A Nano-Pharmaceutical Formula of Quercetin Protects from Cardiovascular Complications Associated with Metabolic Syndrome

Abstract

Metabolic syndrome (MetS) is closely associated with the development of cardiovascular diseases. We recently developed a nano-preparation of the flavonoid quercetin (QU) in a self-nanoemulsifying drug delivery system (SNEDDS). The latter comprised a mixture composed of pumpkin seed oil, D-α-Tocopherol polyethylene glycol 1,000 succinate and polyethylene glycol. The QU SNEDDS preparations exhibited a considerably higher bioavailability compared with the standard quercetin suspension. Here, we investigated whether the quercetin loaded SNEDDS could offer better protection compared with the standard formulation against cardiovascular complications of MetS in rats. MetS was induced by high fructose, high salt and high fat diet for 12 weeks while the nano-preparation or the standard suspension of quercetin was orally administered for the last 6 weeks. Compared to little effect for the standard quercetin suspension (MQ), the treatment of MetS rats with the quercetin loaded SNEDDS (MNQ) virtually abolished the depressant effect of MetS on contractility index (control, 114 ± 4; MetS, 92 ± 3; MQ, 100 ± 2; MNQ, 114 ± 6 1/s) and rate of rise in left ventricular pressure (dP/dtmax) (control, 8,171 ± 274; MetS, 6,664 ± 135; MQ, 6,776 ± 108; MNQ, 7,498 ± 303 mmHg/s). Likewise, the prolongation by MetS of electrocardiographic markers of arrhythmogenesis (QTc, JT, and Tpeak-to-Tend intervals) and concomitant rises in dicrotic notch pressure were preferentially reversed by quercetin nano-preparation. On the other hand, the rises in the isovolumic relaxation constant (Tau, denotes diastolic dysfunction), blood pressure, pulse pressure, and difference between systolic and dicrotic pressure (SDP difference) were equally improved by the two preparations of quercetin. Additionally, no differences were noted in the ability of the two quercetin preparations in abrogating the elevated oxidative (MDA) and inflammatory (TNFα) markers in cardiac tissues of MetS rats. Histopathological, microscopical signs of necrosis, inflammatory cell infiltration, and vascular congestion in MetS hearts were more markedly inhibited by the nano-preparation, compared with the standard preparation of quercetin. In conclusion, the quercetin loaded SNEDDS is evidently more advantageous than the standard preparation of the drug in alleviating functional and histopathological manifestations of cardiac damage incited by MetS.

Keywords: SNEDDS; cardiovascular complications; metabolic syndrome; nano-formulation; quercetin.

FIGURE 1

Effect of oral administration of standard quercetin suspension (MQ), plain nano-pharmaceutical formulation (MN) and the quercetin loaded nano-pharmaceutical formulation (MNQ) both at 83 μmol/kg/day on contractility index (A), dp/dt max (B) and Tau (C) in metabolic syndrome (M) induced by feeding rats a high fructose (10% in drinking water), high salt (3%), high fat (25%) diet for 12 weeks. Panel D shows representative original recording of ventricular pressure. Results are expressed as mean ± SEM (n = 8 for all groups). *p < 0.05 when compared to the corresponding control (C) values, #p < 0.05 when compared to the corresponding MetS values using one-way ANOVA followed by Dunnet’s post-hoc test.

FIGURE 2

Effect of oral administration of standard quercetin suspension (MQ), plain nano-pharmaceutical formulation (MN) and the quercetin loaded nano-pharmaceutical formulation (MNQ) both at 83 μmol/kg/day on QTc (A), JT interval (B) and PR interval (C) in metabolic syndrome (M) induced by feeding rats a high fructose (10% in drinking water), high salt (3%) and high fat (25%) diet for 12 weeks. Panel D shows representative original recording of ECG. Results are expressed as mean ± SEM (n = 8 for all groups). *p < 0.05 when compared to the corresponding control (C) values, #p < 0.05 when compared to the corresponding MetS values using one-way ANOVA followed by Dunnet’s post-hoc test.

FIGURE 3

Effect of oral administration of standard quercetin suspension (MQ), plain nano-pharmaceutical formulation (MN) and the quercetin loaded nano-pharmaceutical formulation (MNQ) both at 83 μmol/kg/day on systolic BP (A), diastolic BP (B) and heart rate (C) in metabolic syndrome (M) induced by feeding rats a high fructose (10% in drinking water), high salt (3%) and high fat (25%) diet for 12 weeks. Panel D shows representative original recording of arterial hemodynamics. Results are expressed as mean ± SEM (n = 8 for all groups). *p < 0.05 when compared to the corresponding control (C) values, #p < 0.05 when compared to the corresponding MetS values using one-way ANOVA followed by Dunnet’s post-hoc test.

FIGURE 4

Effect of oral administration of standard quercetin suspension (MQ), plain nano-pharmaceutical formulation (MN) and the quercetin loaded nano-pharmaceutical formulation (MNQ) both at 83 μmol/kg/day on pulse pressure (A), dicrotic notch pressure (B) and SDP difference (C) in metabolic syndrome (M) induced by feeding rats a high fructose (10% in drinking water), high salt (3%) and high fat (25%) diet for 12 weeks. Results are expressed as mean ± SEM (n = 8 for all groups). *p < 0.05 when compared to the corresponding control (C) values, #p < 0.05 when compared to the corresponding MetS values using one-way ANOVA followed by Dunnet’s post-hoc test.

FIGURE 5

Effect of oral administration of standard quercetin suspension (MQ), plain nano-pharmaceutical formulation (MN) and the quercetin loaded nano-pharmaceutical formulation (MNQ) both at 83 μmol/kg/day on heart MDA (A), heart TNF-α (B) and serum adiponectin (C) in metabolic syndrome (M) induced by feeding rats a high fructose (10% in drinking water), high salt (3%) and high fat (25%) diet for 12 weeks. Results are expressed as mean ± SEM (n = 8 for all groups). *p < 0.05 when compared to the corresponding control (C) values, #p < 0.05 when compared to the corresponding MetS values using one-way ANOVA followed by Dunnet’s post-hoc test.

FIGURE 6

Photomicrograph of sections in the ventricular wall of control (image A), Metabolic syndrome (images B, C), plain formula (image D), quercetin suspension (image E) and quercetin nano-formula (image F) groups. Bifid arrows represent; mononuclear cellular infiltration was evident in between the cardiac myocytes. Circle represent degenerated muscle fibers. “S” represents cardiomyocyte showing loss of striation. Small arrow represents myocytes exhibit dark stained nuclei. “v” represents monocytes with vacuolated cytoplasm (v) Scale bar = 50μm, ×400.