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

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.