Renoprotective effects of Guggulsterone against Cisplatin-Induced Kidney Damage in White Female Albino Rats

 

Ruya Ali Albayaty1*, Munaf Zalzala2

1Department of Forensic Medicine, Salahaddin Health Directorate, Iraq.

2Department of Pharmacology and Toxicology, University of Baghdad-College of Pharmacy, Baghdad, Iraq.

*Corresponding Author E-mail: ruyaalialbayaty@gmail.com

 

ABSTRACT:

Background: Gugglusterone has been reported to provide protection against inflammatory and oxidative reactions of different pathological conditions. Objectives: The main object of this research work is to evaluate the renoprotective effects of guggulsterone in the prevention of cisplatin-induced nephrotoxicity in rats via assessment of renal function and histological study. Materials and methods: Rats in this study were split into four groups which comprise a control group, an induction group, a third group receiving low-dose guggulsterone, and a fourth group receiving high-dose guggulsterone. Results: a single dose of cisplatin drug has jeopardisedrenal physiology that has been demonstrated in histopathology sections and elevation of serum creatinine and urea concentrations. However, concurrent use of Guggulsteronehas provided improved histological findings and significantly (P<0.05) reduced serum creatinine and urea levels compared to the positive control of cisplatin-induced damage. Conclusion:Guggulsteronehas provided a potentially reasonable protective kidney effect against vitiated insults.

 

KEYWORDS: Renoprotection,  Cisplatin Toxicity, Guggulsterone,  Kidney Biomarker.

 

 


INTRODUCTION: 

As both an adjuvant therapy and the first-line treatment for cancer, cisplatin is a widely utilized medication1. Cisplatin is currently used to treat a variety of cancers, including bladder cancer, cervical cancer, non-small cell lung cancer, ovarian cancer, squamous cell carcinoma of the head and neck, and testicular cancer; however, its use is restricted due to tumour cell resistance and severe side effects, such as nephrotoxicity (33%), neurotoxicity, ototoxicity, and high emetogenicity2. The most frequent and dangerous symptom of nephrotoxicity is acute kidney damage (AKI), which affects 20–30% of people taking cisplatin. Numerous mechanisms, such as crystal nephropathy, tubular cell toxicity, inflammation, rhabdomyolysis, and thrombotic microangiopathy, can lead to drug-induced nephrotoxicity3.

 

It has been discovered that biomarkers such as blood urea and serum creatinine help determine nephrotoxicity4. The central platinum atom of cisplatin is surrounded by two ammonia groups, two chloride groups, and two other groups in the cis-position5.

 

The medication is activated inside the cell by a replacement reaction in which water molecules replace the chloride ligands in cisplatin5. This results in the creation of platinum cations, which then form strong covalent bonds with purine DNA bases to produce intra- and interstrand crosslinks3,4. By inhibiting DNA, RNA, and protein, cisplatin-DNA adducts [N-7 adducts at d(GpC) and d(ApG)] cause cytotoxic effects and limit cancer cell proliferation3,5. The primary pathogenic events in CP nephrotoxicity include renal tubule damage and death (apoptosis and necrosis), as well as generation of ROS., which is a reason for nephrotoxicity. The medication has been shown to harm cell mitochondria, stop the cell cycle in the G2 phase, block ATPase activity, and change the cellular transport system. The culmination of all these processes results in cell death, apoptosis, inflammation, and necrosis4.

 

Guggulsterone is a plant steroid made from the resin gum of the traditional Indian medicines known as guggulsterone, which contains the bioactive isomers E- and Z-guggulsterone. It has been used for thousands of years to treat inflammation, arthritis, and inflammation-related bone fractures, as well as for its cardioprotective effects10. Many studies have been done to evaluate the use of guggulsterone as a disease treatment due to its wide range of biological activity. Recent research has shown that guggulsterone significantly binds to the farnesoid X receptor, lowering blood cholesterol and acting as an antioxidant, anti-inflammatory, and low body weight compound6-10.

 

MATERIALS AND METHODS:

Twenty-four white Albino rats(Female, age 8-10 weeks, weight 150-200 g) were used for the present study and scheduled into 4 groups (Figure 1). The laboratory animals were kept under standard conditions handled by local animal house11-13.

 

Blood was collected for analysis, the blood was taken from the rat, placed in a plain tube, and allowed to stand at room temperature for 30 minutes before being centrifuged for 15 minutes (1000xg). The serum was then taken out and stored at (-20oC). This serum is then used to calculate the amounts of plasma urea and creatinine. Urease is a unique enzyme that breaks down urea into ammonium ions and carbon dioxide. Urea was tested using an enzymatic and colourimetric chemical reaction. By colour identifying the amount of urea and using the results of creatinine's interaction with picric acid in an alkaline environment to determine serum creatinine, red colour is used. Colour intensity is directly related to urea levels.

 

 

Figure 1. Dose and dosing interval of used normal saline (Blue circle), Cisplatin single dose (Red box), Guggulosterone-low dose (Orange circle), and Guggulosterone-high dose (Green circle). Numbers represent the day received therapy and day 11 sacrificed for histology and tissue homogenates. Guggulsterone powder (Xi'an geeked biotech, china), Cisplatin (EBEWE, Europe)

RESULTS:

The effects of cisplatin and Guggulsterone on the serum urea and serum creatinine levels in the rat have been quantified. Rats were administered cisplatin at a dose of 7.5mg/kg/day, which significantly (p<0.05) increased blood urea levels (97.66±7.4) and serum creatinine levels (1.66±0.1) compared to control levels [(32.5±3.5) and (0.55±0.1), respectively This was proven by examining the blood test results of rats whose blood had undergone a serum extraction technique. Blood urea levels were dramatically lowered to (62.16±5.4) and serum creatinine was significantly increased to a level of (0.91±0.2) when Guggulsterone 25mg/kg/day and cisplatin were taken together. Guggulsterone 50 mg/kg/day used in conjunction with cisplatin dramatically decreased blood urea levels to (53±7.9) and serum creatinine levels to (1.16±0.1) (Figure 2).

 

 

Figure 2: Renal function tests of Guggulsterone group against cisplatin-induced inflammation. Cis=cisplatin 7.5mg/kg/day, Cis+G25=cisplatin 7.5mg/kg/day+ guggulsterone 25mg/kg/day, Cis+G50=cisplatin 7.5mg/kg/day+ Guggulsterone 50mg/kg/day. Data expressed as mean±SD. *^#P<0.05, *as compared to other parameters, ^# as compared to the cisplatin group.

 

The histological findings (Figure 3) confirmed that guggulsterone protected tissue from the damaging effects of cisplatin, the histological outcomes are outlined in detail in Table 1.

 

 


Table 1: histological findings of the studied groups.

Studied Groups

Histological findings

Control

Oral NS/day

IP NS day 5

The control group's rat kidney cross-section displayed typical renal histological characteristics, including normal glomeruli and normal proximal and distal convoluted tubules. There was also no hyaline cast or inflammatory cell infiltration.

Induction

Oral NS/day

Day 5-IP Cisplatin 7.5 mg\kg

When compared to the control kidney, there is extensive necrosis and damage to the renal architecture tubules, including in the epithelial lining of the renal proximal and distal convoluted tubules and the glomeruli. There is also the presence of hyaline casts inside the tubule lumen and dilated renal tubules, as well as inflammatory cell infiltration.

Treatment group

Gugglusterone 25mg\kg+ Cisplatin 7.5 mg\kg  IP

Typical structural appearance with a low rate of epithelial cell change and a few tubules exhibiting necrosis and degeneration.

Gugglusterone 50mg\kg+ Cisplatin 7.5 mg\kg  IP

Displaying a nice appearance similar to normal with no inflammatory cell infiltration or hyaline cast.

 


 

Figure 3: A representative image for histopathological findings. Guggulsterone restored normal histology against the deleterious insults of cisplatin. Cis=cisplatin 7.5 mg/kg/day, Cis+G25=cisplatin 7.5 mg/kg/day+ guggulsterone 25mg/kg/day, Cis+G50=cisplatin 7.5 mg/kg/day+ guggulsterone 50mg/kg/day. Stain: H&E, magnification: 40X

 

DISCUSSION:

The present study has investigated cisplatin-induced kidney tissue damage indicated by biochemical laboratory tests and histological findings represented in figure 2 and figure 3. The pretreatment of rats with guggulsterone followed by cisplatin has led to the restoration of normal tissue architecture and functionality.

 

Because of the toxic effects of cisplatin, which is an anticancer medication with strong therapeutic effects, its usage is restricted. Since the kidneys are responsible for excreting cisplatin through their globular and tubular systems, it can collect there and cause toxicity, making the kidneys the major organ for cisplatin toxicity14-21.

 

Cisplatin lowers the GFR, which in turn causes the levels of blood urea and serum creatinine to rise, and causes the kidney's blood flow to decrease3-5. Creatinine is an important marker to assess renal function since it is an amino acid produced by the metabolism of creatinine phosphate in skeletal muscle and urea is a nitrogenous product of our body15-19. Acute kidney failure (ARF) occurs when there is adecreasein the level of both markers leading to a decrease in GFR. Compared to the induction group, which saw damage to the proximal and distal tubules in the form of necrosis and degeneration, the group that received cisplatin plus guggulsterone at doses of 25 or 50 mg/kg had a protective effect. Preventing apoptosis is guggulsterone's ineffective mechanism14-21.

 

Several plants derived medications have been used as adjuvant therapy for the treatment of cancer via numerous mechanisms including antitumour, antioxidant properties, anti-inflammatory, immunomodulatory properties, and cell protective properties. These compounds present in the plants might include quercetin, resveratrol, curcumin, c-phycocyanin, β-caryophyllene, lycopene, epigallocatechin-3-gallate, tannic acid and gallic acid, sulforaphane, Penta-O-galloyl-β-D-glucose, luteolin, carnosic acid, and emodin22. Additionally, rat pretreatment with p-coumaric acid has shown reasonable protection to the renal system against cisplatin toxicity23. Moreover, concomitant use of Allium sativum, Curcuma mangga and Acoruscalamushas protected rats against cisplatin-induced uterine damage confirmed by hormonal profile24.  Additionally, Berberine (an isoquinoline alkaloid) has protected against cisplatin-induced renal damage (increased blood urea and serum creatinine) indicated by reduced blood urea and serum creatinine levels compared to the positive control group. Berberine has also provided antioxidant activity against the cisplatin-induced increase in reactive oxygen species25.  Guggulsterone has inhibited the cyclophosphamide-induced renal damage via blocking the production of inflammatory cytokine mediators of tissue damage to the renal system thereby guggulsterone has mitigated the production of IL-2, IL-4, IL-6 and TNF-α26,27. A recent review study outlined the anticancer activities of guggulsterone and reported that these activities have been documented via several reported mechanisms documenting the outcome and relating to the pharmacotherapeutic potential of guggulosterone28,29

 

CONCLUSION:

Guggulsterone protects renal tissue by acting on several receptors. As a result, guggulsterone may serve as a safeguard against the side effects of chemotherapy for cancer while also having some other potential therapeutic properties. Additionally, altering the structure of Guggulsterone may improve its therapeutic effects.

 

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Received on 09.09.2022            Modified on 17.10.2022

Accepted on 28.11.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(5):2133-2136.

DOI: 10.52711/0974-360X.2023.00350