A New Chiral Pyrrolyl α-Nitronyl Nitroxide Radical Attenuates β-Amyloid Deposition and Rescues Memory Deficits in a Mouse Model of Alzheimer Disease

Zhao, Daqing; Wang, Haibo; Feng, Shini; Liu, Shui-bing; Xing, Jiang-hao; Qu, Yang; Gao, Peng; Sun, Xiance; Zhao, Ming

doi:10.1007/s13311-012-0168-z

Cited by 23 publications

(14 citation statements)

References 55 publications

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“…Moreover, the ability of NRbt to regulate the activiy of SOD, CAT and the level of GSH was better than that of tempol (P \ 0.05); this occurred because NITs have extensive unpaired spin density distributions (Fig. 1A) compared with tempol [22]. We hypothesized that the protective effect of nitronyl nitroxides against infrasound-induced injury is the result of their ability to scavenge ROS, such as O 2…”

Section: Discussionmentioning

confidence: 97%

“…We previously synthesized a series of NIT derivatives and found that they were good antioxidants that provided radioprotective effects in vitro and in vivo [20,21]. Recently, we found that the NIT derivative L-NNNBP has good protective effects against bamyloid deposition and memory deficits in an AD rat model of APP/PS1 [22]. Based on our previous research, we synthesized a new cyanuric chloride-based nitronyl nitroxide biradical, 1-chloro-3,5-bis(4,4,5,5-tetramethyl-4-oxylbenzenyl-imidazolidine-1-oxyl-3-oxide)-1,3,5-triazine (NRbt, Fig.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of a Novel Nitronyl Nitroxide Radical and Determination of its Protective Effects Against Infrasound-Induced Injury

Wang

Yang

et al. 2015

Neurochem Res

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Infrasound causes functional disorders and structural injury to the central nervous system. However, few anti-infrasound drugs exist, and they are inefficient. Nitronyl nitroxide radicals have been reported to be good antioxidants that act as superoxide dismutase mimics and directly react with reactive oxygen species, such as ·OH, H2O2, and O 2 (∙) -. Our previous research showed that the nitronyl nitroxide radical L-NNNBP has good protective effects against β-amyloid deposition and memory deficits in an AD rat model of APP/PS1. The objective of the present study was to find a new group of anti-infrasound drugs and determine the underlying pharmacological actions of nitronyl nitroxide radicals against infrasound-induced neuronal impairment in vivo. We synthesized a new stable nitronyl nitroxide radical, NRbt, and characterized its crystal structure. The results of the anti-oxidative damage effects of NRbt and the positive control drug tempol showed that they could significantly increase the SOD activity, CAT activity and GSH level and decrease the MDA level in rat hippocampi compared with infrasound exposure without pretreatment. Moreover, the ability of NRbt to regulate the activity or level of these biochemical markers was better than that of tempol. Our results showed that both NRbt and tempol significantly protected against the learning and memory impairments induced by infrasound exposure in a Morris water maze, but there were no significant differences in the path length or escape latency between the rats in the tempol group and the three NRbt groups (P > 0.05). In addition, the infrasound-induced neuronal apoptosis in rat hippocampi was significantly suppressed by NRbt and tempol. The results demonstrated that compared with the infrasound exposure group, the expression of Bcl-2 was up-regulated and the expressions of Bax and caspase-3 were down-regulated in rats pretreated with NRbt (40 mg/kg) or tempol (40 mg/kg). These results showed that the newly synthesized nitronyl nitroxide radical, NRbt, may be an effective anti-infrasound drug because of its capacity to inhibit the oxidative damage of free radicals induced by infrasound exposure.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Synthesis of a Novel Nitronyl Nitroxide Radical and Determination of its Protective Effects Against Infrasound-Induced Injury

Wang

Yang

et al. 2015

Neurochem Res

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“…The Aβ peptides are important in the pathogenesis of AD. Therefore, inhibiting the generation of Aβ and increasing the rate of clearance of this protein, may be potential therapeutic strategies with which to delay the development of AD (4). While the Aβ hypothesis states that the β-amyloid protein is involved in the progression of AD pathology, the etiology remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Aβ peptide secretion is reduced by Radix Polygalae-induced autophagy via activation of the AMPK/mTOR pathway

Zhao

Wang

Wang³

et al. 2015

Molecular Medicine Reports

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Radix Polygalae is a traditional Chinese medicine that has been used as a sedative and to improve memory for a number of years. The impact of Radix Polygalae in patients with Alzheimer's disease has been investigated. However the mechanisms underlying its effects remain unclear. In the current study, the toxicity of various doses (100, 40, 20, 10, 5 and 0 µg/ml) of Radix Polygalae was measured in the human neuroblastoma cell line (SH-SY5Y) using an MTT assay. Changes in amyloid β (Aβ) levels in the supernatant of Chinese hamster ovary (CHO) cells overexpressing β-amyloid pro-protein (APP) and BACE1 (CHO-APP/BACE1), were detected using an ELISA assay. In order to confirm that the Aβ reduction was associated with autophagy, the autophagy marker protein, light chain 3 (LC3), was measured by western blot analysis and autophagosomes were assessed using MDC staining. In addition, the mechanism underlying the autophagy induced by Radix Polygalae was analyzed using western blotting to measure the protein expression of mammalian target of rapamycin (mTOR), p70s6k, Raptor, protein kinase B and adenosine monophosphate-activated protein kinase (AMPK), in addition to the phosphorylated forms of these proteins. The results demonstrated no significant toxicity of Radix Polygalae in SH-SY5Y cells, at a dose of 100 µg/ml. The secretion of Aβ was markedly reduced following treatment with Radix Polygalae, and this reduction occurred in a dose-dependent manner. The autophagy levels were shown to be enhanced in the drug treatment group, using fluorescence microscopy. In addition, levels of LC3Ⅱ/LC3Ⅰ, the marker protein of autophagy, were also increased. The results of the current study suggest that Radix Polygalae may aid in the elimination of the Aβ peptide, via the induction of autophagy, by the AMPK/mTOR signaling pathway. These results may provide a basis for further kin vivo investigation.

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“…It inhibited cell apoptosis induced by A␤ exposure. In vivo treatment for 1 month induced a marked decrease in brain A␤ deposition and tau phosphorylation in A␤PP/PS1 transgenic mice [80].…”

Section: Antioxidantsmentioning

confidence: 93%

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

Froestl

Pfeifer

Muhs

2014

JAD

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Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review "Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs" was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

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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

Cited by 23 publications

References 55 publications

Synthesis of a Novel Nitronyl Nitroxide Radical and Determination of its Protective Effects Against Infrasound-Induced Injury

Synthesis of a Novel Nitronyl Nitroxide Radical and Determination of its Protective Effects Against Infrasound-Induced Injury

Aβ peptide secretion is reduced by Radix Polygalae-induced autophagy via activation of the AMPK/mTOR pathway

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

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