Active compounds from Fraxinus excelsior L. seeds: Anti-diabetic and body weight control effects

Abstract

Fraxinus excelsior L. seed extract (FE) is recognized as an anti-diabetic agent [1]. Two new secoiridoid glucosides, excelside A (1) and excelside B (2) were isolated and elucidated from FE: (2S, 3E, 4S) 2H-Pyran-4-acetic acid-3-ethylidene-2-[(6-O-β-D-glucopyranosyl-β-D-glucopyranosyl) oxy]-3,4-dihydro-5-(methoxycarbonyl) methyl ester and (2S, 3E, 4S) 2H-Pyran-4-acetic acid-3-ethylidene-2-[(6-O-β-D-glucopyranosyl-β-D-glucopyranosyl) oxy]-3,4-dihydro-5-(methoxycarbonyl) 2-(4-hydroxyphenyl) ethyl ester, respectively. Eight known isolated compounds were identified as nuzhenide (3), GI3 (4), GI5 (5), ligstroside (6), oleoside-11-methyl ester (7), oleoside dimethyl ester (8), 1'''-O-β-D-glucosylformoside (9), and salidroside (10) [2]. Compounds 1-9 showed inhibitory activity against adipocyte differentiation in 3T3-L1 cells. FE (1:10,000) as well as 1, 3, 4, 5, and 8 were activating in PPARα-reporter cell system in the range of 10-4 M comparable to 10-8 M WY14,643. Therefore, PPARα-mediated mechanism is a possible relevant pathway for FE anti-diabetic activity. We also evaluated the effects of a low-fat diet (LFD), high-fat diet (HFD), and high fat diet + 0.5% FE (FED) on C57BL/6J mice during 16-weeks. FED decreased fasting blood glucose (33.2%, P<0.001), plasma insulin level (53.4%, P<0.05), and body weight gain (32.3%, P<0.05) compared to HFD. Finally, we used a screening model against glucose (50g) to assess the effect of FE on plasma glucose and insulin levels. FE (1.0g) was used in a double blind, randomized, crossover, placebo (wheat bran) controlled study on 16 healthy volunteers. FE reduced the glycemic AUC (P=0.02), but not the insulinemic AUC. These results encourage conducting long term clinical studies to further evaluate the efficacy and safety of FE.