β2 adrenergic receptor activation induces microglial NADPH oxidase activation and dopaminergic neurotoxicity through an ERK-dependent/Protein Kinase A-independent pathway

摘要: Activation of the beta2 adrenergic receptor (beta2AR) on immune cells has been reported to possess anti-inflammatory properties, however, pro-inflammatory properties beta2AR activation remain unclear. In this study, using rat primary mesencephalic neuron-glia cultures, we report that salmeterol, a long-acting agonist, selectively induces dopaminergic (DA) neurotoxicity through its ability activate microglia. Salmeterol increased production reactive oxygen species (ROS) by NADPH oxidase (PHOX), major superoxide-producing enzyme in A key role PHOX mediating salmeterol-induced was demonstrated inhibition DA cultures pretreated with diphenylene-iodonium (DPI), an inhibitor activity. Mechanistic studies revealed microglia salmeterol results selective phosphorylation ERK, signaling pathway required for translocation cytosolic subunit p47(phox) cell membrane. Furthermore, found ERK inhibition, but not protein kinase (PKA) significantly abolished superoxide production, translocation, and mediate neurotoxicity. Together, these findings indicate microglial ERK-dependent/PKA-independent pathway.