Secoisolariciresinol diglucoside effects in diet-Induced hyperlipidemic rats

Oral consumption of flaxseed improves serum lipid parameters, and the flaxseed lignan, secoisolariciresinol diglucoside (SDG) may mediate these effects. SDG’s therapeutic potential cannot be fully realized until its mechanism of action and pharmacokinetics are more completely characterized.This research aimed to assess SDG’s effects in dietary models of hypertriglyceridemia, hypercholesterolemia, and obesity. Furthermore, this thesis work provided preliminary pharmacokinetic data on SDG’s aglycone form, secoisolariciresinol (SECO). Dietary manipulations were used to induce hyperlipidemic states in female Wistar or male Sprague-Dawley rats. Groups of 10 rats were randomly assigned to one of three (obesity and cholesterol diets) or four (fructose) treatment groups: 1) Normal diet with 0.0 µmol SDG/kg body weight; 2) Dietary manipulation with 0.0 µmol SDG/kg; 3) Dietary manipulation with 4.4 µmol SDG/kg; and 4) 10% fructose in water with 8.8 µmol SDG/kg. Lignan or vehicle (saline) was administered daily by oral gavage for four weeks (2 weeks for male Sprague-Dawleys). After four (or two) weeks of SDG administration, body and liver weights were recorded, serum lipids were measured using enzymatic kits, hepatic fat accumulation was determined by histochemical analysis and hepatic mRNA expression of triglyceride pathway targets was evaluated using real-time RT-PCR. A 10% fructose in water model was effective for the induction of hypertriglyceridemia in male Sprague-Dawley rats but ineffective in female Wistar rats of similar age. Neither 4.4 nor 8.8 µmol SDG/kg improved serum and hepatic triglyceride parameters in male Sprague-Dawley rats on a 10% fructose in water diet. It is suspected that gender and strain are important factors for this model of hypertriglyceridemia. Dietary manipulations for the induction of hypercholesterolemia and obesity in female Wistar rats were not effective following 4 weeks administration of a 1% cholesterol diet and a 45% fat diet respectively. Since previous studies were able to successfully induce hypercholesterolemia in the same model, it is suspected that the differences in age of the animals accounted for the inconsistent results. Strain, gender and age of animals were identified as important considerations when trying to induce hyperlipidemic states through dietary manipulations.SDG (4.4 µmol/kg) dosed daily for four weeks caused no gross morphological organ changes or alterations in blood chemistry or hematology parameters. Following an intravenous bolus (10 mg/kg), secoisolariciresinol (SECO) disposition was consistent with two-compartment pharmacokinetics, with distribution and elimination half-lives at 26 seconds and 5 minutes, respectively. No SECO was detected in the plasma following an oral bolus (10 mg/kg). Further investigation into SDG’s hypolipidemic effects are required to elucidate its mechanism of action. A complete pharmacokinetic study is warranted to fully understand SDG’s safety and efficacy