The DNA damaging agent etoposide activates a cell survival pathway involving alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors and mitogen-activated protein kinases in hippocampal neurons.

Abstract

Etoposide, an inhibitor of topoisomerase II that induces DNA damage and can trigger cell death, is used as a chemotherapeutic agent. Because chemotherapies can result in neurological complications and because DNA damage in neurons is implicated in the pathogenesis of several neurodegenerative disorders, we studied the effects of etoposide on cultured hippocampal neurons. We found that etoposide induces neuronal apoptosis and that, prior to the cell death commitment point, there is an increase in whole-cell alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-induced current but no change in N-methyl-D-aspartate (NMDA)-induced current. Associated with the increase in AMPA-induced current was an increase in the amounts of AMPA receptor subunits GluR1 and GluR4, whereas levels of the NMDA receptor subunit NR1 were unaffected by etoposide. AMPA receptor activation can result in excitotoxic cell death but can also activate signaling pathways that promote synaptic plasticity and cell survival. We found that etoposide increases the activation of p42 and p44 mitogen-activated protein (MAP) kinases, and that activation of the MAP kinases by etoposide requires AMPA receptor activation. Pharmacological blockade of AMPA receptors and p42/p44 MAP kinases, but not of NMDA receptors, exacerbated etoposide-induced cell death. These findings suggest that, although etoposide is neurotoxic, it also activates a cell survival pathway involving AMPA receptor-mediated activation of p42/p44 MAP kinases. Agents that selectively inhibit the cell life or death pathways triggered by DNA damage may prove useful in the settings of cancer and neurodegenerative disorders, respectively.