Bangladesh Journal of Pharmacology Volume: 15; Number 3; Year 2020 Cite this article as: Purushothaman A, Sundaram R. Lipid lowering efficacy of fraxetin, a coumarin derivative on high fat diet-induced hypercholesterolemic rats. Bangladesh J Pharmacol. 2020; 15: 96-98. Lipid lowering efficacy of fraxetin, a cou- marin derivative on high fat diet-induced hypercholesterolemic rats Sir, Hypercholesterolemia is the key risk factor for cardio- vascular disorders like coronary heart disease and stroke. Statins or hydroxymethylglutaryl-CoA (HMG- CoA) reductase inhibitors are the widely prescribed drug worldwide (Jukema et al., 2012). However, they have notable side effects such as hyperuricemia, diarr- hea, flushing, nausea, myositis, gastric irritation, dys- pepsia and gallstones, abnormal liver function and rhabdomyolysis with renal failure, etc. (Durrington, 2003). Hence, the need to discover antihypercholes- terolemic drug having better efficacy and lower adverse effects is still felt. Phytotherapy could be a suitable alternative for the treatment of hyperlipidemia (Liu et al., 2011). A large number of literatures reported that various medi- cinal plants had lipid lowering effects, for example, Pterodon emarginatus (Dal Forno et al., 2019), Salvia hispanica (Rodrigues et al., 2018), Stellaria media (Khan et al., 2019), Zingiber officinale (Bekkouch et al., 2019), Lagenaria siceraria, Commiphora wightii and Glycyrriza glabra (Srivastava and Srivastava, 2018). Coumarin (1,2-benzopyrone) is a natural phenolic compound found in many plants species and green tea (Tejada et al., 2017). Coumarin and some coumarin derivatives viz. esculetin, scoparone, and 4-methyl- umbelliferone were reported to have lipid lowering effects (Taşdemir et al., 2017). Fraxetin (7, 8-dihydroxy-6 -methoxycoumarin), a coumarin derivative widely present in the citrus fruits, tomatoes, vegetables, green tea and natural food products (Thuong et al., 2009) has attracted research interest as antioxidant, anti-diabetic, anti-inflammatory, antiviral, antitumor and neuropro- tective agent (Mo et al., 2019; Challa and Prasanna, 2018). This study aimed to investigate the lipid lowering efficacy of fraxetin on high fat diet fed hypercholesterolemic rats. The male albino Wistar rats (180 ± 20 g) were procured from the Animal House Facility, Mohamed Sathak A. J. College of Pharmacy, Chennai 119, India. High fat diet [SKM Egg Products Export (India) Ltd.] was prepared according to the method of Xie et al., (2005). High fat diet comprised of normal rat feed 84.3%, 5% lard, 10% yolk powder, cholesterol 0.2% and 0.5% (Sisco Research Laboratories Pvt. Ltd., India), bile salt (Central Drug House Pvt. Ltd., India) were fed to the rats for a period of 56 days. The rats with plasma cholesterol >250 mg/dL were used in the present study. The rats were again fed with high fat diet and treatment with fraxetin (25, 50, 75 mg/kg, orally; Sigma Aldrich, USA) and simvastatin (10 mg/kg) was started on the next day after hypercholesterolemia confirmation and this was considered as day 1 of treatment and it was continued for 30 days. The final body weights were recorded. Other para- meters like waist, body mass index and Lee index were determined as previously reported method (Bernardis, 1970). The rats were sacrificed by cervical decapitation under pentobarbitone sodium (60 mg/kg). The levels of total cholesterol, triglyceride, high density lipoprotein cholesterol (HDL-C) were estimated by using biochemi- cal kits (Agappe Diagnostics Pvt. Ltd., India). For the determination of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol, Friede- wald’s formula was used (Friedewald et al., 1972). Atherogenic index of plasma (AIP), a significant predic- tor of risk for atherosclerosis was calculated as log (TG/ HDL-C) (Tan et al., 2004). Animals fed with HFD had significantly increased in body weight, waist, body mass index and Lee index compared with rats fed with a standard diet (p<0.05). These changes were modulated and brought back to near normal levels on treatment with different concen- trations of fraxetin. The reduction in body weight, waist, body mass index and Lee index was observed in all the 4 doses tested. However, the changes are statistically not significant at the dosage of 25 mg/kg while, fraxetin treatment at higher doses i.e. 50 and 75 mg/kg resulted in a significant decrease in the aforesaid parameters (Figure 1A-D). The plasma levels of total cholesterol, triglyceride, VLDL and LDL cholesterol and atherogenic index were significantly increased, whereas HDL cholesterol was significantly decreased in hypercholeterolemic rats, in comparison to normal control rats. Oral administration of fraxetin significantly reversed all these altered parameters to near normal levels in a dose-dependent manner (Table I). A Journal of the Bangladesh Pharmacological Society (BDPS) Bangladesh J Pharmacol 2020; 15: 96-98 Journal homepage: www.banglajol.info Abstracted/indexed in Academic Search Complete, Agroforestry Abstracts, Asia Journals Online, Bangladesh Journals Online, Biological Abstracts, BIOSIS Previews, CAB Abstracts, Current Abstracts, Directory of Open Access Journals, EMBASE/Excerpta Medica, Global Health, Google Scholar, HINARI (WHO), International Pharmaceutical Abstracts, Open J-gate, Science Citation Index Expanded, SCOPUS and Social Sciences Citation Index ISSN: 1991-0088; DOI: 10.3329/bjp.v15i3.47113 Letter to the Editor This work is licensed under a Creative Commons Attribution 4.0 International License. You are free to copy, distribute and perform the work. You must attribute the work in the manner specified by the author or licensor This study highlights the lipid lowering potential of fraxetin at the dose of 75 mg/kg which is comparable to that of simvastatin. All experiments were conducted according to the ethical norms approved by the CPCSEA and Institutional Animal Ethics Committee (IAEC) Guidelines Ayyakkannu Purushothaman and Ramalingam Sundaram Post-Graduate and Research Department of Biochemistry, Mohamed Sathak College of Arts and Science (Affiliated to the University of Madras), Chennai 600 119, Tamil Nadu, India. Corresponding author: e-mail: purushothamanbiochem@gmail.com Bangladesh J Pharmacol 2020; 15: 96-98 97 Table I Dose-dependent effect of fraxetin on the levels of lipid profile in rats Group Total cholesterol (mg/dL) Triglycerides (mg/dL) VLDL-C (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) AIP Normal control 126.3 ± 11.5 62.9 ± 5.4 12.6 ± 1.8 67.3 ± 3.8 46.4 ± 4.5 -0.0299 Normal control + fraxetin 75 mg/kg 122.8 ± 13.6 59.7 ± 4.6 11.9 ± 2.0 72.9 ± 2.9 38.0 ± 4.2 -0.0866 Hypercholesterolemic 368.5 ± 12.6 153.3 ± 8.3 30.7 ± 3.4 45.1 ± 4.0 292.7 ± 9.0 0.5312 Hypercholesterolemic + fraxetin 25 mg/kg 298.7 ± 9.1a 132.4 ± 5.4a 26.5 ± 2.3a 49.8 ± 3.0a 222.4 ± 6.5a 0.4244a Hypercholesterolemic + fraxetin 50 mg/kg 237.4 ± 11.2a 106.4 ± 6.3a 21.3 ± 2.7a 56.3 ± 3.1a 159.9 ± 5.9a 0.2766a Hypercholesterolemic + fraxetin 75 mg/kg 192.5 ± 11.3a 71.3 ± 4.3a 14.3 ± 2.5a 61.4 ± 3.2a 116.9 ± 5.8a 0.0650a Hypercholesterolemic + simvastatin 10 mg/kg 184.8 ± 10.4a 63.6 ± 4.4a 12.7 ± 1.7a 65.5 ± 3.7a 106.6 ± 5.3a -0.0126a The values are mean ± SD of 6 animals in each group. AIP- Atherogenic Index of Plasma; aThe difference between treated and hypercholeterolem- ic values is significant at p<0.05 Figure 1: Effect of different concentrations of fraxetin treatment on (A) Body weight (B) waist, (C) BMI and (D) Lee index. Values represented by the mean ± SD (n=6); arepresents significant increase at p<0.05 when compared to normal control rats while brepre- sents significant decrease at p< 0.05 when compared to hypercholesterolemic rats; C- control; FRX- fraxetin, HC- hypercholester- olemic, SIM- simvastatin B o d y w e ig h t (g ) 500 Control C + FRX (75 mg\kg) HC - Induced HC + FRX (25 mg\kg) HC + FRX (50 mg\kg) HC + FRX (75 mg\kg) HC + SIM (10 mg\kg) a b 400 300 200 100 0 W a is t (c m ) 30 25 20 15 10 Control C + FRX (75 mg\kg) HC - Induced HC + FRX (25 mg\kg) HC + FRX (50 mg\kg) HC + FRX (75 mg\kg) HC + SIM (10 mg\kg) a b 0 5 L e e i n d e x ( g \c m ) 0.5 0.4 0.3 0.2 0.1 Control C + FRX (75 mg\kg) HC - Induced HC + FRX (25 mg\kg) HC + FRX (50 mg\kg) HC + FRX (75 mg\kg) HC + SIM (10 mg\kg) a b 0 B M I g \c m 2 1 0.75 0.25 0.5 Control C + FRX (75 mg\kg) HC - Induced HC + FRX (25 mg\kg) HC + FRX (50 mg\kg) HC + FRX (75 mg\kg) HC + SIM (10 mg\kg) a b 0 A B C D mailto:purushothamanbiochem@gmail.com References Bekkouch O, Harnafi M, Touiss I, Khatib S, Harnafi H, Alem C, Amrani S. 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