1. Academic Validation
  2. Early administration of galantamine from preplaque phase suppresses oxidative stress and improves cognitive behavior in APPswe/PS1dE9 mouse model of Alzheimer's disease

Early administration of galantamine from preplaque phase suppresses oxidative stress and improves cognitive behavior in APPswe/PS1dE9 mouse model of Alzheimer's disease

  • Free Radic Biol Med. 2019 Dec;145:20-32. doi: 10.1016/j.freeradbiomed.2019.09.014.
Taro Saito 1 Shin Hisahara 1 Naotoshi Iwahara 2 Miho C Emoto 3 Kazuki Yokokawa 1 Hiromi Suzuki 1 Tatsuo Manabe 1 Akihiro Matsumura 1 Syuuichirou Suzuki 1 Takashi Matsushita 1 Jun Kawamata 4 Hideo Sato-Akaba 5 Hirotada G Fujii 6 Shun Shimohama 7
Affiliations

Affiliations

  • 1 Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, 060-8556, Japan.
  • 2 Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, 060-8556, Japan; Department of Pharmacology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, 060-8556, Japan.
  • 3 Department of Clinical Laboratory Science, School of Medical Technology, Health Sciences University of Hokkaido, Sapporo, Hokkaido, 002-8072, Japan.
  • 4 Department of Neurology, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0374, Japan.
  • 5 Department of Systems Innovation, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka, 560-8531, Japan.
  • 6 Cancer Preventive Institute, Health Sciences University of Hokkaido, Ishikari, Hokkaido, 061-0293, Japan.
  • 7 Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, 060-8556, Japan. Electronic address: shimoha@sapmed.ac.jp.
Abstract

Alzheimer's disease (AD) is a common neurodegenerative disease that progressively impairs memory and cognition. Deposition of Amyloid-β (Aβ) Peptides is the most important pathophysiological hallmark of AD. Oxidative stress induced by generation of Reactive Oxygen Species (ROS) is a prominent phenomenon in AD and known to occur early in the course of AD. Several reports suggest a relationship between change in redox status and AD pathology including progressive Aβ deposition, glial cell activation, and inflammation. Galantamine is an acetylcholinesterase inhibitor and has been reported to have an oxidative stress inhibitory function. In the present study, galantamine was administered orally to AD model mice from before the appearance of Aβ plaques (preplaque phase), and in vivo change in redox status of the brain was measured using electron paramagnetic resonance (EPR) imaging. Administration of galantamine from the preplaque phase ameliorated memory decline in Morris water maze test and novel object recognition test. Monitoring of the redox status of the brain using EPR imaging showed that galantamine treatment improved the unbalanced redox state. Additionally, galantamine administration enhanced microglial function to promote Aβ clearance, reducing the Aβ-positive area in the cortex and amount of insoluble Aβ in the brain. In contrast, galantamine treatment from the preplaque phase suppressed the production of proinflammatory cytokines through neurotoxic microglial activity. Therefore, galantamine administration from the preplaque phase may have the potential of clinical application for the prevention of AD. In addition, our results demonstrate the usefulness of EPR imaging for speedy and quantitative evaluation of the efficacy of disease-modifying drugs for AD.

Keywords

Alzheimer's disease; Amyloid-β (Aβ); Electron paramagnetic resonance (EPR) imaging; Galantamine; Inflammation; Microglia; Oxidative stress.

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