title: 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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Tian-Yao
authors.initials: TY
authors.lastname: Shi
authors.forename: Da-Qing
authors.initials: DQ
authors.lastname: Zhao
authors.forename: Hai-Bo
authors.initials: HB
authors.lastname: Wang
authors.forename: Shufang
authors.initials: S
authors.lastname: Feng
authors.forename: Shui-Bing
authors.initials: SB
authors.lastname: Liu
authors.forename: Jiang-Hao
authors.initials: JH
authors.lastname: Xing
authors.forename: Yang
authors.initials: Y
authors.lastname: Qu
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Sun
authors.forename: Ming-Gao
authors.initials: MG
authors.lastname: Zhao
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D015227:Lipid Peroxidation / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000517:prevention & control* / Q000523:psychology*; D051379:Mice; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity; D058225:Plaque, Amyloid / Q000517:prevention & control*; D053764:Presenilin-1 / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D007093:Imidazoles; C583910:N-p-nitrobenzoylpyrrolidinyl(4,5-dihydro-4,4,5,5-tetramethyl-3-oxido- 1H-imidazol-3-ium-1-oxyl-2-yl); D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D013481:Superoxides