1. Selective modulation of brain antioxidant defense capacity by genetic or metabolic manipulations
- Author
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Pierre-Marie Sinet, Annie Nicole, B. Aral, L. Fideler, Mansouria Merad-Boudia, Irène Ceballos-Picot, and P. Briand
- Subjects
chemistry.chemical_classification ,Antioxidant ,biology ,business.industry ,medicine.medical_treatment ,Glutathione peroxidase ,Glutathione reductase ,Glutathione ,Free radical scavenger ,medicine.disease_cause ,Cell biology ,Biotechnology ,Superoxide dismutase ,chemistry.chemical_compound ,chemistry ,Catalase ,medicine ,biology.protein ,business ,Oxidative stress - Abstract
Oxidative stress may play an important role in the pathogenesis of brain injuries associated with aging and neurodegenerative disorders such as Down’s syndrome, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Brain contain several antioxidant enzymes, most importantly, superoxide dismutases (MnSOD and CuZnSOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R) and catalase. The tripeptide reduced glutathione (GSH) serves as one of the major endogenous antioxidants in protecting mammalian cells against oxidative stress. GSH has a role not only as a substrate for GSH-Px to break down hydrogen peroxide and lipid peroxides but also as free radical scavenger. The individual contribution of these antioxidants in neuronal protection remains unknown and requires elucidation. A first approach to this question was to establish a comprehensive profile of the brain antioxidant defense potential during aging in control mice. A second approach was to use genetic manipulations to construct transgenic mice that overexpress CuZnSOD. These constructed transgenic mice which exhibit increased CuZnSOD activity in the brain would provide a suitable model to further investigate the role of an increased CuZnSOD activity in neuronal aging and Alzheimer-like neuropathology in Down syndrome. A third strategy in assessing the role of a particular antioxidant in brain fonction was to use metabolic manipulations to deplete brain GSH levels with electrophiles that conjugate with GSH in the presence of glutathione S-transferases, such as diethylmaleate (DEM), and to correlate this depletion with brain injury or susceptibility to oxidative stress. Obtention of such a variation of a particular antioxidant in the brain and neurobiological consequences will be evaluated and discussed.
- Published
- 1994
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