Abstract
Ethanol withdrawal is linked to elevated oxidative damage to neurons. Here we report our findings on the contribution of phenolic antioxidants (17β-estradiol, p-octyl-phenol and 2,6-di-tert-butyl-4-methylphenol) to counterbalance sudden ethanol withdrawal-initiated oxidative events in hippocampus-derived cultured HT-22 cells. We showed that ethanol withdrawal for 4 h after 24-h ethanol treatment provoked greater levels of oxidative damage than the preceding ethanol exposure. Phenolic antioxidant treatment either during ethanol exposure or ethanol withdrawal only, however, dose-dependently reversed cellular oxidative damage, as demonstrated by the significantly enhanced cell viability, reduced malondialdehyde production and protein carbonylation, compared to untreated cells. Interestingly, the antioxidant treatment schedule had no significant impact on the observed neuroprotection. In addition, the efficacy of the three phenolic compounds was practically equipotent in protecting HT-22 cells in spite of predictions based on an in silico study and a cell free assay of lipid peroxidation. This finding implies that free-radical scavenging may not be the sole factor responsible for the observed neuroprotection and warrants further studies to establish, whether the HT-22 line is indeed a suitable model for in vitro screening of antioxidants against EW-related neuronal damage.
Highlights
Neurotoxicity induced by ethanol causes tissue damage to a variety of organs in humans, a finding which has been corroborated by numerous studies using animal models [1]
We have found that the protective effect of estrogens against ethanol withdrawal (EW)-induced neurotoxicity is in part due to their antioxidant activity [5], classifying them as simple phenolic antioxidants in this regard
First an in silico prediction of the antioxidant potency of the test compounds was done by calculating the bond dissociation enthalpy (BDE) of the phenolic O-H bond (Table 1)
Summary
Neurotoxicity induced by ethanol causes tissue damage to a variety of organs in humans, a finding which has been corroborated by numerous studies using animal models [1]. A major cause of this detrimental effect is believed to be elevated oxidative stress levels via ethanol-induced generation of reactive oxygen species and impairment of the antioxidant defense system [2]. The brain is especially sensitive to oxidative stress, because it has high oxidative metabolic rate and low levels of antioxidant enzymes compared to other tissues [3] It contains high concentrations of redox-active metals [4] that may promote Fenton and Fenton-like reactions [5]. It has been shown that sudden EW results in an increase in glutamate levels/glutamate receptor activity and a compensatory up-regulation of N-methyl-D-aspartate (NMDA) receptors [15,16] as well as in a decrease in GABA levels/GABAreceptor activity [17,18] These events will eventually lead to oxidative stress [19]. An in silico study and a wellestablished cell-free assay of LPO [28,29] have been done to predict the antioxidant potency of the test compounds
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