Studies On Bioactive Constituents Of Lycium Barbarum For The Treatment Of Alzheimer’s Disease

Lycium barbarum(Solanaceae) is a defoliated shrubbery that naturally grows in Asia, primarily in northwestern China. The dried fruit of Lycium barbarum(wolfberry, goji berry), first recorded in “Shen Nong’s Herbal Classic”, is a famous traditional Chinese medicine(TCM) to nourish liver and kidney, and brighten eye. Wolfberry has been used as a TCM and functional food in many countries around the world. Recent pharmacological studies demonstrated that wolfberry possessed a series of beneficial biological activities, including antioxidant, anti-aging, neuroprotective, anti-Alzheimer’s disease(AD), and hepato-protective properties. Previous studies showed that polysaccharides, polyphenols, and carotenoids were the major constituents in wolfberry.Eighty-three compounds were isolated from the 60% EtOH extract of wolfberry using macroporous resin, silica gel, ODS, Sephadex LH-20, HPLC, and other chromatographic methods. Their structures were unambiguously determined by spectroscopic analyses(UV, IR, MS, and NMR) and chemical methods, including 15 dicaffeoylspermidine derivatives(1-15), 15 phenylpropionoyl phenylethylamine derivatives(16-30), 28 phenylpropanoids(31-58), four coumarins(59-62), eight lignans(63-70), five flavonoids(71-75), three isoflavonoids(76-78), two chlorogenic acid derivatives(79 and 80), and three benzoic acid derivatives(81-83). Among them, lycibarbarspermidines A-O(1-15), N-(4-O-β-D-glucopyranosyl-cis-feruloyl)-tyramine(16),(7’’S*, 8’’R*)-canabisine H(25), lycibarbarphenylpropanoids A-I(31-39), and lycibarbarcoumarin A(59) were new compounds. 29 known compounds(17-19, 24, 27, 29, 30, 40-49, 54, 56-58, 64-66, 69, 70, and 76-78) were first obtained from the genus Lycium. Dicaffeoylspermidine derivatives, lignans, and isoflavonoids were obtained from wolfberry for the first time. Dicaffeoylspermidine derivatives, a rare kind of plant secondary metabolites, are primarily distributed in the family of Solanaceae. Only six compounds were structurally identified, and all of them are acyclic aglycones. Compounds 1-15 are the first glycosidic products of dicaffeoylspermidine derivatives, and compounds 14 and 15 are the first cyclization products of dicaffeoylspermidine derivatives. Based on the analysis of the process of isolation and purification of these compounds, dicaffeoylspermidine derivatives can be considered as a major class of constituents in wolfberry.The short-term memory assay on a transgenic fly AD model showed that the extract of Lycium barbarum(LB) exhibited anti-AD activity. The anti-AD activities of five fractions of LB were evaluated by this model, and the results showed that a major fraction(LBB) displayed the short-term memory enhancement capacity. A major class of constituents, dicaffeoylspermidine derivatives(1-15), was firstly obtained from LBB. The transgenic fly AD model was carried out to assess anti-AD activities of dicaffeoylspermidine derivatives. The results showed that 1-15 all exhibited the different levels of anti-AD activity.Four in vitro assays(ThT, Ellman, DPPH radical scavenging, and ORAC assays) were applied to evaluate anti-AD and antioxidant activities of the isolated. The results showed that all these compounds exhibited different levels of oxygen radical absorbance capacity(ORAC), and some compounds displayed DPPH radical scavenging activity. However, one compound(58) had AChE inhibitory activity, and no compounds showed Aβ42 aggregation inhibitory activity. A preliminary relationship between chemical structures of phenylpropanoids and their oxygen radical absorbance capacity(ORAC)/DPPH radical scavenging activity was discussed. These results are beneficial for understanding the scientific basic on the efficacy of wolfberry.