RAPID SUPPRESSION OF FREE-RADICAL FORMATION BY NERVE GROWTH-FACTOR INVOLVES THE MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY

Neurotrophins such as nerve growth factor (NGF) regulate neuronal surv ival during development and are neuroprotective in certain models of i njury to both the peripheral and the central nervous system. Although many effects of neurotrophins involve long-term changes in gene expres sion, several recent reports have focused on rapid effects of neurotro phins that do not involve synthesis of new gene products. Because enha nced formation of reactive oxygen species (ROS) represents one consequ ence of many insults that produce neuronal death, we hypothesized that neurotrophins might influence neuronal function and survival through acute alterations in the production of ROS. Using an oxidation-sensiti ve compound, dihydrorhodamine, we measured ROS formation in a central nervous system-derived neuronal cell line (GT1-1 trk) and in superior cervical ganglion neurons, both of which express the transmembrane NGF receptor tyrosine kinase, trkA. There was enhanced production of ROS in both cell types in the absence of NGF that was rapidly inhibited by application of NGF; complete inhibition of ROS generation in GT1-1 tr k cells occurred within 10 min. NGF suppression of ROS formation was p revented by PD 098059 a specific inhibitor of MEK (mitogen/extracellul ar receptor kinase, which phosphorylates mitogen-activated protein kin ase). The observation that NGF acutely blocks ROS formation in neurons through activation of the mitogen-activated protein kinase pathway su ggests a novel mechanism for rapid neurotrophin signaling, and has imp lications for understanding neuroprotective and other effects of neuro trophins.