Renoprotective and cardioprotective effect of ethanolic extract of Ficus racemosa bark in streptozotocin induced diabetic rats.

Prepared by: Joshi Hiral S. Roll no. 37 M. pharm Sem-IV Pharmacology

Guide Name :Mr. Devendra Vaishnav Asst. Professor Dept. of Pharmaceutical Sciences

Department of Pharmaceutical Sciences, Saurashtra University-Rajkot

Introduction(1)
2

In 2011 there were 366 million people with diabetes, and this is expected to rise to 552 million by 2030. In India 61.3 million people were suffering from diabetes in 2011 in aged of 20 -79 years and in 2030 this population will be 101.2 millions according to International Diabetes Federation (IDF).

Moreover, diabetes is among the leading causes of kidney failure and approximately 10-20% of people with diabetes die due to kidney failure. Diabetes also increases the risk of heart disease and stroke, with a 50% mortality rate of cardiovascular disease. The majority of diabetic complications arise from vascularrelated inflammation apparently initiated by endothelial cell injury and oxidative stress.
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Review of literature(2,3)
3

There are many hypoglycemic agents used in diabetes and related complications continue to be a major medical problem. Treatment of this disease with insulin and its derivatives is an invasive process and make the patients more susceptible to hypoglycemic episodes, premature atherosclerosis due to hyperinsulinemia. Treatment with antihyperglycemic agents may be associated with hypoglycemia, flatulence, weight gain, hyperinsulinemia, paresthesias, transient leucopenia, agranulocytosis, dementia and it is contraindicated in nursing mothers.

Department of Pharmaceutical Sciences, Saurashtra University

Moreover, literature reports quote gain in body weight, cataracts and macular degeneration during oral anti-diabetic treatment in some patients.(3) Therefore, the need to look for a treatment which did not only check the glucose levels in circulation system, but at the same time avoids the adverse effects associated with the currently available commercially available herbal and PHFs and provides an exhaustive list of plants with potential anti-diabetic activity and reduce diabetic complications.(4)

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Plant profile
5

Ficus racemosa plant

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Plant profile(5)
6

Botanical source: Ficus glomerata

Family: Moraceae
Synonyms: Ficus recemosa Common names: Cluster fig (English), Umbaro (Gujarati), Gular (Hindi) . Plant part used: Bark, leaves, fruit, root Selected part: bark Chemical constituents :Flavonoids,Lupeol,Resin,proteins, sitosterol. Traditional Uses: analgesic ,antipyretic, antdiabetic , antiinflammatory ,in infectious diseases.
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The bark of F. racemosa is one of a number of traditional remedies that have several pharmacological actions. The use of ethanolic extract of bark of F.racemosa as an antidiabetic agent has been described in various Ayurvedic texts (6). Ethanolic extract of Ficus racemosa bark possess Hypolipidemic activity(7), antioxidant activity(8) and antiinflammatory activity (9).

However, there is no information about its activity in experimental diabetic complication.

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Aim and objectives

8

Aim The overall aim of proposed study was to explore the application of traditional medicinal F.racemosa antidiabetic plants in diabetic complication. Screening of ethanolic extract of bark of F. racemosa for in-vivo a protective activity on renal and cardiac STZ induced diabetic rats.

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Objectives of the study

9

Review about Diabetic complication and herbal drug used in diabetes and its complication Collection and authentification of plant Extraction of F.racemosa bark using soxhlet apparatus Evaluation of effect of FRBE in serum glucose, serum lipid profile, cardiac biomarkers and urine parameters in STZ induced diabetic rats Evaluation of effect of FRBE in kidney and left ventricle (LV) enzymes SOD, MDA, glutathione, total protein in STZ induced diabetic rats Evaluation of effect of FRBE in LV collagen content in STZ induced diabetic in rats. Histopathological study of kidney and left ventricle of heart
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Materials and methods

10

Collection and authentication of plant material: Barks of F. racemosa were collected and identified by comparing it morphologically with description given in different standard texts and floras (4). The plant was authenticated by Dr. H. B. Singh.NIMS New Delhi. The plant herbarium (SU/DPS/Herb/47) was deposited in the Department of Pharmaceutical Sciences, Saurashtra University, and Rajkot for future reference.

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Preparation of plant Extract

11

The dried powdered barks were extracted with ethanol in a soxhlet extractor. The extract was concentrated to dry residue and a reddish colored residue was obtained (yield 20.87 % w/w with respect to the dry starting material) and was stored in desiccators(10). For pharmacological experiment weighed amount of the dried extract was suspended in a 1% (w/v) aqueous Tween 80 solution(11).

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Experimental protocol
12

Wistar albino rats (200-250g) were used for the present study. Animals were housed in a ventilated room under a 12/12 hr light/dark cycle at 242 C and had free access to water and food. The animal care and experimental protocols was approved by the Institutional Animal Ethics Committee (SU/DPS/IAES/2012/1204). A study was conducted with two different dose of ethanolic extract of F. racemosa (200 and 400 mg/kg) to determine the dose-dependent effect of ethanolic extract of F. racemosa in Streptozotocin (45mg/kg) induced cardiovascular and renal complication in type I diabetes mellitus in rats. Evaluation was observed that after 60 days of experiment(12,13,14).
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13

Group I

control (n = 6)

Group II

Diabetic control group, STZinduced, untreated diabetic rats (n = 8) STZ-induced, FRBE treated diabetic rats (200 mg/kg , p.o.) (n = 8) for 60 days. STZ-induced, FRBE treated diabetic rats (400 mg/kg, p.o.) (n = 8) for 60 days.

Group III

Group IV

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Evaluation of renal and cardiac parameters

14

Serum Profile

Lipid Profile

Cardiac Parameters

Antioxidants enzymes in kidney and Left Ventricle(LV) Malondialdeh yde (MDA)

Superoxide dismutase (SOD) Glutathione (GSH)

Urine Parameters

Glucose
Blood urea nitrogen (BUN) Creatinine

Cholesterol
Low Density Lipoprotein (LDL) High Density Lipoprotein (HDL)

Creatinine kinase(CK)
C-reactive protein (CRP) Lactate dehydrogena se (LDH)

Creatinine clearance
Albumin

Triglyceride Total protein Department of Pharmaceutical Sciences, Saurashtra (TG) University

Results
15

Estimation of glucose
2000
Serum Glucose mg/dl

1500 1000 500

***(a)

Control DC T200 T400

***(b)

***(b)

0 Control DC T 200 T 400

Effect of FRBE on serum glucose in STZ induced type-I diabetes mellitus in rats. FRBE was administered daily to diabetic rats. Values are means SEM of six animal (n= 6) . *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) Diabetic treated (III), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests.
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Estimation Of Lipid Profile

16
200 150 100 50 0 Control DC T 200 T 400
***
(a)

Serum Triglyceride mg/dl

***(b) ***(b)

Control DC T200 T400

Effect of FRBE on TG in STZ-induced type I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). *** (a) (p < 0.001) Diabetic control (II) vs. control (I), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) Diabetic treated (III), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests.
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17
100
***(a)

Serum LDL mg/dl

80 60 40 20 0 Control DC T 200 T 400

***(b) ***(b)

Control DC T200 T400

Effect of FRBE on LDL in STZ-induced type I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). *** (a) (p < 0.001) Diabetic control (II) vs. control (I), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) Diabetic treated (III), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests.
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18
200 150
***(b)

Serum Cholesterol mg/dl

***(a)

100 50 0 Contol DC T 200

Contol DC T200 T400

***(b)

T 400

Effect of FRBE on T-CHO in STZ-induced type I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). *** (a) (p < 0.001) Diabetic control (II) vs. control (I), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) Diabetic treated (III), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests.
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19

80
Serum HDL mg/dl

60 40 20 0 Contol DC

***(b)

***(b)

Contol DC T200 T400

***(a)

T 200

T 400

Effect of FRBE on HDL in STZ-induced type I diabetic mellitus in rats. . Values are means SEM of six animals (n = 6). *** (a) (p < 0.001) Diabetic control (II) vs. control (I), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) Diabetic treated (III), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests.
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Cardiac Markers
20
Serum Creatinine kinase mg/dl

3000

***(a)

2000

Control DC T200 T400

***(b) ***(b)

1000

0 Control DC T 200 T 400

Effect of FRBE on CK in STZ - induced type I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). ***(a) (p < 0.001) Diabetic control (II) vs. control (I), ***(a) (p < 0.001) Diabetic control (II) vs. ***(b) Diabetic treated (III), ***(a) (p < 0.001) Diabetic control (II) vs. ***(b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests
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21
15
Serum CRP mg/dl

10

***(a)

Control DC T200 T400

***(b) ***(b)

0 Control DC T 200 T 400

Effect of FRBE on CRP in STZ - induced type I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). ***(a) (p < 0.001) Diabetic control (II) vs. control (I), ***(a) (p < 0.001) Diabetic control (II) vs. ***(b) Diabetic treated (III), ***(a) (p < 0.001) Diabetic control (II) vs. ***(b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests
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22
2500 2000
LDH mg/dl

***a

1500
***b ***b

Control DC T200 T400

1000 500 0 Control DC T 200 T 400

Effect of FRBE on LDH in STZ - induced type I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). ***(a) (p < 0.001) Diabetic control (II) vs. control (I), ***(a) (p < 0.001) Diabetic control (II) vs. ***(b) Diabetic treated (III), ***(a) (p < 0.001) Diabetic control (II) vs. ***(b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests
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Estimation of Antioxidants in Left ventricle

23

MDA
1.5
***(a)

1.0
***(b) ***(b)

Control DC T200 T400

0.5

0.0 Control DC T 200 T 400

Effect of FRBE on MDA in STZ induced type-I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). *** (a) (p < 0.001) Diabetic control (II) vs. control (I), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) Diabetic treated (III), ***(a) (p < 0.001) Diabetic control (II) vs. **(b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests.
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24

SOD
60
*(b)

40
**(a)

Control DC T200 T400

20

0 Control DC T 200 T 400

Effect of FRBE on SOD in STZ induced type-I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). *** (a) (p < 0.001) Diabetic control (II) vs. control (I), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) Diabetic treated (III), ***(a) (p < 0.001) Diabetic control (II) vs. **(b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests.
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25

Effect of FRBE on GSH in STZ induced type-I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). *** (a) (p < 0.001) Diabetic control (II) vs. control (I), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) Diabetic treated (III), ***(a) (p < 0.001) Diabetic control (II) vs. **(b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests.
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26

COLLAGEN
3
***(a)

Control DC T200 T400

*(b)

1
**(b)

0 Control DC T 200 T 400

Effect of FRBE on collagen in STZ induced type-I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). *** (a) (p < 0.001) Diabetic control (II) vs. control (I), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) Diabetic treated (III), ***(a) (p < 0.001) Diabetic control (II) vs. **(b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests.
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Estimation of Serum parameters

27
2.0 1.5 1.0 0.5 0.0 Control DC T 200 T 400
***(b) ***(a)
Serum Creatinine mg/dl

Control DC T200 T400

***(b)

Effect of FRBE on Creatinine in STZ induced type-I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). *** (a) (p < 0.001) Diabetic control (II) vs. control (I), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) Diabetic treated (III), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests.
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28

Serum Albumin mg/dl

3 2 1 0 Control DC
***(a)

***(b)

***(b)

Control DC T200 T400

T 200

T 400

Effect of FRBE on albumin in STZ induced type-I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). *** (a) (p < 0.001) Diabetic control (II) vs. control (I), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) Diabetic treated (III), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests.
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80
Serum Urea mg/dl

60 40 20 0 Control

***(a)

Control DC T200 T400

***(b) ***(b)

DC

T 200

T 400

Effect of FRBE on urea in STZ induced type-I diabetic mellitus in rats. Values are means SEM of six animals (n = 6). *** (a) (p < 0.001) Diabetic control (II) vs. control (I), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) Diabetic treated (III), *** (a) (p < 0.001) Diabetic control (II) vs. *** (b) (p < 0.001) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests.
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Estimation of urinary markers

30

Creatinine clearance
creatinine clearance (ml/mins)
0.5 0.4 0.3 0.2 0.1 0.0 C DC T 200 T 400
**(b) ***(b)

***(a)

Effect of FRBE on Creatinine clearance in STZ induced type-I diabetic mellitus in rats. FRBE was administered daily to diabetic rats. Values are means SEM. *** (a) (p< 0.001) Diabetic control (II) vs. ** (b) Diabetic treated (III), *** (a) (p< 0.01) Diabetic control (II) vs. *** (b) (p< 0.001) Diabetic treated (IV). One way ANOVA, followed by Turkeys multiple range tests.
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31

2.5
Urine Albumin mg/dl

***a

2.0 1.5 1.0 0.5 0.0 Control DC T 200 T 400

***b ***b

Control DC T200 T400

Effect of FRBE on urine albumin in STZ induced type-I diabetic mellitus in rats. FRBE was administered daily to diabetic rats. Values are means SEM. *** (a) (p< 0.05) Diabetic control (II) vs. *** (b) Diabetic treated (III), *** (a) (p< 0.001) Diabetic control (II) vs. *** (b) (p< 0.001) Diabetic treated (IV). One way ANOVA, followed by Turkeys multiple range tests. Department of Pharmaceutical Sciences, Saurashtra University

Estimation of antioxidants in kidney

32

MDA
1.0
***(a)

0.8 0.6 0.4 0.2 0.0 Control DC T 200 T 400

**(b)

Control DC T200 T400

Effect of FRBE on MDA in STZ induced type-I diabetic mellitus in rats. FRBE was administered daily to diabetic rats. Values are means SEM of six animal (n=6). *(a) (p < 0.05) Diabetic control (II) vs. control (I), *(a) (p < 0.05) Diabetic control (II) vs. Diabetic treated (III) Not significance, *(a) (p < 0.05) Diabetic control (II) vs. ** (b) (p < 0.01) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests Department of Pharmaceutical Sciences, Saurashtra University

33

SOD
400 300
***(b) *(b)

200 100 0 Control DC T 200 T 400

*(a)

Control DC T200 T400

Effect of FRBE on SOD in STZ induced type-I diabetic mellitus in rats. FRBE was administered daily to diabetic rats. Values are means SEM of six animal (n=6). ** (a) (p < 0.01) Diabetic control (II) vs. control (I), ** (a) (p < 0.01) Diabetic control (II) vs. ( p < 0.05) Diabetic treated (III) significance, ** (a) (p < 0.01) Diabetic control (II) vs. *** (b) (p < 0.001) Diabetic treated (IV). One way ANOVA followed by Tukeys T test. Department of Pharmaceutical Sciences, Saurashtra University

34

GSH
3
*(b)

2
*(a)

Control Legend T200 T400

0 Control

DC

T 200

T 400

Effect of FRBE on GSH in STZ induced type-I diabetic mellitus in rats. FRBE was administered daily to diabetic rats. Values are means SEM of six animal (n=6). ** (a) (p < 0.01) Diabetic control (II) vs. control (I),**(a) (p < 0.01) Diabetic control (II) vs. Diabetic treated (III) Not significance, **(a) (p < 0.01) Diabetic control (II) vs. *(b) (p < 0.05) Diabetic treated (IV). One way ANOVA, followed by Tukeys multiple range tests. Department of Pharmaceutical Sciences, Saurashtra University

35

DC

T200

T400

Normal kidney morphology of control (C-40X).Marked glomerular sclerosis, loss of brush border, adhesion to Bowmans capsule as well as thickening and untidiness of tubular and glomerular capillary basement membranes in the STZ-induced diabetic rats (DM, 40X). Treatment with FRBE together with STZ resulted in almost normal tubules and glomeruli(T200, T400, and 40x)

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36

DC

T200

T400

Histopathology of the heart tissues. The images were taken under 40X magnifications. The image indicates that Capillary wall thickening observed in groups DC. Scale bars indicate C-control group rats, DCdiabetic control, T200-diabetic treated (T200 mg/kg, p.o), T400 - diabetic treated (T400 mg/kg, p.o) Department of Pharmaceutical Sciences, Saurashtra

37

Compared to the control normal rats, diabetic rats were significantly (p < 0.001) increased blood glucose, BUN, Creatinine , T-CHO, LDL-C, CK, LDH, CRP and urinary albumin, Creatinine and sodium and lower HDL-C levels. Also, in untreated diabetic rats heart and kidney tissue, MDA significantly (p < 0.01) increased while SOD and GSH were significantly (p < 0.001, 0.01, 0.05) decreased in the cardiac and renal issue. Oral administration of FRBE in dose of 200 and 400 mg/kg body per weight improved serum glucose, lipid profile and serum cardiac and renal parameter. Cardiac and renal GSH and SOD were significantly (p < 0.001, 0.01, 0.05) increased while MDA was reduced. These result may suggest that a beneficial effect of FRBE in diabetic cardiomyopathy and nephropathy.
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Conclusion
38

Hence, these results may reveal that STZ-induced diabetic mellitus increased oxidative stress in cardiac and renal tissue and beneficial effect of ethanolic extract of bark of F.racemosa on diabetic cardiovascular and renal complication and delay the occurrence of diabetic cardiovascular and renal complication.

Department of Pharmaceutical Sciences, Saurashtra University

Acknowledgement
39

We are thankful to Dr. Navin Sheth, Professor and Head, Department of Pharmaceutical Sciences, Saurashtra University, Rajkot for providing the facilities and constant encouragement through out this work.

Department of Pharmaceutical Sciences, Saurashtra University

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Faiyaz, A., Asna, U.,2010. Hepatoprotective effects of Ficus racemosa stem bark against carbon tetrachloride-induced hepatic damage in albino rats Pharmaceutical Biology. 48,2, 210 Veerapur,V.P., Prabhakar, K.R.,2009.Ficus racemosa Stem Bark Extract,A Potent Antioxidant and a Probable Natural Radioprotector eCAM , 6, 3, 317324.

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42 10)

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Sachan, 2009.Antidiabetic potential of alcoholic and aqueos extract of ficus racemosa linn. Bark in normal and alloxan induced diabetic rats IJPCR. 1,1, 24-27. Zulfiker, 2011.Hypoglycemic and in vitro antioxidant activity of ethanolic extracts of Ficus racemosa Linn. Fruits. Ameri. J. Scis industri. res. 3,391.400 Zafar, D., 2009. Altered Kidney Morphology and Enzymes in Streptozotocin Induced Diabetic Rats, Int. J. Morphol. 27,3, 783-790. Kurdak, H., Sandk, S., Ergen,N., Dogan, A., Kurdak, S.,2010. The effects of regular aerobic exercise on renal functions in streptozotocin induced diabetic rats,. J. Sports Sci. Medi. 9, 294-299. Okruhlicova, L., Tribulova,N., Weismann, P., Sotnikova, R.,2005. Ultrastructure and histochemistry of rat myocardial capillary endothelial cells in response to diabetes and hypertension. Cell Research, 15,532-538.
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43

Thank You

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