The mitogen-activated protein kinase pathway mediates estrogen neuroprotection after glutamate toxicity in primary cortical neurons

Pharmacological and biochemical approaches were used to elucidate the invol vement of growth factor signaling pathways mediating estrogen neuroprotecti on in primary cortical neurons after glutamate excitotoxicity. We addressed the activation of mitogen-activated protein kinase (MAPK) signaling pathwa ys, which ate activated by growth factors such as nerve growth factor (NGF) . Inhibition of MAPK signaling with the MAPK kinase inhibitor PD98059 block s both NGF and estrogen neuroprotection in these neurons. These results cor relate with a rapid and sustained increase in MAPK activity within 30 min o f estrogen exposure. The involvement of signaling molecules upstream from M APK was also examined to determine whether activation of MAPK by estrogen i s mediated by tyrosine kinase activity. Estrogen produces a rapid, transien t activation of src-family tyrosine kinases and tyrosine phosphorylation of p21(ras)-guanine nucleotide activating protein. Effects of estrogen on neu roprotection, as well as rapid activation of tyrosine kinase and MAPK activ ity, are blocked by the anti-estrogen ICI 182,780. This provides evidence t hat activation of the MAPK pathway by estrogen participates in mediating ne uroprotection via an estrogen receptor. These results describe a novel mech anism by which cytoplasmic actions of the estrogen receptor may activate th e MAPK pathway, thus broadening the understanding of effects of estrogen in neurons.