INTRODUCTION:

Since ancient times, humans have known natural ingredients, predominantly plants, for the prevention and treatment of disease. More than 20,000 plant species are used as medicine by humans worldwide, according to estimates by the World Health Organization. Many plants are known as herbal medicines because the principles of their use are still traditional. However, the efficacy of herbal medicines is only based on empirical experience^1,2.

High cholesterol is a problem that is often experienced by humans today. Efforts to reduce cholesterol levels include lifestyle changes from an early age, exercising regularly, reducing intake of fatty foods, and treatment with drugs that can lower cholesterol levels and also prevent disease complications due to high cholesterol levels^3,4; this is closely related to increasing total cholesterol levels, LDL cholesterol, triglycerides, and decreased HDL cholesterol levels^5-8.

Lipid peroxidation impairs fat oxidation by generating reactive oxygen species (ROS)⁹. Disturbed fat oxidation processes can trigger fat accumulation in the liver. Lipid peroxidation will cause liver inflammation due to the body's defence reaction^10,11. Disorders in the liver can be detected through the rise of liver enzymes, namely SGOT (serum glutamic oxaloacetic transaminase) and SGPT (and serum glutamic pyruvic transaminase)¹². Damage to hepatocyte cells causing changes in membrane transport function and permeability resulted in the release of SGOT and SGPT enzymes in the cytoplasm to the blood circulation to overcome the occurrence of damage to liver function has been many studies linking antioxidant activity with a hepatoprotector¹³.

One of the habits or lifestyles that can cause cell damage or death is an increase in LDH enzymes can be used as a biomarker in the event of cell damage or death, while increased ROS production leads to decreased activity of superoxide dismutase (SOD). SOD's capacity to transform superoxide into hydrogen peroxide impacts the equilibrium between reactive oxygen species in vascular walls and nitric oxide (NO) generation^14,15.

Saurauia vulcani Korth is a medicinal herb commonly called the Pirdot plant. Previous research has shown that Pirdot leaves have activity as an antihyperglycemic and an antihyperlipidemic due to flavonoids, glycosides, saponins, tannins, and steroids/triterpenoids^16,17.

MATERIALS AND METHODS:

Materials:

Saurauia vulcani Korth leaves were collected in Dairi Regency, North Sumatra. The spectrophotometer used in this experiment was a Shimadzu model, and all chemicals and reagents were of analytical grade unless otherwise specified. Sodium carboxymethylcellulose from Merck, distilled water from Bratachem, lard oil and quail egg yolk as fat induction were obtained from the local market. Atorvastatin 20mg was obtained at the nearest pharmacy¹⁸.

METHODS:

Extract preparation:

One thousand grams of Saurauia vulcani Korth leaf powder was extracted by maceration using ethanol solvent (3×3 days, 10 L). The filtrate is collected and evaporated using a rotary evaporator¹⁶.

Preparation of extract and atorvastatin suspension:

The ethanol extract of Saurauia vulcani Korth (EESVL) leaves was put into a mortar containing a small amount of 0.5% Sodium-CMC suspension while stirring homogeneously and then filled with distilled water. Separately, 50mg of atorvastatin was stirred in a mortar, after which a small amount of 0.5% sodium-CMC suspension was added, and the mixture was stirred regularly until homogeneous.

Preparation of animal studies:

Male white rats weighing 180 and 200g were the experimental animals used in this research. Rats were adapted for 7–14days before testing, and 24 Rats were divided into six groups. Each cage is often provided with food and husks for bedding. Six groups, each consisting of four Rats, were formed from experimental animals, namely 1: sodium-CMC 0.5%; 2: atorvastatin 0.80mg/KgBW, 3: 50mg/KgBW, 4: 100mg/KgBW, 5: 200mg/KgBW, and 6: 400mg/KgBW. Rats were fasted for 18hours after the acclimation phase, and blood total cholesterol (TC) was assessed using a strip test. The Rats were fed twice daily with 2mL/kgBW of quail egg yolk and lard oil. The blood TC of each Rat was assessed after 30 days of induction, and animals with TC levels of more than 200mg/dL were used for testing.

Measurement of cholesterol, HDL, LDL, triglycerides, SGOT and SGPT levels:

Testing of total cholesterol, HDL, LDL, triglyceride, GOT, SGPT, SOD and LDH levels after administration with extract, atorvastatin and 0.5% Natrium-CMC suspension was carried out for 21 days. Mice were fasted for 18 hours after completion of therapy and underwent intraperitoneal ketamine anaesthesia at a dose of 70mg/KgBW. Serum was extracted by taking blood directly from the heart and centrifuging at 3000 rpm for 10minutes. Lipid profiles (total cholesterol, triglycerides, and high-density lipoprotein cholesterol) and liver enzymes, including SGOT and SGPT, were analyzed in the collected sera. Using the Friedewald equation, low-density lipoprotein cholesterol (LDL-C) was estimated.

^19-23

SOD level measurement:

Rats were fasted for 18hours after the last treatment, and all experimental animals were treated with ketamine 70mg/KgBW intraperitoneally. Furthermore, blood from the rat's heart has been immediately taken to measure the SOD activity in the serum and the rat's liver for histology. SOD level measurement has performed by microplate reader based on FineTest Superoxide Dismutase Assay Kit at wavelength 405nm^24,25.

LDH content measurement:

Rats were fasted for 18hours after the last treatment, and all experimental animals were treated with ketamine 70mg/KgBW intraperitoneally. Furthermore, blood from the rat's heart has been immediately taken to measure the LDH level in the serum. The size of LDH enzyme levels is determined using diagnostic reagents²⁸.

Statistical analysis:

One-way ANOVA was utilised to determine statistical significance levels, with a significance threshold set at p < 0.05. The data are shown as the mean SD of five animals per group.

RESULTS AND DISCUSSIONS:

Table 1: Results of average reduction in total cholesterol levels

Group	Cholesterol levels (mg/dL)
Group	Day 7	Day 14	Day 21
Sodium-CMC	300.20 ± 8.13	312.20 ± 3.63	346.60 ± 4.56
Atorvastatin	222.80 ± 3.91	191.10 ± 7.08	173.10 ± 5.54
EESVL 50 mg/KgBW	287.80 ± 5.30	262.80 ± 5.10	237.90 ± 4.82
EESVL 100 mg/KgBW	256.20 ± 3.05	226.90 ± 5.05	199.90 ± 2.96
EESVL 200 mg/KgBW	219.60 ± 3.95	183.10 ± 5.97	162.80 ± 5.95
EESVL 400 mg/KgBW	224.80 ± 6.03	188.90 ± 4.08	173.10 ± 4.05

Table 2: Results of the average increase in HDL, LDL and TG levels for each treatment group

Group	HDL levels (mg/dL)	LDL levels (mg/dL)	Triglyceride (TG) levels (mg/dL)
Sodium-CMC	30.80 ± 0.84	108.20 ± 4.82	147.4 ± 3.05
Atorvastatin	54.80 ± 4.32	72.60 ± 2.96	63.20 ± 2.86
EESVL 50 mg/KgBW	32.80 ± 1.48	75.60 ± 3.36	112.00 ± 3.16
EESVL 100 mg/KgBW	40.80 ± 1.92	67.60 ± 2.61	80.00 ± 2.74
EESVL 200 mg/KgBW	59.00 ± 2.91	54.00 ± 2.55	42.80 ± 2.77
EESVL 400 mg/KgBW	57.80 ± 3.35	54.20 ± 3.35	44.20 ± 3.03

The average lipid profile values in Table 1 and Table 2 show that the ethanol extract of Saurauia vulcani Korth influences the reduction of total cholesterol, LDL and triglyceride levels and increases HDL. These leaves have several active ingredients, namely flavonoids, tannins and saponins. Flavonoids play a role in reducing total cholesterol levels, triglyceride levels and LDL levels²⁷. The enzyme HMG-CoA reductase, essential for cholesterol production, is inhibited by flavonoids, which can prevent an increase in total cholesterol levels.²⁸ Flavonoids also play a role in preventing coronary heart disease based on their impact on biological processes, including inhibition of lipid peroxidation and platelet aggregation^29,30. Because they prevent free radical production and protect α-tocopherol from oxidation, flavonoids are thought to reduce atherosclerosis and inhibit LDL oxidation^31,32.

The saponin content in this plant also has a mechanism for reducing lipids by increasing the excretion of bile acids due to increasing the conversion of cholesterol into bile acids. It can inhibit the absorption of cholesterol and bile acids in the intestine by forming micelles so that cholesterol cannot be absorbed³³.

In addition to flavonoids, tannins also influence the reduction of total cholesterol by blocking the HMG-CoA reductase enzyme, which is involved in cholesterol production. Inhibition of HMG-CoA reductase activity will result in a decrease in apo B 100 production and an increase in LDL receptors on the liver surface. As a result, the liver will be attracted to blood LDL cholesterol, thereby reducing LDL and VLDL^34,35.

Tabel 3: Results of the average SGOT and SGPT levels from each treatment group

Group	SGOT (mg/dL)	SGPT (mg/dL)
Sodium-CMC	257.60 ± 5.32	129.60 ± 4.04
Atorvastatin	230.40 ± 6.19	107.00 ± 4.24
EESVL 50 mg/KgBW	228.60 ± 1.95	111.80 ± 5.31
EESVL 100 mg/KgBW	210.80 ± 2.59	107.20 ± 3.96
EESVL 200 mg/KgBW	177.00 ± 4.12	84.60 ± 4.33
EESVL 400 mg/KgBW	189.40 ± 3.51	99.60 ± 4.39

Based on Table 3, SGOT and SGPT are two transaminase enzymes produced by liver cells. When liver cells are damaged, levels of both of these enzymes in the serum will increase. This enzyme is a sign of liver damage and preclinical toxicity tests. The elevation of SGOT and SGPT enzymes is caused by the excessive entry of toxic substances into the body, which will be metabolised into free radicals by cytochrome P-450 enzymes in the liver^36,37. These free radicals then bond to hepatocyte cells in the liver organs, so the liver membrane changes its permeability (increases)—this inflammatory process results in increased levels of SGOT and SGPT. The results of this study tested the effect of Saurauia vulcani Korth leaf ethanol extract in inhibiting the increase in SGPT levels. The ability to inhibit the increase in average levels of SGOT and SGPT shows the potential of this plant for hepatoprotection. However, this extract also pays attention to the relationship between dose and positive response, which means that the higher the dose, the greater the effect produced. This research with a 400 mg/KgBW dose had higher effectiveness than doses of 50mg/KgBW, 100mg/KgBW, and 200mg/KgBW^38,39.

Decreased SGOT and SGPT levels in the group by administering Saurauia vulcani Korth leaves extract is the mechanism of action of flavonoids. The content of flavonoids can be an antioxidant. Flavonoids work by suppressing the enzyme system cytochrome P-450; it will inhibit the formation of free radicals. Flavonoids can be antioxidants because they have phenolic hydroxy groups in their molecular structures, free radical capture power, and metal-bending⁴⁰. Flavonoids release hydrogen radicals and evoke new radicals that are relatively more stable and inactive due to the aromatic core resonance effect. The number of OH compounds in flavonoids dramatically affects the activity of these antioxidants ^41,42.

Table 4: Results of the average levels of SOD and LDH from each treatment group

Group	SOD (ng/mL)	LDH (U/L)
Sodium-CMC	1.89 ± 0.09	11.86 ± 1.37
Atorvastatin	4.04 ± 0.05^a	79.14 ± 2.85^a
EESVL 50 mg/KgBW	4.18 ± 0.03	145.44 ± 1.80
EESVL 100 mg/KgBW	4.56 ± 0.02	180.60 ± 1.24
EESVL 200 mg/KgBW	5.19 ± 0.03^ab	245.93 ± 1.06^ab
EESVL 400 mg/KgBW	4.81 ± 0.02	226.41 ± 1.05

Descriptive: (a): different in meaning to the Sodium-CMC group; (ab): different means to the atorvastatin group

In Table 4, based on statistical analysis, it is known that administration of Saurauia vulcani Korth leaf ethanol extract had a significant effect on increasing SOD activity compared to the Sodium-CMC group; Administration of the extract was able to increase SOD activity higher in the 200mg/KgBW group (5.19±0.03 ng/mL). From the test results, the higher the dose given, the higher the SOD activity produced.

The ethanol extract of Saurauia vulcani Korth leaves includes polyphenolic, specifically flavonoids, which function as extracellular antioxidants. These compounds help block enzymes like xanthine oxidase and protein kinase C, which produce superoxide radical anions (O₂). Flavonoids inhibit enzymes that produce reactive oxygen species such as cyclooxygenase, lipoxygenase, microsomal monooxygenase, Glutathione S-transferase, and NADH oxidase⁴³, so the antioxidant activity of this extract can be seen by increasing SOD levels in the blood. The action of flavonoid compounds found in the leaves of Saurauia vulcani Korth.

Apart from SGOT and SGPT, other parameters are still used to assess liver damage, including Lactate Dehydrogenase (LDH). Statistical results showed a significant difference in the EESVL 200mg/KgBW group (5.19±0.03ng/mL) compared to the Sodium-CMC group. Therefore, a 200mg/KgBW dose can increase LDH levels in male mice due to its excessive antioxidant content. High or excessive concentrations of antioxidants have a prooxidant effect. Namely, they can increase uncontrolled reactive oxygen species (ROS) and cause oxidative stress in cells, including lipid adequacy⁴⁴. Therefore, EEDP 200mg/KgBW can increase LDH levels. A dose of 400mg/KgBW reduces LDH levels because no phenolic compounds can release hydrogen atoms to reduce oxidant activity, thereby protecting against liver damage caused by free radicals.

At doses of 50mg/KgBW and 100mg/KgBW, it has no effect in lowering LDH levels because it is suspected that high concentrations of antioxidants can have a prooxidant effect because the excessive natural compound activity can decrease the activity of Glutathione (GSH) which is a free radical neutralizer⁴⁶. Suppose the bond between free radicals and exogenous antioxidants is saturated. In that case, these exogenous antioxidants can bind to GSH, an antioxidant of the body's defence system, and GSH cannot neutralize ROS⁴⁷.

CONCLUSION:

The research results showed that the ethanol extract of Saurauia vulcani Korth leaves at various doses was effective in reducing total cholesterol, LDL, triglyceride, SGOT and SGPT levels while also increasing SOD and LDH levels. This effect was compared with atorvastatin and control 0.5% Sodium CMC suspension.

ACKNOWLEDGMENT:

This research was funding by Universitas Sumatera Utara through Non PNBP USU funding 2020 research grant (Basic Research) No. 4142/UN.5.1.R/PPM/2020 (28 April 2020).

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Received on 28.02.2021 Modified on 20.05.2023

Research J. Pharm. and Tech 2024; 17(5):2051-2055.

DOI: 10.52711/0974-360X.2024.00325