Initial Study Of Material Basis For Anti-AD Effect Of Traditional Medicine Curcuma Xanthorrhiza

The incidence of Alzheimer’s disease (AD) is increasing with growing population aging. AD is a complex neurodegenerative disease. Acetylcholinesterase (AChE) inhibitors are one of few clinical drugs in the treatment of AD, which can only relieve some symptoms. Many traditional Chinese medicines (TCM) have anti-AD potential, but their unclear material basis influences their development.TCM application experiences, the epidemiological statistics and some experimental data suggest the anti-AD potential of Curcuma, of which the main chemical compositions are sesquiterpenoids and curcuminoids. Many literature data involved anti-AD effect of curcuminoids. However, their low bioavailability leads to the failure on clinical experiment.During screening test in vitro for AChE inhibitors, a few of curcum species, especially C. xanthorrhiza showed activities. The active fraction was not curcuminiods according to TLC observation. Thus, guided by bioactivity test, we studied C. xanthorrhiza ethanol extract and obtained 22 compounds, including 15 sesquiterpenes:zedoardiol(1), zedoaraldehyde(2), zedoarol(3), gweicurculactone(4), guai-1(10),3,5,7(11),8-pentaen-2-on-11,8-olide(5), zederone (6), germacrone(7),13-hydroxygermacrone(8), gelchomanolide(9) 3,4-dihydroxybisabola-1,10-diene(10), a-curcumene(11), xanthorrhizol(12),8p-hydroxy-isogermafurenolide(13), curcum-adione(14) and curcumenone(15); three curcuminoids:curcumin(16), dihydrocurcumin (17), dehydro-6-gingerdione(18); two phenylpropanoids: 3-hydroxy-6-methylacetophenone(19), vanillin(20); one sterol:β-sitosterol(21); one fatty acid:hexadecanoic acid(22). Among them, compounds 1,2 and 10 are three new compounds; compounds 4,5,9,13,14,15,18,19 and 20 were isolated from C. xanthorrhiza for the first time. Compounds 2,6,7,8 and 19 presented moderate AChE inhibitory activity in vitro with MIQ value at 1-6μg, compared with galantamine.Because of the limited of mass of pure compounds, the C. xanthorrhiza essential oil containing active compounds was further studied for AChE inhibitory activity in vivo using middle-aged SD rats. Results showed that low dose essential oil (30μL/day) could reduce AChE activity, while high dose increased AChE activity. But the acetylcholine level increased in both low and high dose groups in certain degree. The study suggested that C. xanthorrhiza sesquiterpenoids may have impact on cholinergic system.Recent research proved that silent information regulator 1 (SIRT1) is a potent new AD target, since several classic AD targets can be influenced by SIRT1 regulation. Using western blot, we found 10 compounds from C. xanthorrhiza could promote SIRT1 expression in HEK293 cells at a concentration of 20μM. The better ones are sesquiterpenoids 7 and 8, which could promote SIRT1 expression by 1.73- and 1.71-fold. This study indicated that these sesquiterpenoids may act anti-AD effect through SIRT1 regulation.This study evaluated the AChE inhibitory and SIRT1 regulation activities of C. xanthorrhiza for the first time and discovered some active compounds and new structures. Our data suggest that the material basis of anti-AD effect of curcuma should not only focus on curcuminoids. The effect of sesquiterpenoids or the synergy effect of both are worthy of further study for the development of such important traditional medicines.