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Research ArticleNeuropharmacology

Potassium 2-(1-Hydroxypentyl)-Benzoate Improves Memory Deficits and Attenuates Amyloid and τ Pathologies in a Mouse Model of Alzheimer's Disease

Ying Peng, Yanli Hu, Shaofeng Xu, Xianfang Rong, Jiang Li, PingPing Li, Ling Wang, Jinghua Yang and Xiaoliang Wang
Journal of Pharmacology and Experimental Therapeutics August 2014, 350 (2) 361-374; DOI: https://doi.org/10.1124/jpet.114.213140
Ying Peng
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Yanli Hu
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Shaofeng Xu
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Xianfang Rong
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Jiang Li
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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PingPing Li
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Ling Wang
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Jinghua Yang
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Xiaoliang Wang
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition and neurofibrillary tangles. Dl-PHPB [potassium 2-(1-hydroxypentyl)-benzoate], has been shown to have neuroprotective effects on cerebral ischemic, vascular dementia, and Aβ-induced animal models by inhibiting oxidative injury, neuronal apoptosis, and glial activation. The aim of the present study was to examine the effect of dl-PHPB on learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic AD mouse models (APP/PS1) and the mechanisms of dl-PHPB in reducing Aβ accumulation and τ phosphorylation. Twelve-month-old APP/PS1 mice were given 30 mg/kg dl-PHPB by oral gavage for 3 months. Dl-PHPB treatment significantly improved the spatial learning and memory deficits compared with the vehicle-treated APP/PS1 mice. In the meantime, dl-PHPB obviously reduced τ hyperphosphorylation at Ser199, Thr205, and Ser396 sites in APP/PS1 mice. This reduction was accompanied by APP phosphorylation reduction and protein kinase C activation. In addition, expression of cyclin-dependent kinase and glycogen synthase kinase 3β, the most important kinases involved in τ phosphorylation, was markedly decreased by dl-PHPB treatment. Phosphorylated protein kinase B and phosphoinositide 3-kinase levels of APP/PS1 mice were significantly reduced compared with levels in wild-type mice, and dl-PHPB reversed the reduction. The effects of dl-PHPB effecting a decrease in τ phosphorylation and kinase activation were further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human APP695. These data raised the possibility that dl-PHPB might be a promising multitarget neuronal protective agent for the treatment of AD.

Footnotes

    • Received January 15, 2014.
    • Accepted May 29, 2014.
  • This study was supported by the grants from National Natural Sciences Foundation of China [Grant 81373387]; the National Science and Technology Major Special Project on Major New Drug Innovation of China [Grant 2012ZX09301002-004]; and the 2010 Program for New Century Excellent Talents in University [Grant NCET-10-0961].

  • dx.doi.org/10.1124/jpet.114.213140.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 350 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 2
1 Aug 2014
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Research ArticleNeuropharmacology

PHPB Attenuates Aβ and τ Pathologies in APP/PS1 Mice

Ying Peng, Yanli Hu, Shaofeng Xu, Xianfang Rong, Jiang Li, PingPing Li, Ling Wang, Jinghua Yang and Xiaoliang Wang
Journal of Pharmacology and Experimental Therapeutics August 1, 2014, 350 (2) 361-374; DOI: https://doi.org/10.1124/jpet.114.213140

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Research ArticleNeuropharmacology

PHPB Attenuates Aβ and τ Pathologies in APP/PS1 Mice

Ying Peng, Yanli Hu, Shaofeng Xu, Xianfang Rong, Jiang Li, PingPing Li, Ling Wang, Jinghua Yang and Xiaoliang Wang
Journal of Pharmacology and Experimental Therapeutics August 1, 2014, 350 (2) 361-374; DOI: https://doi.org/10.1124/jpet.114.213140
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