Elevation of glutathione as a therapeutic strategy in Alzheimer disease

Abstract

Oxidative stress has been associated with the onset and progression of mild cognitive impairment (MCI) and Alzheimer disease (AD). AD and MCI brain and plasma display extensive oxidative stress as indexed by protein oxidation, lipid peroxidation, free radical formation, DNA oxidation, and decreased antioxidants. The most abundant endogenous antioxidant, glutathione, plays a significant role in combating oxidative stress. The ratio of oxidized to reduced glutathione is utilized as a measure of intensity of oxidative stress. Antioxidants have long been considered as an approach to slow down AD progression. In this review, we focus on the elevation on glutathione through N-acetyl-cysteine (NAC) and γ-glutamylcysteine ethyl ester (GCEE) as a potential therapeutic approach for Alzheimer disease. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.

Figure 1

Recycling of glutathione (GSH) and oxidized glutathione (GSSG).

Figure 2

Synthesis of Glutathione

Figure 3

Structure of N-acetyl-L-cysteine (NAC).

Figure 4

A) Aβ produces ROS that eventually leads to the depletion of antioxidants and oxidative stress in Alzheimer disease. The increased oxidation induces apoptotic signaling pathways and inflammation in astrocytes. Astrocytes release toxic inflammatory mediators and free radicals, accelerating activation of microglia and neurodegeneration, connecting the cycle of negative events perpetuating AD. B) NAC down-regulates APP gene transcription, resulting in undetectable levels of APP mRNA. Thus, since less Aβ is transcribed, fewer free radicals are produced by Aβ. NAC increases antioxidant levels of glutathione and reacts with ROS preventing oxidative stress. The decreased oxidation in the cells induces anti-apoptotic signaling pathways and prevents inflammation of the cell. NAC directly inhibits inflammatory factor NF-κB and blocks production of nitric oxide from inducible nitric oxide synthase and inflammatory cytokines.

Figure 4

A) Aβ produces ROS that eventually leads to the depletion of antioxidants and oxidative stress in Alzheimer disease. The increased oxidation induces apoptotic signaling pathways and inflammation in astrocytes. Astrocytes release toxic inflammatory mediators and free radicals, accelerating activation of microglia and neurodegeneration, connecting the cycle of negative events perpetuating AD. B) NAC down-regulates APP gene transcription, resulting in undetectable levels of APP mRNA. Thus, since less Aβ is transcribed, fewer free radicals are produced by Aβ. NAC increases antioxidant levels of glutathione and reacts with ROS preventing oxidative stress. The decreased oxidation in the cells induces anti-apoptotic signaling pathways and prevents inflammation of the cell. NAC directly inhibits inflammatory factor NF-κB and blocks production of nitric oxide from inducible nitric oxide synthase and inflammatory cytokines.

Figure 5

Structure of γ-glutymylcysteine ethyl ester (GCEE).