effect of BFA suggests that NECA stimulated release of LIF by astrocytes requires de novo LIF synthesis, and does not involve a ready releasable post Golgi pool of LIF. It is now clear that one of the major roles of LIF is directed toward cell protection. Inhibitors,Modulators,Libraries Indeed, it has been shown that LIF is up regulated in astrocytes and neurons after cerebral ischemia as well as in astrocytes after cortical brain injury, suggesting a role of LIF in neuronal repair or protection. In line with these data, treatment of rat with LIF prevented loss of motoneurons after peripheral nerve injury and protection of retinal ganglia cells was compromised Inhibitors,Modulators,Libraries in LIF knock out mice after lens injury. Finally, LIF was shown to limit demyelination in an experimental autoimmune enceph alomyelitis mouse model and has become a promin ent therapeutic candidate for multiple Inhibitors,Modulators,Libraries sclerosis.

We have previously shown that LIF can protect cortical as well as hippocampal neurons against glutamate induced Inhibitors,Modulators,Libraries excitotoxicity. Here we show that LIF coming from the supernatant of NECA treated astrocytes has the same protective effect. Indeed, astrocytes Inhibitors,Modulators,Libraries produce several other cytokines and neurotrophic factors including IL 6, NGF, brain derived neurotrophic factor, neurotrophin 3, S 100B protein and TGFB, that might help neurons to cope with excitotoxic stress. Accordingly, conditioned media from astrocyte cultures protected cortical neurons against glutamate. In order to confine the neuroprotective effect of astrocytic factors that are released in response to NECA treatment, we had to re fresh astrocyte culture medium prior to NECA treatment and testing supernatant on glutamate stressed neurons.

This, together with LIF neutralization, indicates that LIF produced by astrocytes after adenosine receptor stimulation is necessary to witness neuronal protec tion. Our results provide further evidence for sellekchem a role of adenosine in neuronal protection. Indeed, it has been shown that adenosine can protect neurons dur ing hypoxia, ischemia and excessive neuronal activity. This adenosine protection is often mediated through the A1 receptor subtype, but here we show that an indirect protection of adenosine through the stimulation of A2B receptor on astrocytes leading to LIF upregulation exists. This A2B receptor activation might be related to an anti inflammatory process as observed previously by others. Conclusions We demonstrate a protective role of LIF against glutam ate neurotoxicity and we provide clear evidence that ad enosine is required for an increased production of LIF by astrocytes. These data further confirm a neuroprotec tive role of adenosine in the brain.