The antioxidants α‐lipoic acid and N‐acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice

Abstract

Oxidative stress may play a crucial role in age-related neurodegenerative disorders. Here, we examined the ability of two antioxidants, alpha-lipoic acid (LA) and N-acetylcysteine (NAC), to reverse the cognitive deficits found in the SAMP8 mouse. By 12 months of age, this strain develops elevated levels of Abeta and severe deficits in learning and memory. We found that 12-month-old SAMP8 mice, in comparison with 4-month-old mice, had increased levels of protein carbonyls (an index of protein oxidation), increased TBARS (an index of lipid peroxidation) and a decrease in the weakly immobilized/strongly immobilized (W/S) ratio of the protein-specific spin label MAL-6 (an index of oxidation-induced conformational changes in synaptosomal membrane proteins). Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants.

Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer's disease

“…However, interventions with antioxidants delays age-related cognitive decline and improves performance in animal models of AD and other age-related neurodegenerative disorders [10,47,65]. The present study investigated the effect of an antioxidant-fortified diet and a program of behavioral enrichment on the levels of oxidative damage and in restoring antioxidant reserve systems in the aging canine brain.…”

Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

“…We hypothesize that a fraction of the oral NAC entered blood flow, crossed the blood-brain barrier (Farr et al, 2003), was deacetylated into cysteine that could in turn be used to increase GSH levels. GSH being the major antioxidant in a cell system, its presence is necessary to maintain equilibrium on the redox status.…”

“…Given orally, NAC is quickly absorbed, and peak plasma concentration of cysteine is reached within 120 min (Borgstrom et al, 1986;Borgstrom and Kagedal, 1990;Olsson et al, 1988). NAC crosses the blood-brain barrier (Farr et al, 2003), and cysteine can be used in the brain as a GSH precursor. Animal studies have indeed shown that systemic administration of NAC protects the brain against GSH depletion (Aydin et al, 2002;Ercal et al, 1996;Fu et al, 2006;Kamboj et al, 2006).…”

An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly

“…It is reasonable to suspect that an age-related decline in brain glutathione and Nrf2 could exacerbate their progression. Indeed, NAC has shown efficacy in rodent models of these disorders (Offen et al 1996;Martinez 2000;Chen et al 2007;Clark et al 2010;Berman et al 2011;Martinez-Banaclocha 2012;Smeyne and Smeyne 2013;Moreira et al 2007;Huang et al 2010;Pocernich and Butterfield 2012;Hsiao et al 2012;Farr et al 2003). NAC is also beneficial in a mouse model of ALS (Andreassen et al 2000).…”