Abstract
BackgroundGinkgo 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Ginkgo biloba has been reported to possess free radical-scavenging antioxidant activity and anti-inflammatory properties
Effect of YY-1224 or G. biloba extract (Gb) on Aβ (1-42)-induced impairment of visual recognition learning in COX-2 (+/+)- and COX-2 (−/−)-mice The recognition test is based on the natural tendency of rodents to investigate a novel object instead of a familiar one
In the COX-2 (+/+) mice, repeated treatment with Gb or YY-1224 significantly ameliorated the decrease in exploratory preference for a novel object that was induced by Aβ (1-42) [Fig. 2a, Analysis of variance (ANOVA) and post hoc pairwise comparisons indicating the effect of Gb (P < 0.05) or YY-1224 (P < 0.01)]
Summary
Ginkgo biloba has been reported to possess free radical-scavenging antioxidant activity and anti-inflammatory properties. Platelet-activating factor (PAF) is a highly potent inflammatory mediator and a potential neurotoxin [10]. It plays an important role in excitotoxicity, production of free radicals and nitric oxide (NO), and regulation of pro-inflammatory cytokine genes [11,12,13,14]. In vitro studies have shown that activation of epidermal PAFR results in biosynthesis of COX-2 [16]. Both PAFR and COX-2 are involved in memory processing in vivo [17, 18]. Three isoforms of PAF-AH were identified: plasma PAF-AH and PAF-AH II and I [21]
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