Neural Activity

Agarwood has been traditionally used as a medicine for tranquilizing and reducing excitement in China, Southeast Asia, and the Middle East for centuries. Modern pharmacological studies have demonstrated that agarwood has an active effect on the nervous system [48,49]. Okugawa et al. [50] determined that a benzene extract of A. malaccensis agarwood reduced spontaneous motility, prolonged hexobarbiturate-induced sleeping time, and decreased rectal temperature, whereas petroleum ether, chloroform, or water extracts did not have that effect. A further bio-guided isolation of a benzene extract found that jinkoh-eremol and agarospirol were the main active constituents [51,52]. Takemoto et al. [53] reported that agarwood essential oil sedated mice through vapor inhalation, in which the main volatile constituents were benzylacetone, α-gurjunene, and (+)-calarene. As benzylacetone had a sedative effect, a number of derivatives were synthesized and assessed for a sedative effect. The results demonstrated that benzylacetone-like compounds had sedative activities, and their intensities varied depending on the functional group in the carbon chain, the substituent in the benzene ring, and their combinations [54]. Our recent studies showed that both the ethanol extract and essential oil of agarwood, induced by the whole-tree agarwood inducing technique in A. sinensis trees, had a sedative-hypnotic effect, where its potential mechanism is related to regulating the gene expression of GABA_A receptors and potentiating the GABA_Areceptor function [55,56]. Agarofuran, derived from agarwood essential oil, was reported to have anxiolytic and anti-depression activity in mice [49]. To explore a potential drug for treating anxiety and depression, a series of agarofuran-like derivatives were synthesized and the activity screened, among which, buagafuran was an effective compound for anti-anxiety and anti-depression, with low toxicity and a high safety coefficient [49,57]. The potential mechanism might be through modulating central neurotransmitters, such as dopamine [58]. A metabolic study showed that buagafuran could be transformed to hydroxy metabolite and carbonyl one in a human liver microsome, where carbonyl metabolite was the main one [59]. Until now, phase II clinical trials are being conducted on buagafuran. Furthermore, many other activity screening results have also shown that compounds from agarwood have an effect on neural activity. Compound 7 (10 µg/mL) showed neural protective activity against both glutamate-induced and corticosterone-induced neurotoxicity in PC12 pheochromocytoma and human U251 glioma cells [16]. Compounds 118 and 119exhibited potent anti-depressant activity in vitro by inhibiting [³H]-5-HT reuptake in rat synaptosomes [37]. Compound 120 demonstrated remarkable antidepressant activity in vitro, by inhibiting norepinephrine reuptake in rat brain synaptosomes [38]. Simultaneously, seventeen new 2-(2-phenylethyl)chromones, including compounds 22, 27–29, 31–33, 68, 69, 78–80, 82–86, and eleven new terpenoids, such as 103–105and 110–117, had acetylcholinesterase inhibitive effect [8,20,21,26,28,32,33,34,35]. Above all, neural activity of agarwood is one of the most studied aspects with many active compounds and a promising drug candidate found, which will sustain it as a research hotspot in the future.