Paracrine effect of carbon monoxide: astrocytes promote neuroprotection via purinergic signaling

Abstract

Carbon monoxide neuroprotective role has been studied in a cell autonomous mode. Herein a new concept is disclosed: CO affects astrocyte-neuron communication in a paracrine manner towards neuroprotection. Neuronal survival was assessed whenever co-cultured with astrocytes pre-treated or not with CO. CO-pre-treated astrocytes reduced neuronal cell death and the cellular mechanisms were pursued, targeting purinergic signaling. CO modulates astrocytic metabolism and extracellular ATP content in the co-culture media. Moreover, several antagonists of P1 adenosine and P2 ATP receptors partially reverted CO-induced neuroprotection via astrocytes. Likewise, knocking down the neuronal P1 adenosine receptor A2A-R expression reverts neuroprotection. Neuroprotection of CO-treated astrocytes also decreased following prevention of ATP or adenosine release from astrocytic cells and inhibition of extracellular ATP metabolization into adenosine. Finally, the neuronal downstream event involves TrkB receptors and BDNF. Pharmacological and genetic inhibition of TrkB receptor reverts neuroprotection triggered by CO-treated astrocytes. Furthermore, the neuronal ratio BDNF/pro-BDNF increased in the presence of CO-treated astrocytes and decreased whenever A2A-R expression was silenced. In summary, CO prevents neuronal cell death in a paracrine manner by targeting astrocytic metabolism via purinergic signaling.