Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures

Oxidative stress can trigger neuronal cell death and has been implicated in several chronic neurological diseases and in acute neurological injury. Ox idative toxicity can be induced by glutamate treatment in cells that lack i onotrophic glutamate receptors, such as the immortalized HT22 hippocampal c ell line and immature primary cortical neurons. Previously, we found that n europrotective effects of geldanamycin, a benzoquinone ansamycin, in HT22 c ells were associated with a down-regulation of c-Raf-1, an upstream activat or of the extracellular signal-regulated protein kinases (ERKs). ERK activa tion, although often attributed strictly to neuronal cell survival and prol iferation, can also be associated with neuronal cell death that occurs in r esponse to specific insults. in this report we show that delayed and persis tent activation of ERKs is associated with glutamate-induced oxidative toxi city in HT22 cells and immature primary cortical neuron cultures. Furthermo re, me find that U0126, a specific inhibitor of the ERK-activating kinase, MEK-1/2, protects both HT22 cells and immature primary cortical neuron cult ures from glutamate toxicity. Glutamate-induced ERK activation requires the production of specific arachidonic acid metabolites and appears to be down stream of a burst of reactive oxygen species (ROS) accumulation characteris tic of oxidative stress in HT22 cells. However, inhibition of ERK activatio n reduces glutamate-induced intracellular Ca2+ accumulation. We hypothesize that the precise kinetics and duration of ERR activation may determine whe ther downstream targets are mobilized to enhance neuronal cell survival or ensure cellular demise.