Abstract
The aim of the present work is to study the mechanism of the α-tocopherol (α-T) protective action at nanomolar and micromolar concentrations against H2O2-induced brain cortical neuron death. The mechanism of α-T action on neurons at its nanomolar concentrations characteristic for brain extracellular space has not been practically studied yet. Preincubation with nanomolar and micromolar α-T for 18 h was found to increase the viability of cortical neurons exposed to H2O2; α-T effect was concentration-dependent in the nanomolar range. However, preincubation with nanomolar α-T for 30 min was not effective. Nanomolar and micromolar α-T decreased the reactive oxygen species accumulation induced in cortical neurons by the prooxidant. Using immunoblotting it was shown that preincubation with α-T at nanomolar and micromolar concentrations for 18 h prevented Akt inactivation and decreased PKCδ activation induced in cortical neurons by H2O2. α-T prevented the ERK1/2 sustained activation during 24 h caused by H2O2. α-T at nanomolar and micromolar concentrations prevented a great increase of the proapoptotic to antiapoptotic proteins (Bax/Bcl-2) ratio, elicited by neuron exposure to H2O2. The similar neuron protection mechanism by nanomolar and micromolar α-T suggests that a “more is better” approach to patients’ supplementation with vitamin E or α-T is not reasonable.
Highlights
The development of oxidative stress is one of the main causes of brain nerve cell damage and death in neurodegenerative and ischemic diseases, such as Parkinson’s and Alzheimer’s diseases or brain insult
Our work is one of the first attempts to study the mechanism of protective effect of α-T at nanomolar concentrations, which are its physiological concentrations in cerebrospinal fluid and brain extracellular space
The protective effect of α-T against the H2O2 toxic effect on the brain cortical neurons was found to be concentration-dependent in the nanomolar range (1 < 10 < 100 nM) if the preincubation with it was performed for 18 h
Summary
The development of oxidative stress is one of the main causes of brain nerve cell damage and death in neurodegenerative and ischemic diseases, such as Parkinson’s and Alzheimer’s diseases or brain insult. These widespread diseases result in cognitive dysfunction, disablement and death for elderly people. Analysis of the published results of randomized clinical trials (more than 100,000 observations) of vitamin E administration to people with various diseases showed that the all-cause mortality for patients and people in risk groups who received high doses of vitamin E in their diet was higher than for those who received a placebo [1,2,3]. It was shown that ischemic stroke-induced brain injury was exacerbated in the presence of supraphysiologic brain α-T level [4]
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