1. Academic Validation
  2. Oral administration of methysticin improves cognitive deficits in a mouse model of Alzheimer's disease

Oral administration of methysticin improves cognitive deficits in a mouse model of Alzheimer's disease

  • Redox Biol. 2017 Aug;12:843-853. doi: 10.1016/j.redox.2017.04.024.
Athanassios Fragoulis 1 Stephanie Siegl 2 Markus Fendt 3 Sandra Jansen 4 Ulf Soppa 5 Lars-Ove Brandenburg 6 Thomas Pufe 7 Joachim Weis 8 Christoph Jan Wruck 9
Affiliations

Affiliations

  • 1 Department of Anatomy and Cell Biology, Uniklinik RWTH Aachen University, Aachen, Germany. Electronic address: afragoulis@ukaachen.de.
  • 2 Department of Pharmacology and Toxicology, Uniklinik RWTH Aachen University, Aachen, Germany. Electronic address: stephie.siegl@googlemail.com.
  • 3 Institute for Pharmacology and Toxicology, Medical Faculty, University of Magdeburg, Magdeburg, Germany; Center of Behavioral Brain Sciences, University of Magdeburg, Magdeburg, Germany. Electronic address: markus.fendt@med.ovgu.de.
  • 4 Department of Anatomy and Cell Biology, Uniklinik RWTH Aachen University, Aachen, Germany. Electronic address: s.jansen77@gmx.de.
  • 5 Department of Pharmacology and Toxicology, Uniklinik RWTH Aachen University, Aachen, Germany. Electronic address: ulf.soppa@rwth-aachen.de.
  • 6 Department of Anatomy and Cell Biology, Uniklinik RWTH Aachen University, Aachen, Germany. Electronic address: lbrandenburg@ukaachen.de.
  • 7 Department of Anatomy and Cell Biology, Uniklinik RWTH Aachen University, Aachen, Germany. Electronic address: tpufe@ukaachen.de.
  • 8 Institute of Neuropathology, Uniklinik RWTH Aachen and JARA Brain Translational Medicine, Aachen, Germany. Electronic address: jweis@ukaachen.de.
  • 9 Department of Anatomy and Cell Biology, Uniklinik RWTH Aachen University, Aachen, Germany. Electronic address: cwruck@ukaachen.de.
Abstract

Introduction: There is increasing evidence for the involvement of chronic inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD). Nuclear factor erythroid 2-related factor 2 (Nrf2) is an anti-inflammatory transcription factor that regulates the oxidative stress defense. Our previous experiments demonstrated that kavalactones protect neuronal cells against Amyloid β (Aβ)-induced oxidative stress in vitro by Nrf2 pathway activation. Here, we tested an in vivo kavalactone treatment in a mouse model of AD.

Methods: The kavalactone methysticin was administered once a week for a period of 6 months to 6 month old transgenic APP/Psen1 mice by oral gavage. Nrf2 pathway activation was measured by methysticin treatment of ARE-luciferase mice, by qPCR of Nrf2-target genes and immunohistochemical detection of Nrf2. Aβ burden was analyzed by CongoRed staining, immunofluorescent detection and ELISA. Neuroinflammation was assessed by immunohistochemical stainings for microglia and astrocytes. Pro-inflammatory cytokines in the hippocampus was determined by Luminex multi-plex assays. The hippocampal oxidative damage was detected by oxyblot technique and immunohistochemical staining against DT3 and 4-HNE. The cognitive ability of mice was evaluated using Morris water maze.

Results: Methysticin treatment activated the Nrf2 pathway in the hippocampus and cortex of mice. The Aβ deposition in brains of methysticin-treated APP/Psen1 mice was not altered compared to untreated mice. However, methysticin treatment significantly reduced microgliosis, astrogliosis and secretion of the pro-inflammatory cytokines TNF-α and IL-17A. In addition, the oxidative damage of hippocampi from APP/Psen1 mice was reduced by methysticin treatment. Most importantly, methysticin treatment significantly attenuated the long-term memory decline of APP/Psen1 mice.

Conclusion: In summary, these findings show that methysticin administration activates the Nrf2 pathway and reduces neuroinflammation, hippocampal oxidative damage and memory loss in a mouse model of AD. Therefore, kavalactones might be suitable candidates to serve as lead compounds for the development of a new class of neuroprotective drugs.

Keywords

Alzheimer's disease; Astrogliosis; Kava kava; Kavalactone; Methysticin; Neuroinflammation; Nrf2; Oxidative stress.

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