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This study investigated the physiological regulation of brain immune homeostasis in rat primary neuron-glial cultures by sub-nanomolar concentrations of prostaglandin E2 (PGE(2)). We demonstrated that 0.01 to 10 nM PGE(2) protected dopaminergic neurons against LPS-induced neurotoxicity through a reduction of microglial release of pro-inflammatory factors in a dose-dependent manner. Mechanistically, neuroprotective effects elicited by PGE(2) were mediated by the inhibition of microglial NOX2, a major superoxide-producing enzyme. This conclusion was supported by (1) the close relationship between inhibition of superoxide and PGE(2)-induced neuroprotective effects; (2) the mediation of PGE(2)-induced reduction of superoxide and neuroprotection via direct inhibition of the catalytic subunit of NOX2, gp91 (phox) , rather than through the inhibition of conventional prostaglandin E2 receptors; and (3) abolishment of the neuroprotective effect of PGE(2) in NOX2-deficient cultures. In summary, this study revealed a potential physiological role of PGE(2) in maintaining brain immune homeostasis and protecting neurons via an EP receptor-independent mechanism.