Persistent Activation of ERK Contributes to Glutamate-induced Oxidative Toxicity in a Neuronal Cell Line and Primary Cortical Neuron Cultures

Abstract

Oxidative stress can trigger neuronal cell death and has been implicated in several chronic neurological diseases and in acute neurological injury. Oxidative toxicity can be induced by glutamate treatment in cells that lack ionotrophic glutamate receptors, such as the immortalized HT22 hippocampal cell line and immature primary cortical neurons. Previously, we found that neuroprotective effects of geldanamycin, a benzoquinone ansamycin, in HT22 cells were associated with a down-regulation of c-Raf-1, an upstream activator of the extracellular signal-regulated protein kinases (ERKs). ERK activation, although often attributed strictly to neuronal cell survival and proliferation, can also be associated with neuronal cell death that occurs in response to specific insults. In this report we show that delayed and persistent activation of ERKs is associated with glutamate-induced oxidative toxicity in HT22 cells and immature primary cortical neuron cultures. Furthermore, we find that U0126, a specific inhibitor of the ERK-activating kinase, MEK-1/2, protects both HT22 cells and immature primary cortical neuron cultures from glutamate toxicity. Glutamate-induced ERK activation requires the production of specific arachidonic acid metabolites and appears to be downstream of a burst of reactive oxygen species (ROS) accumulation characteristic of oxidative stress in HT22 cells. However, inhibition of ERK activation reduces glutamateinduced intracellular Ca 2؉ accumulation. We hypothesize that the precise kinetics and duration of ERK activation may determine whether downstream targets are mobilized to enhance neuronal cell survival or ensure cellular demise.

Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons

“…On the other hand, it also has a role in apoptosis, which depends on cell type and on the signal that triggers cell death. It was observed that persistent activation of ERK 1/2 contributes to apoptosis in primary cortical neuronal cultures (Satoh et al, 2000;Stanciu et al, 2000). The SAPK/JNK is a central mediator of stress and is essential for the regulation of physiological and pathological processes (Johnson and Nakamura, 2007).…”

N-(4-Hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells

“…Furthermore, oxidative stress has been shown to activate ERK as a protective mechanism (Guyton et al, 1996;Aikawa et al, 1997;Bhatt et al, 2002). However, a proapoptotic role has been demonstrated for ERK in several studies with different stimuli, including anticancer drugs (Stanciu et al, 2000;Wang et al, 2000;Guise et al, 2001;Xiao and Singh, 2002;Lee et al, 2003;Zhang et al, 2003;Nguyen et al, 2004).…”

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

“…The molecular mechanisms underlying oxidative stress-induced neuronal damage are emerging and appear to involve an apoptotic mode of death in which ERK1/2 [175,196] and JNK [48,136,226] have been strongly implicated. Furthermore, there is strong evidence for involvement of mitochondrial defects in neurodegenerative diseases, with neuronal cell death arising directly from mitochondrially generated ROS, ATP depletion or activation of the mitochondrialdependent apoptotic pathways [48,202,226].…”