Serotonin Derivatives, Major Safflower (Carthamus tinctorius L.) Seed Antioxidants, Inhibit Low-Density Lipoprotein (LDL) Oxidation and Atherosclerosis in Apolipoprotein E-Deficient Mice

Abstract

The effects of defatted safflower seed extract and its phenolic constituents, serotonin derivatives, on atherosclerosis were studied. Ethanol-ethyl acetate extract of safflower seeds (SSE) inhibited low-density lipoprotein (LDL) oxidation induced in vitro by an azo-containing free-radical initiator V70 or copper ions. Two serotonin derivatives [N-(p-coumaroyl)serotonin, CS; N-feruloylserotonin, FS] and their glucosides were identified as the major phenolic constituents of the extract. The study with chemically synthesized materials revealed that a majority of the antioxidative activity of SSE was attributable to the aglycones of these two serotonin derivatives. Orally administered CS and FS suppressed CuSO(4)-induced plasma oxidation ex vivo. Long-term (15 week) dietary supplementation of SSE (1.0 wt %/wt) and synthetic serotonin derivatives (0.2-0.4%) significantly reduced the atherosclerotic lesion area in the aortic sinus of apolipoprotein E-deficient mice (29.2-79.7% reduction). The plasma level of both lipid peroxides and anti-oxidized LDL autoantibody titers decreased concomitantly with the reduction of lesion formation. Serotonin derivatives were detected as both intact and conjugated metabolites in the plasma of C57BL/6J mice fed on 1.0% SSE diet. These findings demonstrate that serotonin derivatives of SSE are absorbed into circulation and attenuate atherosclerotic lesion development possibly because of the inhibition of oxidized LDL formation through their strong antioxidative activity.

Safflower seed polyphenols (N-(p-coumaroyl)serotonin and N-feruloylserotonin) ameliorate atherosclerosis and distensibility of the aortic wall in Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits

“…They suggested that the decreased plasma T-Chol level was due, in part, to the increased formation of HDL-Chol and the excretion of cholesterol. Koyama et al 17 also found in apolipoprotein E-deficient mice fed CS+FS and SSE for 15 weeks that serum T-Chol levels decreased significantly without a significant increase in the HDL-Chol level. These findings were inconsistent with our results in KHC rabbits.…”

“…CS and FS were synthesized from 5-HTÁHCl, p-coumaric acid and trans-ferulic acid. 17 The purity of CS (96.4%) and FS (99.5%) was determined using HPLC.…”

“…24,25 SSE contains some serotonin derivatives composed mainly of CS and FS, which have been reported to act as potent radical scavengers. 16,17 Koyama et al 17 showed that serotonin derivatives (CS and FS) were detectable in both intact and conjugated forms in the plasma in apolipoprotein E-deficient mice fed an SSE-containing diet. They also found that intragastric bolus administration and long-term supplementation of serotonin derivatives inhibited CuSO 4 -induced plasma oxidation ex vivo and decreased the plasma titer of autoantibodies to oxidized LDL, plasma lipid peroxides and the sclerotic lesioned area in apoE-deficient mice.…”

“…14 Serotonin derivatives, N-(p-Coumaroyl)serotonin (CS) and N-Feruloylserotonin (FS), have been identified as major and unique phenolics in defatted safflower seed extract (SSE). [15][16][17] It has been documented that serotonin derivatives or SSE show potent antioxidative properties, 16,17 cholesterol-lowering activity 16 and protective effects on postischemic myocardial dysfunction. 18 Koyama et al 17 showed that SSE and serotonin derivatives inhibited LDL and plasma oxidation in vitro and ex vivo, respectively, and reduced atherosclerotic lesion formation in apolipoprotein E-deficient mice.…”

“…[15][16][17] It has been documented that serotonin derivatives or SSE show potent antioxidative properties, 16,17 cholesterol-lowering activity 16 and protective effects on postischemic myocardial dysfunction. 18 Koyama et al 17 showed that SSE and serotonin derivatives inhibited LDL and plasma oxidation in vitro and ex vivo, respectively, and reduced atherosclerotic lesion formation in apolipoprotein E-deficient mice. In addition to animal studies, improvement in several antioxidative and proinflammatory markers by SSE supplementation has recently been reported in healthy volunteers by the same authors.…”