Studies On Active Lignans From Schisandra Chinesese For Anti-Alzheimer's Disease

Schisandrae Fructus are originated from the dried ripen fruits of Schisandra chinensis (Turcz.) Baill. (Magnoliaceae). Lignans are its main active components effecting on central nervous system. In the present study, systematic studies of lignans on chemical isolation, pharmacological effects on Alzheimer's disease in vitro and in vivo, and the preliminary research on metabolism and distribution in brain of deoxyschizandrin (DS), an active constituent, were studied. The preliminary influence of DS on the pharmacokinetics of docetaxel, a drug metabolized by CYP3A4, were also investigated.40 compounds were isolated from the EtOAc extract of Schisandrae Fructus by means of column chromatography of silica gel, Sephadex LH-20 and reversed phase ODS, preparation TLC and HPLC. Using physico-chemical and spectroscopic data,and by comparison of reference substance, 34 compounds were identified as schisanchinin A (1), schisanchinin B (2), schisanchinin C (3), tigloylgomisin P (4),(-)-tigloyl-deangeloyl-gomisin F (5), gomisin F (6), gomisin G (7), gomisin B (8),schisantherin D (9), deoxyschizandrin (10), (±)-y-schizandrin (11), gomisin A (12),schizandrin (13), pre-gomisin (14), gomisin N (15), schizandrin C (16), (±)-gomisin M1(17),(-)-gomisin M1 (18),(-)-gomisin L1 (19),(+)-gomisin M2(20),gomisin J (21),(+)-gomisin k3 (22a),kadsulignan N (23),methylgomisin O (24),methylisogomisin O(25), 7(18)-dehydroschisandro A (26), epigomisin O (27a), gomisin O (27b),rubschisantherin (28), gomisin D (29), gomisin E (30), dibutylphthalate (31),?-sitosterol (32) and ganwuweizic acid (33). Compound 1-3 were new compounds,compound 23, 24, 25 and 28 were isolated for the first time from Schisandra sp. and S.chinensis, respectively. Compound 26 was a new natural compound.Using NO release in lipopolysaccharide (LPS)-induced mice BV2 microglial cells as a bioassay marker in vitro, the inhibition effects of 28 lignans isolated from Schisandrae Fructus were assayed. The results indicated that lignans with S conformation of dibenzen ring were more active than those with R conformation.Lignan with one methylene-dioxy group in benzene ring was stonger than that with two. Lignan with methylene-dioxy group at carbon 2 and 3 was better than that on carbon 12 and 13. The activity sequence with different substituent groups was following: 6-OCH3 > 6-OAng > C-6 and C-14 connected > 6-OAc > 6-OBz > C-6 and C-9 connected to form one ring.The effects of schizandrin (SCH) and deoxyschizandrin (DS) on the amyloid-beta142(A?1-42) induced memory impairment in mice and the possible antioxidative mechanism were studied by means of behavioral experiment and biochemical tests. Our results showed that SCH and DS (36, 12 mg/kg) significantly improved A?1-42 induced working memory impairments in Y-maze test. SCH and DS (36 mg/kg) significantly improvedA?1-42 induced spatial reference memory in water maze test on day 2-3 and day 3, respectively. In the cerebral cortex and hippocampus of mice, superoxide dismutase (SOD) and glutathione peroxidase(GSH-px) activities, glutathione (GSH) level were increased, and levels of malondialdehyde (MDA) and oxidized glutathione (GSSG) were decreased by the treatment of SCH and DS (36 mg/kg). DS (12 mg/kg) significantly improved MDA and GSH levels indicated that the antioxidative effect of DS is better than that of SCH.Drugs used for central nervous system must pass through blood brain barrier.Therefore, the distribution of DS in the brain was investigated. The metabolism of DS was also studied as there were no reports on the in vivo metabolites of DS. The results showed that except for SCH, iso-SCH was another main metabolite of DS. DS and its metabolite, SCH were detected in the brain after administrated DS (i.g./i.v.).Previous research revealed DS possessed high affinity with CYP3A4. In order to evaluate the possible pharmacokinetic inter-actions of DS and other drugs metabolized by CYP 3A4 enzyme, the pharmacokinetics of docetaxel (DOX) after administration of DS were investigated. The results suggested that, compared with given DOX only, AUC(0-t),Cmax and F of co-administration were lower,but MRT(0-t)were longer. DS had no substantial effect on the pharmacokinetics of DOX and these results laid the foundation on co-administration of DS and other drugs in the new drug development.