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A new chiral pyrrolyl α-nitronyl nitroxide radical attenuates β-amyloid deposition and rescues memory deficits in a mouse model of Alzheimer disease.

Abstract
The generation of reactive oxygen species causes cellular oxidative damage, and has been implicated in the etiology of Alzheimer's disease (AD). L-NNNBP, a new chiral pyrrolyl α-nitronyl nitroxide radical synthesized in our department, shows potential antioxidant effects. The purpose of this study was to investigate the protective effects of L-NNNBP on β-amyloid (Aβ) deposition and memory deficits in an AD model of APP/PS1 mice. In cultured cortical neurons, L-NNNBP acted as an antioxidant by quenching reactive oxygen species, inhibiting lipid peroxidation, nitrosative stress, and stimulating cellular antioxidant defenses. L-NNNBP inhibited cell apoptosis induced by Aβ exposure. In vivo treatment with L-NNNBP for 1 month induced a marked decrease in brain Aβ deposition and tau phosphorylation in the blinded study on APP/PS1 transgenic mice (1 mM in drinking water, initiated when the mice were 6 months old). The L-NNNBP-treated APP/PS1 mice showed decreased astrocyte activation and improved spatial learning and memory compared with the vehicle-treated APP/PS1 mice. These actions were more potent compared with that of curcumin, a natural product, and TEMPO, a nitroxide radical, which are used as free radical scavengers in clinics. These results proved that the newly synthesized L-NNNBP was an effective therapeutic agent for the prevention and treatment of AD.
AuthorsTian-Yao Shi, Da-Qing Zhao, Hai-Bo Wang, Shufang Feng, Shui-Bing Liu, Jiang-Hao Xing, Yang Qu, Peng Gao, Xiao-Li Sun, Ming-Gao Zhao
JournalNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (Neurotherapeutics) Vol. 10 Issue 2 Pg. 340-53 (Apr 2013) ISSN: 1878-7479 [Electronic] United States
PMID23212232 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Cyclic N-Oxides
  • Free Radical Scavengers
  • Imidazoles
  • N-p-nitrobenzoylpyrrolidinyl(4,5-dihydro-4,4,5,5-tetramethyl-3-oxido- 1H-imidazol-3-ium-1-oxyl-2-yl)
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Superoxides
Topics
  • Alzheimer Disease (drug therapy, psychology)
  • Amyloid beta-Peptides (antagonists & inhibitors, metabolism, toxicity)
  • Amyloid beta-Protein Precursor (metabolism)
  • Animals
  • Cell Survival (drug effects)
  • Cells, Cultured
  • Cyclic N-Oxides (pharmacology)
  • Fluorescent Antibody Technique
  • Free Radical Scavengers (pharmacology)
  • Humans
  • Imidazoles (pharmacology)
  • In Situ Nick-End Labeling
  • Lipid Peroxidation (drug effects)
  • Maze Learning (drug effects)
  • Memory Disorders (prevention & control, psychology)
  • Mice
  • Mice, Transgenic
  • Microsomes, Liver (drug effects, metabolism)
  • Neurons (drug effects)
  • Peptide Fragments (antagonists & inhibitors, toxicity)
  • Plaque, Amyloid (prevention & control)
  • Presenilin-1 (metabolism)
  • Superoxides (metabolism)
  • tau Proteins (metabolism)

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