Natural anti-neuroinflammatory inhibitors in vitro and in vivo from Aglaia odorata

Abstract

Fifty compounds including seven undescribed (1, 13, 18–20, 30, 31) and forty-three known (2–12, 14–17, 21–29, 32–50) ones were isolated from the extract of the twigs and leaves of Aglaia odorata with anti-neuroinflammatory activities. Their structures were determined by a combination of spectral analysis and calculated spectra (ECD and NMR). Among them, compounds 13–25 were found to possess tertiary amide bonds, with compounds 16, 17, and 19–21 existing detectable cis/trans mixtures in 1H NMR spectrum measured in CDCl3. Specifically, the analysis of the cis–trans isomerization equilibrium of tertiary amides in compounds 19–24 was conducted using NMR spectroscopy and quantum chemical calculations. Bioactivity evaluation showed that the cyclopenta[b]benzofuran derivatives (2–6, 8, 10, 12) could inhibit nitric oxide production at the nanomolar concentration (IC50 values ranging from 2 to 100 nM) in lipopolysaccharide-induced BV-2 cells, which were 413–20670 times greater than that of the positive drug (minocycline, IC50 = 41.34 μM). The cyclopenta[bc]benzopyran derivatives (13–16), diterpenoids (30–35), lignan (40), and flavonoids (45, 47, 49, 50) also demonstrated significant inhibitory activities with IC50 values ranging from 1.74 to 38.44 μM. Furthermore, the in vivo anti-neuroinflammatory effect of rocaglaol (12) was evaluated via immunofluorescence, qRT-PCR, and western blot assays in the LPS-treated mice model. The results showed that rocaglaol (12) attenuated the activation of microglia and decreased the mRNA expression of iNOS, TNF-α, IL-1β, and IL-6 in the cortex and hippocampus of mice. The mechanistic study suggested that rocaglaol might inhibit the activation of the NF-κB signaling pathway to relieve the neuroinflammatory response.