Studies (Glutathione and Alzheimer's Disease)

J Pharmacol Exp Ther. 2007 Apr;321(1):73-83. Epub 2007 Jan 4.

1. Inhibition of acrolein-induced apoptosis by the antioxidant N-acetylcysteine.

Tanel A, Averill-Bates DA.

Département des Sciences Biologiques, Université du Québec à Montréal, CP 8888, Succursale Centre Ville, Montréal, QC H3C 3P8, Canada.

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde to which humans are exposed in many situations. It is an environmental pollutant that is responsible for multiple respiratory diseases and has been implicated in neurodegenerative diseases such as Alzheimer's disease. The hypothesis of the study is that the antioxidant N-acetylcysteine (NAC), a precursor of glutathione, could protect cells against acrolein-induced apoptosis. Exposure of Chinese hamster ovary cells to a noncytotoxic dose of acrolein (4 fmol/cell) depleted intracellular glutathione to 45% of initial levels. NAC, which increased intracellular glutathione levels by 30%, afforded protection against acrolein-induced cytotoxicity (loss of cell proliferation) and apoptosis. NAC protected against apoptosis by diminishing acrolein-induced activation of the mitochondrial death pathway. NAC inhibited acrolein-induced Bad translocation from the cytosol to the mitochondria, as well as Bcl-2 translocation from mitochondria to the cytosol, as evaluated by Western blot analysis. However, NAC had no effect on acrolein-induced Bax translocation to mitochondria and cytochrome c liberation into the cytosol. Meanwhile, NAC inhibited depolarization of mitochondrial membrane potential, as evaluated by rhodamine fluorescence using flow cytometry. NAC also inhibited procaspase-9 processing, activation of enzymatic activity of caspase-9, -7, and -8, and poly(ADP-ribose) polymerase cleavage induced by acrolein. Inhibition of acrolein-induced apoptosis using NAC was confirmed morphologically by diminished condensation of nuclear chromatin, as evaluated by fluorescence microscopy. These findings suggest that NAC could be potentially useful as a protective agent for people exposed to acrolein.

PMID: 17204747 [PubMed - indexed for MEDLINE]

Brain Res. 2006 Sep 13;1109(1):201-6. Epub 2006 Jul 26.

2. Protective effect of N-acetyl-L-cysteine on amyloid beta-peptide-induced learning and memory deficits in mice.

Fu AL, Dong ZH, Sun MJ.

Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China.

This study aimed to examine the effects of N-acetyl-L-cysteine (NAC) on protecting neurons function and improving learning and memory deficits in mice. Mice were intracerebroventricularly (icv) injected with the aggregated amyloid beta-peptide (Abeta) to produce Alzheimer's disease (AD). Learning and memory functions in mice were examined by the step through test and the water maze performance. The results showed that the mice pretreated with NAC had significantly greater retention in the step through test and shorter latencies in the water maze performance. Biochemical studies showed the potential role of free radical toxicity and the damage of cholinergic neurons in the Abeta-treated mice. There was an increased lipid peroxidation as indicated by elevated malondehyde (MDA) and decrease of glutathione (GSH) levels. There was also an increase in acetylcholinesterase (AChE) activity and a reduction in the choline acetyltransferase (ChAT) activity and acetylcholine (ACh) levels. NAC pretreatment significantly reversed the elevated MDA, AChE and the reduced GSH, ChAT and ACh in the Abeta-model mice. The results of the present study suggest the potential usage of the neuroprotective action of NAC on AD.

Brain Res. 2006 May 23;1090(1):35-44. Epub 2006 May 2.

3. Age-related changes in glutathione and glutathione-related enzymes in rat brain.

Zhu Y, Carvey PM, Ling Z.

Department of Pharmacology, Rush University Medical Center, Chicago, IL 60612, USA.

The most reliable and robust risk factor for some neurodegenerative diseases is aging. It has been proposed that processes of aging are associated with the generation of reactive oxygen species and a disturbance of glutathione homeostasis in the brain. Yet, aged animals have rarely been used to model the diseases that are considered to be age-related such as Parkinson's or Alzheimer's disease. This suggests that the results from these studies would be more valuable if aged animals were used. The present study was designed to provide insight into the glutathione redox state in young and aged rat siblings of both genders by studying the enzyme activities related to glutathione synthesis, cycling, and usage. The results suggested a significant age-related reduction of reduced glutathione (GSH) level in all brain regions examined, associated with an increase of GSH oxidation to glutathione disulfide (GSSG) and decrease of the GSH/GSSG ratio. These changes were accompanied by diminished gamma-glutamylcysteine synthetase activity in de novo glutathione synthesis and increased lipid peroxidation. In addition, these changes were associated with increased enzyme activities related to the GSH usage (glutathione peroxidase, gamma-glutamyl transpeptidase, and glutathione S-transferase). The results indicate that aged animals are likely more vulnerable to oxidative stress and insinuate the roles of aged animals in modeling age-related neurodegeneration diseases.

PMID: 16647047 [PubMed - indexed for MEDLINE]

J Neural Transm. 2006 May;113(5):645-57. Epub 2005 Oct 27.

4. Lack of glutathione peroxidase-1 exacerbates Abeta-mediated neurotoxicity in cortical neurons.

Crack PJ, Cimdins K, Ali U, Hertzog PJ, Iannello RC.

Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Monash University, Melbourne, Australia.

The aetiologies of Alzheimer's disease (AD) are complex and multifactorial. Current therapies are largely ineffective, as the pathophysiological pathways are poorly understood. Observations in AD autopsies, as well as in vivo and in vitro observations in transgenic mice, have implicated oxidative stress as pathogenic in AD. This study used the Glutathione Peroxidase-1 knockout mouse (Gpx1--/--) model to investigate the role of antioxidant disparity in neuropathologies. Cultured neurons from control and Gpx1--/-- embryos were treated with AD-related peptides and the degree of cell loss compared. Results show that antioxidant disparity makes Gpx1--/-- cells more susceptible to Abeta toxicity. Surrogate replacement of Gpx1 with the reactive oxygen species scavenger N-acetyl cysteine and the Gpx1 mimetic ebselen, reverses the Gpx1--/-- increased susceptibility to Abeta toxicity. Such results support a role for oxidative stress in AD-related neuronal loss. This study is the first to report such findings using the Gpx1--/-- model, and supports a role for oxidative stress as one of the contributing factors, in development of AD-like pathologies.

PMID: 16252075 [PubMed - indexed for MEDLINE]

Curr Med Chem. 2006;13(9):1075-83.

5. Oxidative stress in Alzheimer patients in different stages of the disease.

Zafrilla P, Mulero J, Xandri JM, Santo E, Caravaca G, Morillas JM. Universidad Católica San Antonio, Escuela Universitaria de Nutrición Humana y Dietética, Murcia, Spain.

Increasing evidence demonstrates that oxidative stress causes damage to cell function with aging and is involved in a number of age-related disorders including atherosclerosis, arthritis, and neurodegenerative disorders. Cellular changes show that oxidative stress is a condition that precedes the appearance of the hallmark pathologies of the disease, neurofibrillary tangles and senile plaques. The aim of this article is to analyze the different biomarkers of oxidative stress in Alzheimer patients, in different stages of the illness, and compare the results with a control group. A nutritional evaluation was carried out, including anthropometric and biological measures and a 3 day dietary record. The concentration of substances which react to thiobarbituric acid (TBARS) was measured as a marker of the degree of peroxidation using the HPLC method. The oxidation of proteins was analyzed by measuring the carbonyl groups in plasma. In addition, measurements were made of the total antioxidant activity in plasma and the activity of endogenous antioxidant enzymes such as gluthatione peroxidase, gluthatione reductase and superoxide dismutase. The total antioxidant plasmatic status of the patients with Alzheimer both in light-moderate phase and in advanced phase was lower than in the control. No significant differences were observed between the different stages of the disease in protein oxidation levels. Peroxidation was higher in patients in the advanced stage of the disease than in the control group. However, no significant differences were observed between the different stages of the disease. In this preliminary study, it was observed that Alzheimer patients in the light-moderate stage already present oxidative stress levels above those of the control group.

PMID: 16611085 [PubMed - indexed for MEDLINE]