Nadira Noushida¹, Roopa P Nayak^1*, Manodeep Chakraborty², Thriveni Raunak Salian³ and Mohammed Gulzar Ahmed³

¹Pharmacology Department, Yenepoya Medical College, Mangalore, Karnataka, India.

²Pharmacology Department, Himalayan Pharmacy Institute, Sikkim, India

³Pharmaceutics Department, Yenepoya Pharmacy College and Research Centre, Mangalore, Karnataka, India.

Corresponding Author E-mail: roopapnayak@yenepoya.edu.in

DOI : https://dx.doi.org/10.13005/bpj/2800

Abstract

Hyperlipidemia is characterized by an abnormal elevation in the major circulatory lipids and lipoproteins; this adversely affects the pathways of cholesterol transport. Syzygium campanulatum Korth is an evergreen shrub in the kingdom of Myrtaceae. Leaves are popular for their hepatoprotective, antiangiogenesis, and anticancer properties. The purpose of this research was to assess the antihyperlipidemic effect of ethanolic leaf extract of S. campanulatum in experimental rats against atherogenic diet-induced hyperlipidemia. During the 20 days, rats were fed an atherogenic diet mixed with standard pellets. The treatment of S. campanulatum (250/500 mg/kg) was given for 14 days. After 48 h blood samples from rats were collected, serum was collected for evaluation of lipoproteins (high-density lipoprotein, low-density lipoprotein, total cholesterol, triglycerides), and liver tissue was separated for evaluation of tissue antioxidants (superoxide dismutase, catalase, thiobarbituric acid reactive species, and glutathione). The results showed that when compared to rats on a normal diet, an atherogenic diet generated a substantial (p <0.001) decrease in serum HDL-C and a substantial (p <0.001) rise in blood TC, TG, and LDL-C. The hyperlipidaemic groups that received S.Campanulatum 250/500 mg/kg and  Atorvastatin 10 mg/kg showed a substantial (p < 0.001) decrease in serum levels of TC, TG, LDL-C, and significant (p < 0.001) increase in HDL-C respectively, compared to rats with hyperlipidemia control. The study indicates that the ethanolic extract of S.Campanulatum has substantial antihyperlipidemic action, indicating that it might be a potential natural medicine used in addition to currently prescribed hyperlipidemia treatments.                

Keywords

Atherogenic diet; Atorvastatin; Hyperlipidemia; Syzygium Campanulatum

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Copy the following to cite this article: Noushida N, Nayak R. P, Chakraborty M, Salian T. R, Ahme M. G. Protective effect of Ethanolic Extracts of Syzygium Campanulatum leaf in Wistar Albino Rats Against Triton and Atherogenic Diet-Induced Hyperlipidemia. Biomed Pharmacol J 2023;16(4).

Copy the following to cite this URL: Noushida N, Nayak R. P, Chakraborty M, Salian T. R, Ahme M. G. Protective effect of Ethanolic Extracts of Syzygium Campanulatum leaf in Wistar Albino Rats Against Triton and Atherogenic Diet-Induced Hyperlipidemia. Biomed Pharmacol J 2023;16(4). Available from: https://bit.ly/47mmLED

Introduction

 Syzygium campanulatum Korth (S. Campanulatum) is an evergreen bush in the kingdom of Myrtaceae. In Malaysia and Singapore, it’s also known as “kelat paya,” and it’s commonly grown as a hedge. It is a typical decorative tree that is grown in public spaces like parks and roadways. When crushed, its leaves emit a cinnamon-like odor. Some of its regional names are pokok kelat paya, red lip, Chinese red-wood (Chinese name), Australian brush cherry, wild cinnamon, Ubah Laut (East Malaysia), and kelat oil. Despite its traditional use as a stomachic, no pharmacognostic or phytochemical profiling of S. campanulatum has been reported to date, except for the isolation of betulinic acid. The fruits, which resemble blackberries, are visible from December to January and April to May. The shades of the juvenile leaves and flowers distinguish the two kinds of S. campanulatum: one has yellow foliage and white-creamy flowers, while the other has red foliage and red blossoms. It contains different phytoconstituents such as flavonoids, phenolics, antioxidants, and betulinic acid. Leaves are known for hepatoprotective, antiangiogenesis, and anticancer properties.^1,2

Hyperlipidemia is characterized as an elevation in the blood’s TG, TC, and LDL-C concentrations.^3,4 It is a severe risk factor for cardiovascular illnesses, in particular atherosclerosis, coronary heart disease, and hypertension, according to various studies^.5 Hyperlipidemia is characterized by an abnormal elevation in the major circulatory lipids and lipoproteins; this adversely affects the pathways of cholesterol transport.^6,7 Increased formation of free radicals/reactive oxygen species in hyperlipidemic conditions is known to participate in cardiac dysfunction, CVD progression, cardiac apoptosis, and necrosis.^7,8 Theconstancy of hyperlipidemia is influenced by a variety of causes, including ethnicity, genetic background, lifestyle factors such as poor dietary and exercise habits, poorly controlled diabetes, excessive alcohol consumption, and stress are all examples of risk factors. These diseases are caused by an increase in the consumption of a high-fat diet, which harms human health and life.⁹

Several classical hypolipidemic medicines are commonly used in clinical practice to treat this illness, including fibrates, nicotinic acid, its derivatives, bile acid sequestrants, and HMG-CoA reductase inhibitors. However, these medications can cause skeletal muscle toxicity, cutaneous flushing, decreased renal function, liver toxicity, and gastrointestinal discomfort in patients. As a result, new effective hypolipidemic medications with fewer (or no) side effects are urgently needed.¹⁰ Elevated blood triglyceride and cholesterol levels are the key risk factor for atherosclerosis, according to the American Heart Association. As a result, therapists consider hyperlipidemia therapy to be one of the most important strategies for slowing the atherogenic process.^11,12 Because of their low toxicity and health benefits, phytomedicines are becoming more popular, and they are suitable for long-term use as a dietary functional food. Flavonoids may help prevent and treatment of overweight, dyslipidemia, diabetes, and atherosclerosis, according to findings from preclinical pharmacologic tests and epidemiological investigations.^13-16 Phytomedicines might thus play a crucial part in the establishment of innovative treatment techniques. Therefore, the current study investigates the anti-hyperlipidemic action of the polyphenol-rich ethanolic leaf extract of S.Campanulatum against triton and atherogenic diet-induced hyperlipidemia in experimental rats.

Materials and methodology

Drugs, Reagents, and Chemicals

 Experimental hyperlipidemic diet: Triton WR-1339 was obtained from Sigma-Aldrich, Experimental feed containing a well-powdered mixture of cholesterol (2%) was Procured from Loba Chemie Pvt. Ltd., cholic acid (1%) and peanut oil (10%) from Sisco Research Laboratories Pvt. Ltd., sucrose (40%) from Merck Life Science Pvt. Ltd., and normal laboratory diet (47%) (figure 3a). Atorvastatin was obtained from a local pharmacy. Total cholesterol, HDL, LDL, and Triglyceride kits were procured from Agappe diagnostics Ltd (Kerala, India).

Collection of Plant Materials

Syzygium campanulatum fresh leaves werecollected from Udupi Manjunath Melkaje medicinal garden. The leaves were authenticated by DR H.S Shenoy, Principal scientist and Head of the division, Pilikula nisargadhama, Mangalore. Voucher specimen (9489/Syzygium campanulatum Korth.)  

Preparation of ethanol extract

After collecting the leaves, they were placed in a clean tray and dried in the shade. By utilizing a dry grinder, the dried leaves were reduced in size to a coarse powder and then sieved (20 Mesh). The powdered sample was extracted by using Soxhlet Apparatus with ethanol.

Experimental animals

 The male adult Wistar albino rats with body weights 170-220 g was used as experimental animals. Rats were procured from CPCSEA-approved breeders and maintained at CPCSEA approved institute animal house of Yenepoya University. The study protocol was approved by the Institutional Animal Ethical Committee Yenepoya medical college (YU /IAEC /8/2020) and the study was initiated only after the approval of the institutional animal ethics committee. The rats used in the experiment were categorized into five groups, consisting of six rats each (60 Numbers).

Tritron induce hyperlipidemia model (n=6)

Group 1: Normal control pre-treatment with vehicle

Group 2: Disease control (Triton WR-1339 (400 mg/kg))

Group 3: Standard drug  Atorvastatin 10 mg/kg

Group 4: Low dose of S. Campanulatum 250 mg/kg

Group 5: High dose of S. Campanulatum 500 mg/kg

After fasting 24hrs rats were treated with triton at a dose of 400 mg/kg i.p, the hyperlipidemia was induced with triton WR-1339 for all groups except the normal control group. The treatment of S. Campanulatum 250/500 mg/ml, was administered immediately following the triton injection, and the second dose of extracts was given 20 hours later.

Atherogenic diet-induced hyperlipidemia model (n=6)

 Group 1: Normal control pre-treatment with vehicle

Group 2: Disease control (atherogenic diet)

Group 3: Standard drug (Atorvastatin (dose of 10 mg/kg)) + atherogenic diet). ¹⁷

Group 4: Low dose of S. Campanulatum (250 mg/kg) + atherogenic diet

Group 5: High dose of S. Campanulatum (500 mg/kg) + atherogenic diet

For the 20 days of the period, an atherogenic diet was mixed with a standard pellet and given to rats. The treatments were started on the 8^th day of the atherogenic diet and continued till the 20^th day, a total of 14 days oftreatment of S. Campanulatum extracts (250/500 mg/kg) was given.

Blood collection and biochemical parameter analysis and estimation of liver enzymes

In triton induced hyperlipidemia model 4 hours after the second dosage, blood samples were drawn, and serum was separated from the blood for evaluation of lipoproteins. The hyperlipidemia was induced with an atherogenic diet model  48 h after the last dose blood samples were collected via cardiac puncture technique and centrifuged at 2500rpm for 10 minutes and the blood serum was collected and utilized to analyze biochemical parameters and estimation of liver enzymes and the standard diagnostic kits and semi autoanalyzer instrument was used for evaluation of lipoproteins (HDL, triglycerides, LDL, total cholesterol), liver enzymes (SGOT, SGPT, ALP, and LDH) and tissue antioxidants (superoxide dismutase, catalase, thiobarbituric acid reactive species, and glutathione).¹⁸

In vivo antioxidant enzymes assay and histological Analysis

Immediately following sacrifice, a tiny part of the liver tissues from each rat group was removed and with ice-cold phosphate buffer it was homogenized for estimation of tissue antioxidants was performed using a UV spectrophotometer (SHIMADZU 1900), and other parts of the liver tissues of each group were fixed for histopathology study in 10% formalin were prepared with pH of 7.4 phosphate buffer kept at room temperature for 24 hours. Before being examined under a light microscope, tissue-fixed slides were stained with hematoxylin and eosin.

Statistical analysis

The data were presented as mean±SEM and were analyzed using one-way ANOVA followed by Tukey-Kramer multiple comparison tests, with P<0.05 considered statistically significant. The statistical program used for data analysis was GraphPad Prism 6.01.

Results and discussion

Ethanolic extraction and Phytochemical screening

In the current study, the percentage yield was obtained at 18% and AishaFA et al., (2013)performed a study on S.Campanulatum methanolic extract was obtained with a percentage yield (16.4 percent, w/w) compared to this study in the present study percentage yield was higher i.e. in the percentage yield is high in ethanolic extracts than methanolic extract. The qualitative phytochemical results showed the existence of alkaloids, flavonoids, steroids and triterpenoids, cardiac glycosides, carbohydrates, phenol, saponin, and tannins.

Effect of extracts on serum lipid level

The increased blood lipid concentration is a significant modifiable dangerous factor for developing atherosclerosis and cardiovascular disease. It is a class of metabolic diseases characterized by a rise in blood lipid levels. Cholesterol, cholesterol esters, phospholipids, and triglycerides are examples of lipids. LDL cholesterol levels that are elevated are linked to the development of atherosclerosis.

Effect of extracts on triton-induced hyperlipidemia

The hyperlipidemia induced by triton is via several mechanisms, primarily by inhibiting lipoprotein lipase activity, preventing their uptake from circulation through extrahepatic tissues, resulting in an increased level of circulating lipoproteins, which can result in the blockage of TG-rich lipoprotein clearance. A single dose of triton in experimental animals increased serum lipid levels.^19,20 which was compared to our study the experimental animals were injected with alone triton WR-1339 400 mg/kg led to the elevation of serum triglyceride 1021.455±3.986, cholesterol 304.892±3.825, LDL-C 32.931±4.003 level, and decreased HDL-C 0.139±0.031 values in rats when compared with normal control rats triglyceride 48.749±1.524, cholesterol 41.181±0.998, LDL-C 0.903±0.209 and HDL-C 2.178±0.264. At this time, in the rats treated with S.Campanulatum 250 and S.Campanulatum 500 mg /kg and standard drug atorvastatin10 mg/kg significant serum lipid-lowering effect was observed triglyceride 738.359±3.348, 80.505±3.840 59.900±0.649, cholesterol 171.823±1.821, 48.141±2.905, 49.758±0.918, LDL-C 20.798±2.570, 6.697±2.041, 10.758±1.825 when compared to triton 400 mg/kg and increased level of HDL-C 0.831±0.050, 1.822±0.154 and 1.136±0.092 was also observed. S.Campanulatum hypolipidemic activity could, therefore, either increase the activity of lipolytic enzymes or stimulate fecal bile acid excretion, resulting in lower circulating lipoprotein levels. ^21,22

S. Campanulatum appears to have no negative effects in normal rats based on its effects on organ function markers and other biochemical indices, and it is pharmacologically effective and independent of negative side effects in hyperlipidemic rats with impaired cardiac, hepatic, and renal functions. increased serum creatinine levels as a defense against kidney damage.^23,24 The histopathological investigation of the liver segment of the normal control rats (Fig. 4a) revealed normal hepatic cell arrangements with no changes. Histopathological investigation of the liver section of rats treated with triton 400 mg/kg treated group (Fig. 4b) revealed that different degrees of pathological changes such as the nucleus was absent, there is degeneration of fat in the center lobules, hepatic cell necrosis, and cloudy swelling. The microscopic examination revealed that in rats treated with S.Campanulatum 250 mg/kg (Fig.4c), there is moderate damage in liver cells some nucleus are absent but there was the recovery of the damaged cells to normal. The liver section of rats treated with S.Campanulatum 500 mg/kg and atorvastatin 10 mg/kg (Fig. 4d, 4e,) revealed that near normal arrangement hepatic cells and central vein were present, the results are related to the normal control group.

Effect of extracts on diet-induced hyperlipidemia

Induction of hyperlipidemia with atherogenic diet rats showed hair fall (Figure 3b) and the presence of extended adipose tissue in their intra-abdominal space and fatty liver were seen in the rats treated with atherogenic diet as compared to normal control rats where abdominal space consist of normal fats and normal liver organ and the rats treated with extracts recover from the hair fall and intra-abdominal fat was reduced as compared to atherogenic diet groups (Figure 3c). Jayant S et al., (2012)noticed that providing all the animals with repeated administration of cholesterol and cholic acid (dissolved in ground nut oil) for 28 days elevated the main lipid profile parameters, including LDL-C, TG, VLDL-C, cholesterol, and decreased HDL-C.¹⁷ The atherogenic diet used in this study was also containing a mixture of cholesterol and cholic acid dissolved in peanut oil. The data shown in Table 1 represent that feeding rats with an atherogenic diet caused a substantial (p < 0.001) rise in serum triglyceride 335.036±2.764, LDL-C 351.296±2.187, total cholesterol 186.203±1.328, and a significant (p < 0.001) reduction in serum HDL-C 0.245±0.029 when compared to the control group. When compared to the atherogenic diet group, oral administration of atorvastatin to rats resulted in a substantial (p < 0.001) decrease in blood levels of triglyceride 154.120±4.606, LDL-C 172.128±1.649, and, total cholesterol 83.207±3.818 as well as a significant (p < 0.001) rise in HDL-C 2.563±0.032 levels. The hyperlipidaemic rats that received S.Campanulatum 250/500 mg/kg showed a significant (p < 0.001) decline in serum levels of triglyceride 254.940±4.279, 148.804±2.655, total cholesterol 145.739±1.352, 98.074±2.681, LDL-C 304.591±2.661, 184.932±4.768and substantial (p < 0.001) increase in HDL-C 1.556±0.045, 2.4±0.028 respectively, compared to rats on a high-fat diet. Significant (p< 0.01) differences were identified between doses of both plant extracts, indicating that this lipid-lowering action was dose-dependent.²⁵ However, the lipid-lowering impact of conventional medicine (atorvastatin) was still greater than that of s.campanulatum leaf extracts. A possible mechanism of action for S. campanulatum extracts is an increase in HDL-C, which is linked to the mobilization of cholesterol from peripheral cells to the liver by the activity of Lecithin Cholesterol O-acyltransferase (LCAT).²⁶ The LCAT enzyme is involved in the processes of HDL maturation, cholesterol flux from cell membranes into HDL, and cholesterol transesterification. Diet-induced hyperlipidemia tends to result in a decrease in enzyme activity. ²⁷

Effects of extracts on liver function enzymes in an atherogenic diet-induced hyperlipidemic rat model

A chronic disease called nonalcoholic fatty liver disease has a strong correlation with obesity. Additionally, the emergence of a fatty liver is one of the most typical symptoms of those with hyperlipidemia. Various studies have shown that high-fat feeding caused laboratory animals to have decreased HDL-C levels and increased TC, TG, LDL-C, and Atherogenic index levels in their serum.²⁸ Thus, we also investigated S.Campanulatum’s impact on liver lipids.The liver function enzymatic activities were evaluated in the control group, atherogenic diet group, and atherogenic diet rats were given the standard drug atorvastatin or extracts at two different doses for comparison (Table 1). When the disease group was compared to the normal control, there was a significant (p<0.001) increase in liver function enzymatic activities (SGOT, SGPT, ALP, LDH) in the atherogenic diet-induced hyperlipidemic rat group. The hyperlipidaemic rats receiving S.Campanulatum 250/500 mg/kg revealed a substantial (p < 0.001) decline in serum levels of SGOT, SGPT, ALP, and LDH compared to rats of atherogenic diet control.²⁹ Furthermore, atorvastatin treatment improved the levels of SGOT, SGPT, ALP, and LDH in rats with atherogenic diet-induced hyperlipidemia.

Table 1: Effect of S.Campanulatum on SGOT, SGPT, ALP, and LDH in atherogenic diet-induced hyperlipidemia in Rats.

Treatment	SGPT     (IU/L)	SGOT      (IU/L)	ALP     (IU/L)	LDH         (IU/L)
N.Control	64.547±1.141	114.385±1.264	166.513±0.949	293.246±1.011
Atherogenic diet	131.946±2.692***	229.769±0.657***	690.201±4.735***	769.417±4.140***
S. Campanulatum  250 mg/kg	113.970±0.982abc	180.804±0.855 abc	465.081±4.761abc	513.496±0.816abc
S. Campanulatum 500 mg/kg	68.530±2.014abc	144.776±3.022 abc	249.081±1.866abc	338.236±0.776abc
Atorvastatin 10 mg/kg	96.072±0.791abc	120.802±0.924 abc	179.966±0.794abc	394.781±0.813abc

The results were reported as mean±SEM and analyzed using one-way ANOVA followed by Tukey-Karmer multiple comparison tests. Values were considered statistically significant when ^*P<0.05, ^**P<0.01, ^***P<0.001 as compared to the normal group and ^aP<0.05, ^abP<0.01, ^abcP<0.001 compared to the atherogenic diet group (n=6). SGPT- Serum Glutamic Pyruvic Transaminase, SGOT-Serum Glutamic Oxaloacetic Transaminase, ALP- Alkaline phosphatase, LDH- Lactate dehydrogenase.

Effect of extracts on in vivo antioxidant enzymes in atherogenic diet hyperlipidemic rat model

It is known that high-fat diets cause more oxidative stress across different tissues, which may lead to some physically degenerative diseases. Although the activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) were assessed as indicators of serum or liver antioxidant capacities, the contents of malondialdehyde (MDA) in the serum or liver served as a marker to ascertain the lipid peroxidation levels in the serum and liver, respectively.²⁸ In this study Administration of an atherogenic diet for 5 weeks lowered the liver GSH level and at the same time increased the LPO. Treatment with extracts S.Campanulatum 250/500 mg/kg replenished GSH levels and caused a decrease in LPO levels caused by the treatment of an atherogenic diet. The activities of the antioxidant enzyme SOD were decreased in atherogenic diet group administration compared to induced liver damage (Table 2). Treatment of the extracts counteracted the observed decrease in the activity of the enzyme.

Table 2: Effect of S.Campanulatum on in vivo antioxidant enzymes in diet hyperlipidemic rat model.

Treatment	Glutathione (µg/mg protein)	LPO (µg/mg protein)	Catalase (µg/mg protein)	SOD (µg/mg protein)
N.Control	77.213±0.803	6.535±0.603	95.390±1.557	24.873±0.156
Atherogenic diet	2.121±0.382***	26.101±0.826***	21.053±0.725***	4.308±0.362***
S. Campanulatum  250 mg/kg	22.926±0.513abc	14.550±0.377abc	49.691±1.375abc	9.685±0.763abc
S. Campanulatum 500 mg/kg	57.308±0.550abc	7.065±0.374abc	78.726±2.807abc	19.201±0.710abc
Atorvastatin 10 mg/kg	65.668±1.533abc	6.830±0.626abc	89.180±1.611abc	23.240±0.291abc

The results were reported as mean±SEM and analyzed using one-way ANOVA followed by Tukey-Karmer multiple comparison tests. Values were considered statistically significant when ^*P<0.05, ^**P<0.01, ^***P<0.001 as compared to the normal group and ^aP<0.05, ^abP<0.01, ^abcP<0.001 compare atherogenic diet group (n=6). LPO-Malondialdehyde, (Lipid peroxidation), SOD- Superoxide dismutase.

Histopathological observation

Microscopical analysis of a liver segment from the normal control group (Fig. 5a) revealed normal hepatic cell organization. Microscopical examination of the atherogenic diet-treated group’s liver segment (Fig. 5b) revealed varying degrees of pathological alterations, including severe fatty degeneration, cloudy swelling, and hepatic cell necrosis, Boobalan Raja found comparable fatty changes in the hepatic tissue of hypercholesterolemic rats.³⁰ Histopathological study of rats treated with S.Campanulatum 250 mg/kg (Fig. 5c) showed less severe fatty changes compared to disease control. Some damaged hepatic cells were seen. Microscopical examination of S.Campanulatum 500 mg/kg treated group’s liver section (Fig. 5d) revealed mild fatty changes and recovery of damaged hepatic cells to normal. Rats given the standard drug (Fig. 5e) had normal hepatic cells and central veins, which were comparable to the normal control group.

Figure 1: Effect of S.Campanulatum on triton-induced hyperlipidemic rat’s serum triglycerides, total cholesterol, LDL, and HDL level. Click here to view Figure

Figure 2: Effect of S.Campanulatum on atherogenic diet-induced hyperlipidemic rat’s serum total cholesterol, triglycerides, and phospholipids level. Click here to view Figure

Figure 3: (3a) Atherogenic diet (3b) Hair loss during treatment and changes after treatment (3c) Difference between the pathology of liver of normal control, hyperlipidemic rats and rats treated with extracts. Click here to view Figure

Figure 4: Effect of S.Campanulatum on the morphology of liver in Triton 400 mg/kg diet-induced hyperlipidemia in rats (magnification 40x). Click here to view Figure

Figure 5: Effect of S.Campanulatum on the morphology of liver in atherogenic diet-induced hyperlipidemia in rats (magnification 40x).   Click here to view Figure

Conclusion

The present study concluded that this is the first study of the antihyperlipidemic activity of S.Campanulatum ethanolic leaf extract. Ethanolic extract at a high dose (500 mg/kg) has an effective reduction of hyperlipidemia in a triton and high atherogenic diet model, with comparable effects when compared to the Atorvastatin-treated group. The protective effect of plant extract is also revealed by histopathological studies. The active component in the plant may be able to reverse the lipid metabolic abnormalities seen in hyperlipidemia, however further research is needed to find out the active elements responsible for the activity and mechanisms of these benefits. As a result, it can be used as a therapeutic antihyperlipidemic drug or as an adjuvant to current hyperlipidemia treatment.

Acknowledgment

The authors are thankful to the management of Yenepoya (Deemed to be University), Mangalore

Conflict of Interest

There are no conflicts of interest regarding the publication of this article

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