{"id":62884,"date":"2024-12-30T10:36:39","date_gmt":"2024-12-30T10:36:39","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=62884"},"modified":"2025-01-07T04:01:10","modified_gmt":"2025-01-07T04:01:10","slug":"assessment-of-nephroprotective-properties-of-vitex-agnus-castus-extract-in-cisplatin-treated-wistar-rats-a-pilot-study","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no4\/assessment-of-nephroprotective-properties-of-vitex-agnus-castus-extract-in-cisplatin-treated-wistar-rats-a-pilot-study\/","title":{"rendered":"Assessment of Nephroprotective Properties of Vitex Agnus castus Extract in Cisplatin-Treated Wistar Rats: A Pilot Study"},"content":{"rendered":"\n

Introduction <\/strong><\/p>\n\n\n\n

Cisplatin (CP) is a platinum-containing drug that treats various cancers like sarcomas, lymphoma carcinomas, and germ cell tumors1<\/sup>. Cisplatin enters the cells via organic cationic transporters (OCT), hydrolyzes due to low ICF chloride concentration, and gets activated, which later causes havoc within the cell1,2<\/sup>. Activated cisplatin attaches to the DNA strands and forms covalent bonds, creating cross-links in DNA and preventing the cancer cells from dividing and growing, thus leading to the death of the cancer cell3,4<\/sup>. While it is an effective chemotherapy drug, its use can also adversely affect healthy cells, particularly in the kidneys, because cisplatin is eliminated via the kidneys. Kidneys have organic cationic transporters (OCT 1 & OCT 2) at the basolateral membrane of proximal convoluted tubular (PCT) cells. OCT 2 is primarily responsible for the cellular uptake of cisplatin in the kidneys5,6<\/sup>. Efflux of cisplatin from the PCT cells is handled by multidrug and toxin extrusion (MATE) channels, which are present on the brush border membrane of the tubular cells. It is suggested that MATE channels transport cisplatin less than OCT 2, which results in a quick entry but slow release of cisplatin in cells. Consequently, cisplatin accumulates in higher concentrations in renal tubular cells5<\/sup>. This accumulation manifests as an acute kidney injury or chronic kidney disease, as activated cisplatin generates reactive oxygen species (ROS) and triggers an inflammatory response. The severity of the kidney damage can vary depending on the dose and duration of cisplatin treatment7<\/sup>. About 30% of patients treated with cisplatin suffer from nephrotoxicity. It manifests a swift decline in the excretory mechanism of the kidney, which in turn causes an accumulation of metabolites resulting from protein metabolism in the body (Urea, creatinine, and blood urea nitrogen)8\u201310<\/sup>. Cisplatin causes acute kidney injury by activating the NF-\u1e35B pathway in the renal tubules11<\/sup>, which promotes the release of cytochrome c from mitochondria, initiating intrinsic apoptotic pathway12,13<\/sup> and also enabling the activation of multiple proinflammatory mediators, thus inhibiting NF-kB may facilitate the protection of kidneys from cisplatin induced injury14<\/sup>. The interaction of CP with female gender-specific sex hormones and the effects of estradiol in preventing the nephroprotective effects of antioxidants in CP-induced renotoxicity have been demonstrated15<\/sup>. Reports also suggest that G Protein-Coupled Estrogen Receptor\u00a0(ER)may have a protective role in acute kidney injury caused by cisplatin16<\/sup>. Despite extensive research on cisplatin’s nephrotoxicity mechanism, effective safeguards remain inconclusive; hence, there is always a need to identify adequate protection against cisplatin-induced nephrotoxicity without bargaining its anticancer potential. Herbal plants like Curcuma longa<\/em>, Pulsatilla dahurica17<\/sup>,<\/em> <\/strong>Mucuna pruriens18<\/sup>, and <\/em>Ginger extract19<\/sup> have been used to treat various ailments of kidneys for decades. The biotic and abiotic stress helps the plants develop resistance by producing intricate phytochemicals. These compounds can synergistically target different pathways\/mechanisms to boost therapeutic effects. Compounds like curcumin20<\/sup> and quercetin21<\/sup> have been studied for their potential to alleviate the harmful effects of cisplatin-induced kidney damage. Curcumin neutralizes reactive oxygen species, enhances antioxidant enzymes, and reduces oxidative stress. It also suppresses inflammatory pathways and the production and activation of cytokines20<\/sup>. Green tea extract has been found to reduce oxidative stress and inflammation while preserving renal function22<\/sup>. Quercetin has also shown promise in affecting oxidative stress pathways and inhibiting inflammation, suggesting its potential to mitigate cisplatin-induced nephrotoxicity21<\/sup>. Along with neutralizing reactive oxygen species, it enhances antioxidant enzymes, reduces oxidative stress, and suppresses cisplatin-induced inflammation. These compounds also improve renal functions by reducing BUN, Urea, and Creatinine levels in the blood. Vitex Agnus Castus<\/em> (VAC) (Sanskrit: Sinduvara; Family: Verbenaceae) is a deciduous shrub native to Mediterranean Europe and Central Asia. Traditionally, the VAC berry extract is used to treat menstrual disorders, menopausal symptoms, and acne23<\/sup>. It contains chemical compounds like essential fatty acids (oleic acid and linolenic acid); Iridoid glycosides (aucubin and agnoside); Essential oils (limonene, pinene, and sabinene), Flavonoids (casticin and isovitexin), Diterpenes (vitexilactone, rotundifuran), Essential fatty acids (oleic acid and linolenic acid)24,48<\/sup>. VAC extract has antinociceptive, anti-inflammatory, antioxidant, anticancer, and antitumor properties 48,49<\/sup>. VAC contains essential oils & flavonoids that remarkably cause inflammation and inflammatory pain, as seen in xylene-induced ear edema48<\/sup>. Isovitexin, a component of VAC extract, has also shown anti-inflammatory effects by reducing ROS generation and inhibiting MAPK pathways50<\/sup>. Studies have demonstrated hydroethanolic extract from fruits has antitumor and anti-proliferative activities against prostate cancer and other cancer cell lines49,51<\/sup>, and it may have relatively low toxicity against normal cells in the living body. Casticin, a flavonoid in VAC, was found to be a potent immunomodulatory and cytotoxic compound 52<\/sup>. It is hypothesized that VAC could help alleviate cisplatin-induced renal toxicity because of its anti-inflammatory and antioxidant properties. This preliminary study aimed to assess the gender-specific responses to cisplatin-induced acute nephrotoxicity and evaluate the nephroprotective effects of VAC extract against cisplatin-induced toxicity.<\/p>\n\n\n\n

Materials and Methods<\/strong><\/p>\n\n\n\n

Chemicals and Drugs <\/strong><\/p>\n\n\n\n

Cisplatin<\/strong>: Commercially available Cisplatin injection (\nKemoplat 50mg\/50 ml vial) was obtained from FRESENIUS KABI INDIA PVT LTD, Pune,\nMaharashtra, India. The injection volume was calculated based on the animal’s\nbody weight, and an undiluted CP injection (7 mg\/kg body weight) was\nadministered. The cisplatin dose for inducing acute nephrotoxicity was selected\nbased on the previous literature 53<\/sup>.<\/p>\n\n\n\n

Vitex Agnus Castus<\/strong><\/p>\n\n\n\n

Vitex Agnus castus berry extract (fine, rose-pink powder with Agnuside content >0.5%) was procured from Navchetana Kendra, New Delhi, India. The extract (200mg) was dissolved in 1 ml of deionized water, and a stock solution was prepared. During the experiment, the animals were weighed daily. The volume of the extract was calculated and administered orally based on the specified dose (165 mg\/kg body weight of VAC)54<\/sup><\/p>\n\n\n\n

Experimental Animals <\/strong><\/p>\n\n\n\n

Four-month-old, 36 Wistar rats (24 male and 12 female)\nweighing 160\u2013250 gms were randomly selected and grouped. These animals were kept in\npolypropylene cages lined with sterilized husks. They were maintained under\nnormal conditions at a 25\u00b0C\u201327\u00b0C temperature range, with a 12-hour light\/dark\ncycle and continuous access to a regular rat pellet diet and drinking water. Three\nanimals were housed in each cage to prevent overcrowding, and they were\nacclimatized to the laboratory environment.<\/p>\n\n\n\n

Experimental Design<\/strong><\/p>\n\n\n\n

The experiment was conducted in two phases; the first phase involved the assessment of the gender-based difference in cisplatin induced nephrotoxicity, where 12 male and 12 female Wistar rats were recruited and randomly divided into two groups: Normal control and Cisplatin control (n=6 per group per gender). In the Normal control groups (6 males & 6 females), animals were left untreated, and animals of the Cisplatin control group (6 males & 6 females) received a single cisplatin (7mg\/Kg bw) intraperitoneal injection. These animals were observed for 7 days. A nephrotoxicity assessment was done by estimating plasma Creatinine, Urea, and Blood Urea Nitrogen (BUN) using standard kits procured from Agappe Diagnostics Ltd, Mumbai, India.<\/p>\n\n\n\n

The\nstudy’s second phase assessed the nephroprotective effects of Vitex Agnus castus <\/em>(VAC) extract on the gender group exhibiting\nhigher nephrotoxicity determined in the first phase. 12 male Wistar rats were\nrecruited for the second part of the study, and they were randomly divided into\nthe VAC control group (n=6), which received an oral\ndose of 165 mg\/kg body weight for 7 days. The Cisplatin + VAC group (CP+VAC)\n(n=6) received daily oral doses of VAC extract for 7 days following the\ncisplatin injection. <\/p>\n\n\n\n

The\nbody weight of all the animals was recorded, blood was drawn in EDTA tubes for\nbiochemical analysis at the end of the experimental duration, and animals were\nsacrificed. Biochemical analysis was done using kidney function test kits procured from Agappe\nDiagnostics Ltd, Mumbai, India. Kidneys were\nexcised, weighed, and processed for hematoxylin and eosin staining. The\nsections were examined for morphometrical changes in the renal tubules under a\nlight microscope using 10x magnification. The Organosomatic index (OSI) was\nalso calculated using the body and kidney weights.<\/p>\n\n\n\n

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Statistical\nAnalysis <\/strong><\/p>\n\n\n\n

The data was analyzed using the Statistical Package for the\nSocial Sciences (SPSS) version 16.0, and normally\ndistributed data are expressed as mean \u00b1 standard deviation. We used the Independent Samples Test for the first phase and One-way\nANOVA with the post hoc Tukey test for the second phase. A p-value < 0.05\nwas considered statistically significant.<\/p>\n\n\n\n

Results<\/strong><\/p>\n\n\n\n

Assessment of gender-specific responses to Cisplatin-induced nephrotoxicity<\/strong><\/p>\n\n\n\n

Cisplatin administration impaired kidney function (indicated by increased plasma concentration of creatinine, Urea, and BUN) in Wistar rats (both males and females) as compared to normal controls (shown in Graph 1, Graph 2, Graph 3). Cisplatin-treated Male rats showed significantly higher (p<0.05) plasma creatinine, urea, and BUN levels than the normal male control group rats. Female rats receiving cisplatin also showed increased creatinine, Urea, and BUN, but these changes were statistically insignificant compared to the normal female control group. When comparing cisplatin induced kidney function impairment among genders, we found higher plasma creatinine and urea levels in males, with plasma creatinine levels being statistically significantly higher only in males (p<0.05), which starkly contrasts with females who exhibited elevated levels of BUN. <\/p>\n\n\n\n

The results also indicate that cisplatin administration caused a significant decrease (p<0.01) in body weight in both genders compared to the normal controls (Graph 4). Histological evaluation revealed that cisplatin administration disrupts tubular epithelial cells, causes brush border loss, induces tubule dilation, and appearance of vacuoles in both genders (Figure 1). <\/p>\n\n\n\n\n\n
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Graph 1: Compaison of mean plasma creatinine concentration in male and female Wistar rats. Values are represented as mean \u00b1S. D(n=6). *p <0.05 when compared to the respective normal control.<\/strong><\/p>\n

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Graph 2: Compaison of mean plasma urea concentration in male and female Wistar rats. Values are represented as mean \u00b1S. D (n=6). *p <0.05 when compared to the respective normal control.<\/strong><\/p>\n

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Graph 3: Compaison of mean plasma Blood Urea Nitrogen (BUN) concentration in male and female Wistar rats. Values are represented as mean \u00b1S. D (n=6). *p <0.05 when compared to the respective normal control.<\/strong><\/p>\n

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Graph 4: Compaison of mean body weight (in grams) in male and female Wistar rats on the baseline (day 0) and after 7 days (day 8) of cisplatin injection. **p <0.05 ststistically different when compared to\u00a0 the normal control.<\/strong><\/p>\n

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Figure 1: Effect of cisplatin treatment on the morphological changes following cisplatin-induced acute kindney injury.<\/strong><\/p>\n

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Nephroprotective effect of VAC extract (165mg\/kg bw) in male Wistar rats on cisplatin facilitated nephrotoxicity. \u00a0<\/strong><\/p>\n\n\n\n

Cisplatin\ncontrol and Cisplatin +VAC groups showed a lower (reduced) body weight (p<0.05)\nwhen compared to normal control, and the change in the body weight from the\nbaseline (day 0) to day 8 was highly significant (p<0.001) (Graph 5). The Cisplatin control group had higher plasma\nconcentrations of creatinine, urea, and BUN (p<0.05) compared to normal\ncontrols. VAC administration after cisplatin reduced the plasma concentrations\nof renal function indicators like creatinine, urea, and BUN compared to the Cisplatin\ncontrol group. However, the reduction was not statistically significant (shown\nin Graph 6, Graph 7, Graph 8). On the other hand, the organosomatic\nindex (OSI) of the kidney of the cisplatin control group (p<0.01) was higher\ncompared to normal controls. It was also observed that the Cisplatin + VAC group (p<0.05) had\nsignificantly lower relative kidney weights than those treated with cisplatin\n(Graph 9).<\/p>\n\n\n\n

Histopathological examination showed a well-organized and compact interstitial space, with intact epithelial lining of the proximal and distal convoluted tubules and cells with intact nuclei with eosinophilic cytoplasm in both the Normal and VAC control groups. However, the groups that received cisplatin showed disrupted interstitium and the presence of vacuoles. The proximal tubules show disrupted epithelial lining, loss of the brush border, and dilated lumen (Figure 2). <\/p>\n\n\n\n\n\n
\"\"<\/td>\nGraph 5: Compaison of mean body weight (in grams) in controls and experimental groups on the baseline (day 0) and after 7 days (day 8) of cisplatin injection. <\/strong>
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\"\"<\/td>\nGraph 6: Compaison of mean plasma creatinine concentration in) in controls and experimental groups.<\/strong>
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Graph 7: Compaison of mean plasma urea concentration in controls and experimental groups.<\/strong><\/p>\n

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Graph 8: Compaison of mean plasma Blood Urea Nitrogen (BUN) concentration in controls and experimental groups.<\/strong><\/p>\n

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Graph 9: Compaison of mean organosomatic index (OSI kidney) in controls and experimental groups.<\/strong><\/p>\n

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Figure 2: Compaison of the morphological changes in the kindney in the control and the experimental groups.<\/strong><\/p>\n

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Discussion \u00a0<\/strong><\/p>\n\n\n\n

The\npresent study aimed to investigate gender-based differences in cisplatin\ninduced nephrotoxicity in Wistar rats, and we observed that both genders of Wistar rats exhibited impaired\nrenal function parameters like plasma creatinine, urea, and BUN, which increased\nafter injecting cisplatin6,25,26<\/sup>. Females only exhibited higher BUN levels,\nwhereas males have significantly higher plasma creatinine and urea\nconcentrations than females. These alterations may be due to the action of\ncisplatin, which activates the NF-kB pathway in the renal tubules, as it facilitates\nnumerous pathways that lead to inflammation and apoptosis, resulting in acute\nkidney damage11,12,14,27\u201329<\/sup>. The results also show\nthat the administration of cisplatin caused a significant decrease in body\nweight in both genders. This change in body weight\ncould be attributed to cisplatin-induced anorexia, which causes a decrease in hypothalamic\nghrelin secretion, which in turn leads to reduced food intake30,31<\/sup>. Studies have also suggested that impaired lipid metabolism pathways, such\nas increased lipolysis and fatty acid oxidation along with a reduction in\nlipogenesis30<\/sup>, or dysregulated muscle protein metabolism (synthesis\nand degradation) caused by increased atrophic gene expression32<\/sup>, are\nprobable causes for cisplatin-induced weight loss.<\/p>\n\n\n\n

Kidney\nhistology shows more cellular degeneration and cytoplasmic vacuolization in\nmales than in females. Based on the evidence, it is clear that cisplatin has\nnephrotoxic effects at a dose of 7 mg\/kg body weight. Additionally, it was\nobserved that male Wistar rats were more affected than their female\ncounterparts. These results are consistent with other studies on renal damage\nbrought on by cisplatin and its side effects20,21,33<\/sup>.\nOur findings corroborated with earlier research, which shows that the\ntoxicities differ depending on gender, and male rats exhibit higher toxicity to\ncisplatin compared to female rats 25,26<\/sup>. The explanation\nbehind this observation is that the uptake of cisplatin in the renal tubular\ncells varies in males and females, which is because there are higher levels of\nmRNA and protein expression of the Organic Cation Transporter 2 (OCT2) in male\nkidney compared to female kidney15,34<\/sup>.\n<\/p>\n\n\n\n

For\nthe second phase of our study, we selected male Wistar rats to evaluate the\npotential therapeutic effects of Vitex Agnus castus fruit extract; as our study\nindicated, male rats were more susceptible to cisplatin-induced injury.<\/p>\n\n\n\n

Cisplatin\ntreatment resulted in significant body weight loss, possibly due to increased\nmuscle wastage, decreased intake of food, or gastrointestinal toxicity, which\nis reported in previous studies30\u201332,35,36<\/sup>. When VAC is administered\npost-Cisplatin treatment, the body weight does not change significantly\ncompared to the Cisplatin control group. Similarly, Plasma creatinine level is\nmarkedly increased(p<0.05), which indicates kidney damage. Treatment with\nVAC has decreased the plasma creatinine level, but the change is insignificant.\nThis observation may be due to the vasodilator effect of VAC, which would have reduced\nthe plasma creatinine levels by increasing the GFR37<\/sup>.<\/p>\n\n\n\n

Similarly,\nimprovement in renal clearance due to the vasodilator effect of VAC has\ndecreased the plasma urea and BUN compared to the cisplatin control group.\nHowever, the decrease is not statistically significant. Furthermore, kidney\nhistology shows cellular degeneration, tubular dilation, and cytoplasmic\nvacuolization of proximal tubules and a hyaline cast, indicating severe kidney\ndamage in the cisplatin control group. In contrast, the CP + VAC group shows\nlesser tubular damage, vacuolization, and no hyaline cast. The organosomatic\nindex (OSI) of the kidney was significantly increased in the cisplatin control\ngroup, whereas a significant decrease in OSI was observed in the Cp+ VAC group.\nTubular dilation and inflammation increase the kidney’s relative weight, which\nindicates renal damage. Previous studies also report similar observations 38,39<\/sup>.<\/p>\n\n\n\n

It\nis well-documented that cisplatin damages the kidney by increasing oxidative\nstress. Free radical generation and intracellular antioxidant defence become\nunbalanced due to oxidative stress, with the latter taking precedence. The free\nradicals damage the cell membrane by lipid peroxidation and protein\ndenaturation40<\/sup>.\nFlavonoids in VAC extract have antioxidant activity, so they help in decreasing\nthe oxidative stress caused by cisplatin. VAC extract also contains\nphytoestrogen, which acts via estrogen receptors (ER)24,41\u201343<\/sup>, and\nstudies also report that ER alpha receptors are present in male rats’ kidneys44,45<\/sup>.\nSo, these mechanisms of action could help protect kidneys from the deleterious\neffects of cisplatin. Cisplatin causes acute kidney injury through\nvasoconstriction by activating adenosine A1 receptors in the kidney, resulting\nin decreased blood flow and damage to the tubular vascular endothelium, which leads\nto increased vascular resistance, a reduced renal blood flow, a decreased GFR,\nrenal tubular hypoxia, and ultimately renal damage46,47<\/sup>. According\nto reports, VAC extract has vasorelaxant properties37<\/sup> that could\npotentially counteract the negative effects of cisplatin on the kidneys, which\nin turn may increase GFR and facilitate the removal of Creatinine, Urea, and\nBUN from the blood. The current study indicates that treatment with VAC after\ncisplatin has lowered the renal impairment function parameters compared to the\ncisplatin control group, but the reduction is not statistically significant. <\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

In toto, cisplatin injection at 7mg\/kg\nbody weight leads to acute kidney injury, with male rats being more susceptible\nthan female rats to renal damage. The presence of flavonoids and phytoestrogens\nin VAC extract helped to shield the kidney from damage caused by cisplatin and\npartially mitigated renal damage in male rats. Therefore, VAC can help in\ncurtailing renal damage in patients undergoing cisplatin therapy and improve\ntheir overall quality of life.<\/strong><\/p>\n\n\n\n

Limitations of the Study <\/strong><\/p>\n\n\n\n

The initial\nfindings indicate some protective effects against cisplatin-induced\nnephrotoxicity; however, further research is required to determine the ideal\ndosage and duration of VAC extract administration for maximum protection\nagainst cisplatin-induced nephrotoxicity. Studying the pharmacological profile\nof the extract will help identify the specific protection mechanism.\nUnderstanding these nephroprotective mechanisms will improve our knowledge of\nVAC’s overall efficacy and potential clinical applications.<\/p>\n\n\n\n

Acknowledgement<\/strong><\/p>\n\n\n\n

We thank Manipal Academy of Higher Education, India, for\nproviding the infrastructure and support required for the study. <\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

The author(s) received no\nfinancial support for the research, authorship, and\/or publication of this\narticle.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The author(s) do not have any conflict of\ninterest.<\/p>\n\n\n\n

Data Availability <\/strong> Statement<\/strong> <\/p>\n\n\n\n

The manuscript incorporates all datasets\nproduced or examined throughout this research study.<\/p>\n\n\n\n

Ethical Statement<\/strong> <\/p>\n\n\n\n

This study was approved by the\nInstitutional Animal Ethics Committee of the Manipal Academy of Higher\nEducation (IAEC\/KMC\/53\/2018). Experiments were conducted\nfollowing CPCSEA  (Committee for the\nPurpose of Control and Supervision of Experiments on Animals) guidelines. <\/p>\n\n\n\n

Informed\nConsent Statement<\/strong><\/p>\n\n\n\n

This study did not involve human\nparticipants, and therefore, informed consent was not required.<\/p>\n\n\n\n

Clinical Trial Registration<\/strong><\/p>\n\n\n\n

This\nresearch does not involve any clinical trials<\/p>\n\n\n\n

Author Contributions<\/strong><\/p>\n\n\n\n

Aparna Tripathy, <\/strong>Archana Parampalli Raghavendra, <\/strong>Sudarshan Surendran : Study conceptualization & Study design; <\/p>\n\n\n\n

Aparna Tripathy <\/strong>and Babi Dutta: Performed experiments & investigations. <\/p>\n\n\n\n

Aparna Tripathy, Babi Dutta and Sudarshan Surendran: Statistical analysis; <\/p>\n\n\n\n

Aparna Tripathy <\/strong>and Archana Parampalli Raghavendra : Initial draft of the manuscript; <\/p>\n\n\n\n

Aparna Tripathy, <\/strong>Babi Dutta, <\/strong>Archana Parampalli Raghavendra, <\/strong>Sudarshan Surendran: Review, editing, and final approval of the manuscript;<\/p>\n\n\n\n

Aparna Tripathy and Archana Parampalli Raghavendra : Overall project supervision.<\/p>\n\n\n\n

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