The Safety and Anti‐Hypercholesterolemic Effect of Coptisine in Syrian Golden Hamsters

Abstract

Current work was conducted to evaluate the cholesterol-lowering effect of coptisine extracted from Rhizoma coptidis in Syrian golden hamsters. The safety results indicated that coptisine was a safe and low-toxic compound. Coptisine showed a beneficial effect in the abnormal serum lipid levels induced by a high-fat and high-cholesterol diet (HFHC): at a concentration of 70.05 mg/kg, coptisine significantly led to a decrease in total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-c) levels by 26.70, 15.38, and 22.22 %, respectively, and high-density lipoprotein cholesterol (HDL-c) was increased by 41.74 % in serum of hamsters (p < 0.01). In addition, total bile acid (TBA) levels in feces of hamsters were elevated after coptisine administration. Further investigation has suggested that the mRNA and protein expression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) in the liver of hamsters was down-regulated by high-dosage coptisine treatment (p < 0.05); mRNA and protein expression of low-density lipoprotein receptor (LDLR) and cholesterol 7α-hydroxylase (CYP7A1) were dramatically up-regulated by coptisine administration. The apical sodium-dependent bile salt transporter expression was down-regulated in the coptisine-treated animals, but showed no significant differences from the HFHC groups. Taken together, our results demonstrate that a high dosage of coptisine could inhibit cholesterol synthesis via suppressing the HMGCR expression and promoting the use and excretion of cholesterol via up-regulating LDLR and CYP7A1 expression. These findings suggest a critical role for coptisine in anti- hypercholesterolemia, and thus it needs to be considered as a potential natural cholesterol lowering agent.

Biologically active isoquinoline alkaloids covering 2014–2018

“…229 A meta-analysis of randomized clinical trials indicated that berberine can improve lipid profiles in dyslipidemia with acceptable safety. 230 He et al 231 suggested that the related alkaloid coptisine might be used as an anti-hypercholesterolemia agent as it inhibited cholesterol synthesis by suppressing 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) expression and increasing the use and excretion of cholesterol through upregulation of low-density lipoprotein receptor (LDLR) and CYP7A1 expression.…”

Pharmacokinetics and tissue distribution of coptisine in rats after oral administration by liquid chromatography–mass spectrometry

“…Recently, several biological actions of coptisine have been reported. In vivo , coptisine (25, 50 and 100 mg/kg) exerts cardioprotective effect on isoproterenol‐induced myocardial infarction in rats (Gong et al, ); coptisine (10 and 30 mg/kg) protects rat heart against myocardial ischemia/reperfusion injury (Guo et al, ); coptisine (46.7 and 70.07 mg/kg) shows a beneficial effect on anti‐hypercholesterolemia and attenuates obesity‐related inflammation in Syrian golden hamsters (He et al, ; Zou et al, ); coptisine (50 mg/kg) prevents neuron loss, reduces amyloid plaque formation and ameliorates impaired cognition in A β PP/PS1 transgenic mice (Yu et al, ). In vitro , coptisine prevents vascular smooth muscle cell proliferation with a 50% growth‐inhibitory concentration of 3.3 μ m (1.2 μg/mL) (Tanabe et al, ); coptisine relaxes the NE (1 μ m ) and KCl (60 m m ) pre‐contracted aortic rings with pEC 50 of 4.49 ± 0.48 and 4.85 ± 0.57, respectively (Gong, Fang, Qin, Lv, & Du, ); coptisine (12.5–50 μ m ) exerts anti‐adipogenic activity on 3 T3‐L1 adipocytes (Choi et al, ); coptisine (10 μ m ) increases cell viability in PC12 cells induced with A β 1–42 and IFN‐ γ (Yu et al, ); and coptisine (1–40 μ m ) increases the cell viability in t ‐BOOH‐induced cytotoxicity in SH‐SY5Y (Friedemann, Schumacher, Tao, Leung, & Schröder, ).…”

Coptisine from Coptis chinensis exerts diverse beneficial properties: A concise review

“…97,99 Concerning the basis of CC's toxic substance, Ma et al concluded berberine and coptisine were the main constituents responsible for the toxicity of CC. 100 The LD 50 value of berberine was, respectively, 329 (oral), 9.0386 (i.v) and 57.6103(i.p) mg/kg, and coptisine's LD 50 value was 880.10 mg/kg, 66,101 which indicates berberine and coptisine have relatively wide range of safety.We also notice that, even ignoring the distribution loss from blood to tissues, the plasma level of coptisine with the highest dose in animal experiment is in fact, not able to reach the minimum concentration level used in cell experiment, so the main death cause of mice in LD 50 study is probably due to the gastrointestinal toxicity, rather than systemic toxicity.…”

“…Coptisine reduced mRNA level of p65, VCAM-1, ICAM-1 and IL-6/1β in aorta and liver, and it also prevented the phosphorylation of both p38 and JNK1/2 65. Also to assess lipid-lowering effect of coptisine, He et al announced modified serum level of TC, TG, LDL-c, HDL-c and TBA followed by coptisine treatment (70.05 mg/kg, oral, once daily for 4w) in obesity syrian golden hamsters, and this effect was related to the reduced HMGCR and elevated CYP7A1 gene level, which were important markers of cholesterol metabolism 66. In the model of isoproterenolinduced myocardial infarction rats, oral pre-treatment of coptisine (25-100 mg/kg, oral, once daily for 21 days) displayed potent antioxidative and mitochondrial respiratory dysfunction-ameliorative activity through restraining signalling transduction of ROCK pathway 67.…”