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A new chiral pyrrolyl ?-nitronyl nitroxide radical attenuates ?-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 ?-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 ?-amyloid (A?) 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 A? exposure. In vivo treatment with L-NNNBP for 1 month induced a marked decrease in brain A? 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.

SUBMITTER: Shi TY

PROVIDER: S-EPMC3625382 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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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.

Shi Tian-Yao TY Zhao Da-Qing DQ Wang Hai-Bo HB Feng Shufang S Liu Shui-Bing SB Xing Jiang-Hao JH Qu Yang Y Gao Peng P Sun Xiao-Li XL Zhao Ming-Gao MG

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20130401 2

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 qu ...[more]

PMID: 23212232

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Project description:Two stable nitronyl nitroxide free radicals {R 1 = 4'-methoxy-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide (NNPhOMe) and R 2 = 2-(2'-thienyl)-4,4,5,5-tetramethylimidazoline 3-oxide 1-oxyl (NNT)} are successfully synthesized using Ullmann condensation. The reactions of these two radicals with 3d transition metal ions, in the form of M(hfac)2 (where M = Co or Mn, hfac: hexafluoroacetylacetone), result in four metal-organic complexes Co(hfac)2(NNPhOMe)2, 1; Co(hfac)2(NNT)2·(H2O), 2; Mn(hfac)2(NNPhOMe)·x(C7H16), 3; and Mn(hfac)2(NNT)2, 4. The crystal structure and magnetic properties of these complexes are investigated by single-crystal X-ray diffraction, dc magnetization, infrared, and electron paramagnetic resonance spectroscopies. The compounds 1 and 4 crystallize in the triclinic, P1̅, space group, whereas complex 3 crystallizes in the monoclinic structure with the C2/c space group and forms chain-like structure along the c direction. The complex 2 crystallizes in the monoclinic symmetry with the P21/c space group in which the N-O unit of the radical coordinates with the Co ion through hydrogen bonding of a water molecule. All compounds exhibit antiferromagnetic interactions between the transition metal ions and nitronyl nitroxide radicals. The magnetic exchange interactions (J/K B) are derived using isotropic spin Hamiltonian H = -2J∑(S metal S radical) for the model fitting to the magnetic susceptibility data for 1, 2, 3, and 4. The exchange interaction strengths are found to be -328, -1.25, -248, and -256 K, for the 1, 2, 3, and 4 metal-organic complexes, respectively. Quantum chemical density functional theory (DFT) computations are carried out on several models of the metal-radical complexes to elucidate the magnetic interactions at the molecular level. The calculations show that a small part of the inorganic spins are delocalized over the oxygens from hfac {∼0.03 for Co(II) and ∼0.015 for Mn(II)}, whereas a more significant fraction {∼0.24 for Mn(II) and ∼0.13 for Co(II)} of delocalized spins from the metal ion is transferred to the coordinated oxygen atom(s) of nitronyl nitroxide.

Dataset Information

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

Publications

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

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