Alpha-tocopherol prevents long-term activation of ERK1/2 in neurons of the brain cortex under conditions of oxidative stress

Abstract

We found that long-term (18 h) preincubation with alpha-tocopherol at microand nanomolar concentrations significantly increases the viability of H₂O₂-treated immature cultured neurons that were isolated from the cortex of the rat brain. We showed that H₂O₂ activates extracellular signal regulated protein kinase (ERK1/2) in neurons of the rat brain cortex. The maximum activity of the enzyme in cells was achieved in 5 min from the moment of application of the prooxidant. High activity of ERK1/2 was maintained at the same high level for 24 h after application of H₂O₂. Preincubation of immature cortical neurons for 18 h with 100 nM or 100 µM alpha-tocopherol did not prevent ERK1/2 activation (or enhanced it) at the early stage of H₂O₂ action. However, alpha-tocopherol significantly decreased (to values close to the control) ERK1/2 activity 5, 12, and 24 h after the onset of H₂O₂ treatment. According to the literature data, oxidative stress in the brain, which is caused by ischemia or other unfavorable treatments, results in persistent activation of ERK1/2 and administration of its inhibitors strongly prevents the death of brain neurons. These data suggest that the protective effect of alpha-T on the brain neurons in vivo is largely determined by alpha-Tinduced prevention of persistent ERK1/2 activation during oxidative stress.