YY-1224, a terpene trilactone-strengthened Ginkgo biloba, attenuates neurodegenerative changes induced by β-amyloid (1-42) or double transgenic overexpression of APP and PS1 via inhibition of cyclooxygenase-2

J Neuroinflammation. 2017 Apr 27;14(1):94. doi: 10.1186/s12974-017-0866-x.

Abstract

Background: Ginkgo biloba has been reported to possess free radical-scavenging antioxidant activity and anti-inflammatory properties. In our pilot study, YY-1224, a terpene trilactone-strengthened extract of G. biloba, showed anti-inflammatory, neurotrophic, and antioxidant effects.

Results: We investigated the pharmacological potential of YY-1224 in β-amyloid (Aβ) (1-42)-induced memory impairment using cyclooxygenase-2 (COX-2) knockout (-/-) and APPswe/PS1dE9 transgenic (APP/PS1 Tg) mice. Repeated treatment with YY-1224 significantly attenuated Aβ (1-42)-induced memory impairment in COX-2 (+/+) mice, but not in COX-2 (-/-) mice. YY-1224 significantly attenuated Aβ (1-42)-induced upregulation of platelet-activating factor (PAF) receptor gene expression, reactive oxygen species, and pro-inflammatory factors. In addition, YY-1224 significantly inhibited Aβ (1-42)-induced downregulation of PAF-acetylhydrolase-1 (PAF-AH-1) and peroxisome proliferator-activated receptor γ (PPARγ) gene expression. These changes were more pronounced in COX-2 (+/+) mice than in COX-2 (-/-) mice. YY-1224 significantly attenuated learning impairment, Aβ deposition, and pro-inflammatory microglial activation in APP/PS1 Tg mice, whereas it significantly enhanced PAF-AH and PPARγ expression. A preferential COX-2 inhibitor, meloxicam, did not affect the pharmacological activity by YY-1224, suggesting that the COX-2 gene is a critical mediator of the neuroprotective effects of YY-1224. The protective activity of YY-1224 appeared to be more efficacious than a standard G. biloba extract (Gb) against Aβ insult.

Conclusions: Our results suggest that the protective effects of YY-1224 against Aβ toxicity may be associated with its PAF antagonistic- and PPARγ agonistic-potential as well as inhibition of the Aβ-mediated pro-inflammatory switch of microglia phenotypes through suppression of COX-2 expression.

Keywords: APPswe/PS1dE9 transgenic mice; Cyclooxygenase-2 knockout mice; Microglia; Peroxisome proliferators-activated receptor γ; Platelet-activating factor; Terpene trilactone-strengthened G. biloba.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / toxicity*
  • Amyloid beta-Protein Precursor / biosynthesis
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Cyclooxygenase 2 / metabolism*
  • Gene Expression
  • Ginkgo biloba*
  • Lactones / isolation & purification
  • Lactones / therapeutic use
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / prevention & control
  • Peptide Fragments / toxicity*
  • Plant Extracts / isolation & purification
  • Plant Extracts / pharmacology
  • Plant Extracts / therapeutic use*
  • Presenilin-1 / biosynthesis
  • Presenilin-1 / genetics
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Terpenes / isolation & purification
  • Terpenes / therapeutic use

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Lactones
  • Peptide Fragments
  • Plant Extracts
  • Presenilin-1
  • Reactive Oxygen Species
  • Terpenes
  • amyloid beta-protein (1-42)
  • trilactone
  • Cyclooxygenase 2