Anti-Amyloidogenic Effects of Asarone Derivatives From Perilla frutescens Leaves Against Beta-Amyloid Aggregation and Nitric Oxide Production

Abstract

Alzheimer's disease (AD) is a progressive, neurodegenerative brain disorder associated with loss of memory and cognitive function. Beta-amyloid (Aβ) aggregates, in particular, are known to be highly neurotoxic and lead to neurodegeneration. Therefore, blockade or reduction of Aβ aggregation is a promising therapeutic approach in AD. We have previously reported an inhibitory effect of the methanol extract of <i>Perilla frutescens</i> (L.) Britton (Lamiaceae) and its hexane fraction on Aβ aggregation. Here, the hexane fraction of <i>P. frutescens</i> was subjected to diverse column chromatography based on activity-guided isolation methodology. This approach identified five asarone derivatives including 2,3-dimethoxy-5-(1<i>E</i>)-1-propen-1-yl-phenol (<b>1</b>), β-asarone (<b>2</b>), 3-(2,4,5-trimethoxyphenyl)-(2<i>E</i>)-2-propen-1-ol (<b>3</b>), asaronealdehyde (<b>4</b>), and α-asarone (<b>5</b>). All five asarone derivatives efficiently reduced the aggregation of Aβ and disaggregated preformed Aβ aggregates in a dose-dependent manner as determined by a Thioflavin T (ThT) fluorescence assay. Furthermore, asarone derivatives protected PC12 cells from Aβ aggregate-induced toxicity by reducing the aggregation of Aβ, and significantly reduced NO production from LPS-stimulated BV2 microglial cells. Taken together, these results suggest that asarone derivatives derived from <i>P. frutescens</i> are neuroprotective and have the prophylactic and therapeutic potential in AD.