Reduced Progression of Diabetic Nephropathy in Streptozocin-Induced Diabetic rats by Lannea coromandelica Leaf Extract
*1,2Department of Pharmacology, Vignan Institute of Pharmaceutical Technology, Duvvada, Visakhapatnam. 530049.
1Department of Pharmacognosy, Dhanvanthari Institute of Pharmaceutical Sciences, Khammam, 507120.
*Corresponding Author E-mail: drvasanthaniper@gmail.com
ABSTRACT:
Objectives: An important contributor to end-stage renal failure globally is diabetic kidney disease. The current study looked at the safeguarding results of an infusion of Ethanol from Lannea coromandelica houtt leaves (ELCL)in diabetic kidney disease that was caused by streptozotocin with the intention to treat diabetic nephropathy, creating supportive and substitute medicine is necessary. The development of DN may be slowed down by itsanti-inflammatory, anti-diabetic and antioxidant qualities. The novelity lies in the plant selection for the study. Methods: Streptozotocin (45mg/kg, i.p.) was administered as a single dosage to rats to induce diabetes. During 8 weeks, oral dosages of ELCL (100mg/kg and 200mg/kg.) were given to rodents with STZ diabetes. Blood sugar amounts and body and kidney weights were measured at the conclusion of the trial period. The parameters of serum and urine were evaluated. The kidney levels of lipid peroxide and antioxidant enzymes were assessed. Results: In STZ-diabetic rats and rats treated with extract, ethylacetate extract dramatically raised body weight and decreased blood glucose, blood urea levels, blood nitrogen levels, and the creatinine levels. All kidney antioxidants, including glutathione synthetase, glutathione-S-transferase, catalase, superoxide dismutase and NAD(P) H dehydrogenase [quinone]1 were highly upregulated by the extract. Conclusion: According to research, ELCL may have antioxidant, antihyperglycemic, and anti-glycation properties that could slow the progression of diabetic nephropathy.
KEYWORDS: L. coromandelica, Streptozotocin, Antioxidant, Antihyperglycemic, Diabetic nephropathy.
INTRODUCTION:
Hyperglycemia causes abnormalities in insulin action, secretion, or both in people with diabetes mellitus.1,2 Dialysis or kidney transplantation are necessary for chronic kidney failure, which is often brought on by diabetes3. Nephropathy appears in 30–40% of diabetics and has been documented to be associated with end-stage, renal failure globally.4,5 Diabetic nephropathy is characterised by structural abnormalities in addition to functional issues.6 The two main causes of diabetic nephropathy are the buildup of Advanced Glycation End Products (AGEs) and insufficient glycemic control.
One pathophysiological indicator of diabetic nephropathy is the excretion of albumin in the urine7, extracellular matrix augmentation and thickening of basement membranes3, loss of glomerular epithelial cells (podocytes) within the glomeruli, as well as mesangial expansion and hypertrophy. However, diabetic nephropathy cannot be stopped from progressing by these treatments.6-8
The development of powerful therapeutic drugs involves the use of medicinal plants significantly. Herbal medicines have been used to address a large range of human disease. In addition, there is a steady increase in demand for natural medicines. L. coromandelica is a tropical tree that belongs to the Anacardiaceae family and is also referred to as the Indian ash tree. L.coromandelica is used in Ayurveda for a variety of ailments, including body aches, toothaches, stomachaches, ulcers, impotence, and its anti-inflammatory, antibacterial, hypotensive, and anticancerous properties. Oxygenated hydrocarbons and mostly flavonoids are discovered to be the promising compounds with the greatest therapeutic value.9 These many active phytochemicals may be in-charge of a variety of processes that could aid in the defence against fatal diseases. Moreover, L. coromandelica is one of the plants with a potential hypoglycemic impact, and its components gallic.10-13
MATERIALS AND METHODS:
Procurement and authentication of plant:
In Guntur, Andhra Pradesh, leaves of L.coromandelica were gathered. Dr. S. M. Khasim, a botanist at Acharya Nagarjuna University in Guntur, Andhra Pradesh, recognized and verified the plant material.
Plant extract preparation:
The leaves were cleansed with distilled water, allowed to dry in the shade, and then milled into a coarse powder. Before the ethylacetate was extracted using a Soxhlet technique, the powder was defatted using petroleum ether. Subsequently, the extract was retained in an airtight container for future use and concentrated at a lower pressure using a rotary evaporator (yield: 50.71%).
Preliminary phytochemical screening:
Wagner et al.'s standardized method was followed in the phytochemical analysis of ethylacetate extract (1996).14,15 A plant preparation was examined for steroids, triterpenoids, flavonoids, glycosides, tannins and saponins. The total phenolic contented was determined using the calibration curve, which was made by measurement of the absorbance of reference solutions of known gallic acid concentrations (10-100g/ml. in ethanol). The findings indicated that the Gallic Acid Equivalent (GAE) in each gramme of extract was measured in milligrams. Using the alluminium chloride colorimetric method, the total flavonoid concentration was determined and expressed as milligrams of rutin equivalents/gram of the extract.16
Experimental Animals:
Male-Sprague Dawley rats in good health weighing between 250 and 300gm were acquired from Teena Labs, Pvt. Ltd. and placed in polypropylene cages in a licensed animal house with a 12-hour light/dark cycle and an ambient temperature of roughly 22±1°C. The Institutional Animal Ethics Committee (IAEC), in India, endorsed the execution of the protocols during the animal studies, which were approved by the Committee for the Control and Supervision of Experiments on Animals (1048/a/07/CPCSEA). Throughout the trial, the animals were given a regular pellet meal and were allowed free access to water.
Experimental design:
Streptozotocin (STZ, 45mg/kg, i.p. freshly made in a 0.1M citrate buffer with a pH of 4.5) was used in a single injection to cause diabetes in rats. The control group was treated with the same care (0.1M citrate buffer, pH of 4.5). The glucose levels in the blood were measured. Seven days adhering to injection, a glucose meter (ACCU-CHEK advantage) was utilized from the tail vein. If blood glucose levels were above 14mmol/L, animals were treated and used in further studies as diabetic rats. For eight weeks, rats were given ethylacetate orally. The STZ-induced diabetic group (n=6) was given ethylacetate 100mg/kg, the STZ-induced diabetic group got ethylacetate extract of 200 mg/kg, and the STZ-induced diabetic group got merely ethylacetate extract 200mg/kg. There were five sets of rats total. The two extract levels were chosen after taking into account of both previous research on the plant and the plant's documented acute oral toxicity study.13,18 Before to treatment and on the first, second, fourth, sixth, and eighth weeks, respectively, blood glucose levels were assessed. Both before and after the experiment, the weight of each animal was noted. Blood was removed using the retro orbital plexus method after 8 weeks. Until the assay, blood samples were kept at 20°C after being centrifuged at 1300g to separate the serum. After the trial, animals received saline perfusions to flush any lingering reminants of blood cells.
Making the renal homogenate:
Following the sacrifice, the two kidneys were separated using a homogenizer, cleaned with isotonic saline, and weighed. A 10% (w/v) phosphate-buffered (0.1M, pH 7.4) renal homogenate was then produced. Centrifuging the kidney homogenate was enabled for the determination of the kidney antioxidant properties from the supernatent.18
Serum and urinary parameters:
Serum was utilised to assess the measurement of Blood Urea Nitrogen (BUN) and creatinine levels. The creatinine value of 24hour urine was assessed. Using biochemical kits, the aforementioned characteristics were estimated (ACCUREX, Biomedical Pvt. Ltd). A 96-plate spectrophotofluorimeter was used to determine fluorescence AGE. After excitation at 370nm, the intensity of fluorescence was measured at 440nm. Relative fluorescence intensity was used to express the results.17
Characteristics of kidney antioxidants parameters:
The quantities of glutathione-S-transferase (GST) and reduced glutathione (GSH) in tissue homogenates were measured using the 5-5-dithiobis (2-nitrobenzoic acid) (DTNB) reagent. At 412nm, the absorbance was measured. Using a standard curve that was developed and expressed in terms of GSH per total tissue protein, the quantities of GST and GSH in the sample were measured in micrograms per milliliter 19. Kidney homogenate was subjected to examination for lipid peroxidation levels, superoxide dismutase (SOD), NAD(P)H dehydrogenase [quinine]1 (NQO1), and catalase (CAT) activities employing the procedures of Nishi et al. and Halliwell and Chirico20.
Statistical Examining:
Using SEM (Standard Error of the Mean), the statistics were expressed as mean standard deviation. After doing a one-way ANOVA statistical analysis at the 0.05 level of significance, a post hoc Dunnett's test for multiple comparisons was carried out. SEM and mean are used to display values.
RESULTS:
Preliminary phytochemical screening:
The initial phytochemical analysis of ethylacetate extract found the existence of phytoconstituents like carbohydrates, flavonoids, mucilage, flavonols and gums. A total of 127.67±5.6mg of rutin per gram of extract was determined to be the flavonoid content.
Body weight:
Rats with STZ diabetes and rats treated with the extract during the 8-week treatment both groups have lost weight significantly more than normal rats. Rats treated with 200mg/kg of ethylacetate extract and extract after 8 weeks showed a significant increase in body weight when compared to the diabetes control group. (Figure 1) (Table 1).
Figure 1: Effect of the ethylacetate preparation of the leaves of Lannea coromandelica houtt on participants' body weight.
Figure 2: Effects of the research groups kidney weights on Lannea coromandelica houtt leaves ethylacetate extract.
Figure 3: Effects of the research groups' blood glucose levels on Lannea coromandelica houtt leaves ethylacetate extract.
Figure 4: Effect of ethylacetate preparation of the leaves of Lannea coromandelica houtt on BUN in the research groups.
Figure 5: Effect ofethylacetate preparation of the leaves of Lannea coromandelica houtt on creatinine levels in the research groups.
Table 1: Impact of the ethylacetate extract of Lannea coromandelica houtt leaves on BUN, creatinine, body weight, kidney weight, and blood sugar in the study groups.
|
Group |
Glucose (mg/dl) |
Body Weight (gm) |
Kidney Weight (gm) |
BUN (mg/dl) |
Creatinine (mg/dl) |
|
Control |
91.6±1.10 |
450.2±6.4 |
1.5±0.14 |
12.5±0.6 |
0.26±0.05 |
|
Streptozocin |
433.5±10.5 |
172.4±2.2 |
2.4±1.06 |
27.0±2.6 |
0.7±0.06 |
|
LC Extract (100 mg/kg b.w)+STZ |
319.8±10.5 |
259.1±5.2 |
2.2±0.04 |
17.0±3.5 |
0.6±0.05 |
|
LC Extract (200 mg/kg b.w)+STZ |
254.1±9.34 |
282.3±5.4 |
1.7±0.05 |
16.4±3.1 |
0.42±0.03 |
|
Pure Extract |
90.1±3.72 |
447.2±6.4 |
1.5±0.06 |
13.0±2.3 |
0.31±0.18 |
Kidney weight and kidney hypertrophy:
Rats with STZ diabetes had significantly larger kidney weights and kidney hypertrophy metrics than rats in the rats in the healthy control group. Renal hypertrophy index improved in STZ-diabetic animals given 200 mg/kg of ethylacetate extract and in the extract treatment group (Figure 2; Table 1).
Blood glucose level:
Compared to the healthy control group, the diabetic group's fasting blood glucose levels increased considerably when they got Streptozocin eight weeks after induction. Moreover, Streptozocin diabetic rats administered 100mg/kg of ethylacetate extract for eight weeks demonstrated a decrease in their fasting blood sugar levels; yet, the same animals administered 200 mg/kg of ethylacetate for eight weeks demonstrated a noteworthy decrease in their abstinence blood sugar levels (Figure 3) (Table 1).
Parameters of serum and urine:
The STZ-diabetic rats displayed a marked drop in urine creatinine levels and a substantial increase in serum levels when compared to the healthy control group. Following ethylacetate extract treatment, serum creatinine prominently dropped while the amount of creatinine in the urine significantly increased. While it considerably decreased in the animals given ethylacetate leaf extract treatment, the blood urea nitrogen content dramatically increased in the STZ-diabetic rats (Figure 4 and Figure 5)(Table 1)
Kidney antioxidant parameters:
In comparison to the healthy control rats, the kidney of STZ-diabetic rats had significantly reduced GST,GSH, CAT, NQO1, and SOD activities. Treatment with ethylacetate plant extract significantly raised the reduced activities of GST, GSH, CAT, NQO1 and SOD at both dose levels. Furthermore, there was also a dose-dependent result seen. The amount of ethylacetate extract administered at 200 mg/kg resulted in a notable rise in catalase activity Figure 6, 7, 8, 9, and 10 (Table 2).
Figure 6: Effect of the research groups GSH levels on Lannea coromandelica houtt leaves ethylacetate extract.
Figure 7: Effect of the research groups GST on the ethylacetate extract of Lannea coromandelica houtt leaves.
Figure 8: Catalase in the research groups was affected by an ethylacetate extract of the leaves of Lannea coromandelica houtt
Figure 9: Effect of the research groups SOD levels on Lannea coromandelica houtt leaves ethylacetate extract
Figure 10: Effects of the research groups NQO1 on Lannea coromandelica houtt leaves ethylacetate extract
Table 2: Effect of the Lannea coromandelica houtt leaves ethylacetate extract on the research groups' GSH, GST, catalase, SOD, and NQO1.
|
GROUP |
GSH (mg/g tissue) |
GST activity (nmol of CDNB conjugated/min/ml) |
Catalase activity (Units per mg protein) |
SOD activity (percentage of control) |
NQO1 activity (nmol of DCIP reduced / min / mg protein) |
|
Control |
4.3±0.5 |
41.4±0.3 |
5.4±0.2 |
100.2±0.5 |
98.5±10.4 |
|
Streptozocin |
2.3±0.04 |
20.8±0.4 |
3.4±0.3 |
89.5±1.2 |
48.3±4.7 |
|
LC Extract (100mg/kg b.w)+STZ |
3.0±0.2 |
26.2±0.8 |
4.5±0.4 |
95.2±0.8 |
86.9±5.8 |
|
LC Extract (200mg/kg b.w)+STZ |
3.4±0.3 |
37.4±2.3 |
5.6±0.3 |
97.5±0.8 |
96.2±7.1 |
|
Pure Extract |
4.1±0.2 |
48.7±0.2 |
5.3±0.2 |
99.2±0.49 |
110.8±11.9 |
DISCUSSION:
Type 1 diabetics are 15–25% more likely to develop diabetic nephropathy than type 2 diabetics, who are between 30–40% more likely to develop it.21,22 Although there are medications to treat diabetic nephropathy, there is growing interest in using natural treatments to halt the progression of this condition.32-35
Among the many polyphenolic substances found in the leaves of the tropical tree L. Coromandelica are flavonoids and flavonols23 has generated a lot of interest because of its potential to prevent diabetes, which might be utilised as a springboard for further research into how this plant component affects diabetic sequel including nephropathy.24 Due to this, we examined in the present research the preventive effects of ELCL on rats with STZ-induced diabetic nephropathy.36-40
Because streptozotocin can cause selective necrosis of the pancreatic beta cells, which results in degranulation and a decrease in the amount of insulin released, it is the drug of choice for developing experimental diabetes mellitus.25,26 Hence, in the current investigation, rats were given STZ to induce diabetes. Blood glucose levels significantly increased after receiving STZ, but they decreased after receiving ethylacetate extract, supporting the extract's antihyperglycemic efficacy as described by other investigations.13,24 Some studies have suggested that the presence of reducing sugars may result in the production of free glucose after digestion, which may work against the hypoglycemic effects of the active hypoglycemic agents to increase blood sugar levels.27
Because of hyperglycemia and hypoinsulinemia caused by STZ-induced diabetes, there is a substantial reduction in body weight,25-27 increased protein loss from tissues and muscle atrophy.28 Rats with STZ diabetes who had been losing weight progressively underwent a dramatic increase in body weight after receiving ethylacetate extracttreatment. This implies that hyperglycemia-related deterioration of muscular tissue can be avoided 41,42.
Kidney weight (hypertrophy) rises in mice exposed to STZ in a proportional manner to body weight.29,30 The onset of diabetic nephropathy is marked by an increase in serum creatinine levels and BUN as well as a decline in creatinine excretion in urine.22 In STZ-diabetic rodents treated with ethylacetate extract, these effects were reversed. Increased Reactive Oxygen Species (ROS) generation brought on by hyperglycemia plays a role in the pathogenesis of a number of complications relevant to diabetes, including diabetic nephropathy.28,30 The antioxidant defenses of the cell are depleted by Reactive oxygen species, rendering it more vulnerable to oxidative harm. It also attacks lipids, DNA, and proteins, causing oxidation and further altering cellular structure and function. GSH functions as a crucial free radical scavenger in addition to maintaining the antioxidant status of plasma. Superoxide dismutase converts superoxide to less hazardous ROS, hydrogen peroxide, which catalase then further decreases to water. So, catalase aids SOD in completely neutralizing ROS. MDA, a result of late-stage lipid oxidation, is a key sign of lipid peroxidation brought on by free radicals.28 Proximal tubule cells, Mesangial cells, renal cortex and plasma, all have elevated MDA concentrations.30In STZ-diabetic rodents receiving ethylacetate extratc of the plant, elevated MDA levels were suppressed. Additionally, rats with STZ diabetes who were given ELCL treatment had higher amounts of GSH, SOD, and catalase, indicating that ethylacetate extract has antioxidant properties.
CONCLUSION:
In the current study, giving ethylacetate extract to STZ-diabetic rats reduced their blood glucose levels, improved their urine and serum parameters, and restored their kidneys' antioxidant status. To summarise, ethylacetate extract has anti-oxidant, antihyperglycemic, antihyperlipidemic, and anti-glycation properties, which helps it prevent diabetic nephropathy caused by STZ. In comparison to the control group, the extract at a dose of 200 mg/kg had a more encouraging outcome. The activity might be caused by the presence of flavonoids. Furthermore, more research is necessary to completely comprehend the cellular and molecular processes that underlie the therapeutic benefits of ethylacetate extract.
CONFLICTS OF INTERESTS:
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Received on 16.07.2022 Modified on 26.05.2023
Accepted on 01.12.2023 © RJPT All right reserved
Research J. Pharm. and Tech 2024; 17(1):120-126.
DOI: 10.52711/0974-360X.2024.00019