The correlation between early alcohol withdrawal severity and oxidative stress in patients with alcohol dependence

Abstract

Oxidative stress is enhanced in alcoholic patients. This clinical study aimed to explore the correlation between alcohol withdrawal severity and two oxidative stress markers, malondialdehyde (MDA) and superoxide dismutase (SOD). Seventy-six inpatients fulfilled the DSM-IV-TR criteria for alcohol dependence and 19 healthy controls were enrolled. Serum MDA level and SOD activity were measured within 24 h of alcohol detoxification. The severity of alcohol withdrawal was evaluated by the Chinese version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar-C) every 8 h. Average and highest scores of the CIWA-Ar-C at the first day were recorded as the baseline withdrawal severity. We compared the differences of MDA and SOD between groups, and examined the correlation between baseline withdrawal severity and oxidative stress markers. Compared to controls, serum MDA levels were significantly elevated and SOD activity was significantly lowered in alcoholic patients. In stepwise multiple regression analysis, MDA was the only variable significantly correlated with the average (β = 0.48, p < 0.0001) and highest (β = 0.47, p < 0.0001) CIWA-Ar-C scores at the first day of detoxification. In agreement with previous studies, alcoholic patients encountered high oxidative stress. Although there was a correlation between early withdrawal severity and MDA levels, the meanings of the correlation are worth further studies in the future.

Introduction

Alcohol is metabolized primarily by alcohol dehydrogenase and aldehyde dehydrogenase. In addition, the alcohol-inducible cytochrome P450 isoform 2E1 (CYP2E1), which is also expressed in the central nervous system, plays an important role in chronic alcoholics (Lieber and DeCarli, 1970). The high rate of CYP2E1 oxidative activity causes the formation of reactive oxygen species (ROS) and ethanol-derived (hydroxyethyl) free radicals, and can thus initiate lipid peroxidation (Cederbaum, 1989, Shaw, 1989). Lipid peroxidation reflects the interaction between oxygen molecules and polyunsaturated fatty acids, producing oxidation of various breakdown products of the latter. Among them, malondialdehyde (MDA) is a reliable marker of oxidative damage (Esterbauer et al., 1991, Shaw, 1989, Song, 1996). The chief antioxidant defense mechanism equipped in cells, superoxide dismutase (SOD), prevents superoxide from generating further toxic oxidative radicals resulting from alcohol consumption (Davis et al., 1990) and thus participates in the neutralization of ROS.

The excitatory neurotransmitters are involved in the adaptive up-regulation of N-methyl-d-aspartate (NMDA) receptors after chronic alcohol exposure (Bleich et al., 2004). NMDA-induced excitotoxic damage is mediated by its high Ca²⁺ permeability, evoked generation of ROS and subsequent enhancement of oxidative stress. Previous clinical studies have demonstrated that chronic ethanol consumption is accompanied by excessive oxidative damage and reduced levels of endogenous antioxidants (Lecomte et al., 1994, Peng et al., 2005). In addition, both excitatory neurotransmission and lipid peroxidation have been found to be significantly elevated in alcoholic patients (Bleich et al., 2000). Since oxidative stress and glutamate overactivation are regarded as sequential as well as interacting processes (Coyle and Puttfarcken, 1993), both of them have been postulated to contribute to neurobiological manifestations of chronic alcoholism (Crews et al., 2004).

Central excitotoxicity caused by overstimulation of NMDA receptors following alcohol cessation has long been implicated in the mechanism underlying alcohol withdrawal symptoms (AWS) (Lovinger, 1993, Nagy et al., 2001, Tsai et al., 1998). Importantly, increased glutamatergic neurotransmission after alcohol withdrawal has been shown to have a positive correlation with lipid hydroperoxide levels in human cerebrospinal fluid (CSF) (Tsai et al., 1998). This implies that AWS, a manifestation of central glutamate overexcitation, are linked with underlying oxidative damage. Thus, we hypothesized that AWS could clinically reflect the excessive oxidative stress. By measuring both serum MDA levels and SOD activity, we first examined alcoholic patients suffering from higher oxidative stress than control subjects in this study. Then we aimed to investigate the correlation between clinical withdrawal severity and MDA levels as well as SOD activity in alcoholic patients.