Interleukin-6 enhances expression of adenosine A(1) receptor mRNA and signaling in cultured rat cortical astrocytes and brain slices

The inhibitory neuromodulator adenosine is released in the brain in high co ncentrations under conditions of exaggerated neuronal activity such as isch emia and seizures, or electroconvulsive treatment. By inhibiting neural ove ractivity, adenosine counteracts seizure activity and promotes neuronal sur vival. Since stimulation of adenosine A(2b) receptors on astrocytes induces increased synthesis and release of interleukin-6, which also exerts neurop rotective effects, we hypothesized that the effects of interleukin-6 and of adenosine might be related. We report here that stimulation with interleuk in-6 of cultured astrocytes, of cultured organotypic brain slices iom newbo rn rat cortex, and of freshly prepared brain slices from rat cortex induces a concentration- and time-dependent upregulation of adenosine A(1) recepto r mRNA. This increased adenosine A(1) receptor mRNA expression is accompani ed in astrocytes by an increase in adenosine A(1) receptor-mediated signali ng via the phosphoinositide-dependent pathway. Since upregulation fo adenos ine A(1) receptors leads to increased neuroprotective effects of adenosine, we suggest that the neuroprotective actions of interleukin-6 and adenosine are related and might be mediated at least in part through upregulation of adenosine A(1) receptors. These results may be of relevance for a better u nderstanding of neuroprotection in brain damage but also point to a potenti al impact of neuroprotection in the mechanisms of the antidepressive effect s of chronic carbamazepine, electroconvulsive therapy, and sleep deprivatio n, which are all accompanied by adenosine A(1) receptor upregulation. (C) 2 000 American College of Neuropsychopharmacology. Published by Elsevier Scie nce Inc. All rights reserved.