Single Intraperitoneal Dose Of Cisplatin Research Articles

A combination of generated hydrogen sulfide and nitric oxide activity has a potentiated protectant effect against cisplatin induced nephrotoxicity

AimHydrogen sulfide and nitricoxide possess cytoprotective activity and in vivo, they are generated from exogenous sodium hydrosulfide and L-arginine respectively. Cisplatin is a major chemotherapeutic agent used to treat cancer and has a high incidence of nephrotoxicity as a side effect. The study aim was to explore the effects of NaHS and L-arginine or their combination on cisplatin induced nephrotoxicity in rats. MethodsWistar Kyoto rats were given a single intraperitoneal dose of cisplatin (5 mg/kg) followed either by NaHS (56 μmol/kg, i. p.), L-arginine (1.25 g/L in drinking water) or their combination daily for 28-days. Post-mortem plasma, urine and kidney samples were collected for biochemical assays and histopathological analysis. ResultsCisplatin decreased body weights and increased urinary output, while plasma creatinine and urea levels were elevated, but sodium and potassium concentrations were diminished. The renal function parameters, blood urea nitrogen and creatinine clearance, were raised and decreased respectively. Regarding markers of reactive oxygen species, plasma total superoxide dismutase was reduced, whereas malondiadehyde was augmented.Cisplatin also diminished plasma and urinary H2S as well as plasma NO, while NaHS and L-arginine counteracted this activity on both redox-active molecules. Cisplatin cotreatment with NaHS, and/or L-arginine exhibited a reversal of all other measured parameters. ConclusionIn current study, NaHS and L-arginine as monotherapy protected the rats from cisplatin-induced nephrotoxicity but the combination of both worked more effectively suggesting the augmented anti-inflammatory and antioxidative potential of test treatments when administered together.

Olesoxime protects against cisplatin-induced acute kidney injury by attenuating mitochondrial dysfunction

BackgroundMitochondrial dysfunction is a critical factor in the pathogenesis of acute kidney injury (AKI). Agents that ameliorate mitochondrial dysfunction hold potential for AKI treatment. The objective of this study was to investigate the impact of olesoxime, a novel mitochondrial-targeted agent, on cisplatin-induced AKI. MethodsIn vivo, a cisplatin-induced AKI mouse model was established by administering a single intraperitoneal dose of cisplatin (25 mg/kg) to male C57BL/6 mice for 72 hours, followed by gavage of either olesoxime or a control solution. In vitro, human proximal tubular HK2 cells were cultured and subjected to treatments with cisplatin, either in the presence or absence of olesoxime. ResultsIn vivo, our findings demonstrated that olesoxime administration significantly mitigated the nephrotoxic effects of cisplatin in mice, as evidenced by reduced blood urea nitrogen (BUN) and serum creatinine (SCr) levels, improved renal histopathology, and decreased expression of renal tubular injury markers such as kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, olesoxime administration markedly reduced cisplatin-induced apoptosis, inflammation, and oxidative stress in the kidneys of AKI mice. Additionally, olesoxime treatment effectively restored mitochondrial function in the kidneys of AKI mice. In vitro, our results indicated that olesoxime treatment protected against cisplatin-induced apoptosis and mitochondrial dysfunction in cultured HK2 cells. Notably, cisplatin's anticancer effects were unaffected by olesoxime treatment in human cancer cells. ConclusionThe results of this study suggest that olesoxime is a viable and efficient therapeutic agent in the treatment of cisplatin-induced acute kidney injury presumably by alleviating mitochondrial dysfunction.

Renoprotective effects of Cucumeropsis mannii seed oil on cisplatin-induced nephrotoxicity in Wistar rats

BackgroundThe growing prevalence of cancer and the concomitant rise in chemotherapy use have led to an increased incidence of kidney-related diseases, including nephrotoxicity. Cisplatin (CP) is a widely used and potent anticancer drug, but nephrotoxicity limits its clinical application. PurposeOur study aimed to determine the phytochemicals and median lethal dose of Cucumeropsis mannii seed oil (CMSO) using standard methods and to further investigate the effects of CMSO on CP-induced nephrotoxicity in male Wistar rats. MethodsTwenty-one rats (100 to 150 g) were randomly divided into seven groups (n = 3) and treated with CMSO or normal saline for ten days. Group A received 1.0 mL of normal saline, irrespective of the body weight (b.w.). Groups B-D received 2500, 5000, and 7500 mg/kg b.w., respectively, of the CMSO and a single intraperitoneal dose of CP (8 mg/kg) on the seventh day. Groups E and F were administered 2500 mg/kg and 7500 mg/kg b.w., respectively, of the CMSO without CP administration. Group G received a single intraperitoneal dose (8 mg/kg b.w.) of CP on the seventh day without CMSO treatment. ResultsThe analysis of CMSO revealed the presence of various phytochemicals such as hydrogen cyanide, glycosides, saponins, steroids, tannins, alkaloids, terpenoids, phenols, and flavonoids. Acute toxicity testing demonstrated the safety of CMSO up to 5000 mg/kg b.w. We discovered that the CP administration increased serum creatinine (sCr), urea, blood urea nitrogen (BUN), and malondialdehyde (MDA) levels in rats and markedly decreased renal superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities and glutathione (GSH) levels. CMSO attenuated kidney dysfunction, oxidative stress, and lipid peroxidation. Interestingly, CMSO prominently decreased sCr, urea, and BUN levels, boosted the activity of SOD, CAT, and GPx, increased GSH levels, and significantly (p < 0.05) decreased MDA levels. Histological assessment corroborated these biochemical findings. ConclusionOur findings highlight the potential of CMSO as a protective agent against CP-induced nephrotoxicity. The observed effects are attributable to the rich phenolic and flavonoid content of CMSO. These findings have significant implications for developing complementary therapies to mitigate chemotherapy-associated kidney damage, potentially enhancing the safety and efficacy of cisplatin-based cancer treatments. Further investigation is needed to explore the clinical applications of CMSO for cancer patients.

Early diagnostic biomarkers for acute kidney injury using cisplatin-induced nephrotoxicity in rat model

Chronic kidney diseases (CKD) caused by acute kidney injury (AKI) results rapid and reversible loss in renal function. A real-time, highly accurate, and sensitive acute kidney injury biomarker is urgently required in order to keep these patients alive and prevent end stage renal disease and related complications that include hypertension, fluid and electrolyte retention, metabolic acidosis, anemia, stroke etc. This study was designed to develop a specific and sensitive model for the early identification of renal damage in male albino rats. Using a single intraperitoneal dose of cisplatin (10 mg/kg body weight) to the rats, the various duration-dependent nephrotoxic activities were compared using multiple physiological, biochemical, genomic, and histopathological markers. We looked into when renal dysfunction would start occurring after receiving a single high dose of cisplatin while blood urea nitrogen (BUN) and serum creatinine (sCr) remained normal. Following a single cisplatin injection, various measurements were taken in plasma, urine, and/or kidney tissues of rats euthanized on days 1, 2, 3, 5, and 7. When the urine kidney injury molecule (KIM-1), interleukine 18 (IL-18), nephrin, neutrophil gelatinase-associated lipocalin (NGAL) and serum cystatin C (Cys C) levels are greatly raised on day 3 after cisplatin treatment, BUN and sCr levels remain normal. Nephrotoxicity of cisplatin is also indicated by the upregulated mRNA expression of KIM-1, IL-18, Cys C, and NGAL and downregulated expression of nephrin in kidney tissue at very initial stage. Protein expression of KIM-1, IL-18 and NGAL level of kidney tissues was upregulated indicated confirmatory results done by western blot. Utilising an array of kidney impairment indicators has emerged as an earlier, more effective, and more reliable technique to diagnose AKI when compared to the most sophisticated signs now available.

Hesperidin ameliorates cisplatin induced hepatotoxicity and attenuates oxidative damage, cell apoptosis, and inflammation in rats

Cisplatin is one of the most widely used chemotherapeutic anti-cancer drugs that is associated with multiple systemic toxicities limiting its use. The present study aimed to evaluate the hepato-protective effect of hesperidin against cisplatin-induced toxicity. Thirty-two adult male albino rats were equally split into four groups, the first group served as control received normal saline, the second group (CIS) received a single intraperitoneal dose of cisplatin (7.5 mg/kg bw) on the 22nd day of the experiment, the third group (HES) treated once daily with hesperidin (200 mg/kg bw, orally) for 21 days, and the last group (HES + CIS) pretreated once daily with hesperidin followed by a single intraperitoneal dose of cisplatin. Twenty-four hours later, samples were collected for further investigations. CIS-intoxication resulted in a significant decrease in the erythrogram along with thrombocytopenia leukopenia, and lymphopenia. Furthermore, CIS administration significantly elevated serum activity of liver enzymes, total, and indirect bilirubin as well serum glucose, total cholesterol, and triglycerides levels, meanwhile serum total protein, and globulin levels were significantly reduced. The hepatic MDA was markedly elevated with a concomitant decline in the hepatic antioxidant enzymes and severe alterations in the hepatic tissue architecture in CIS-intoxicated rats. Additionally, CIS-induced overexpression of hepatic Bax, caspase-3, and TNF-α, with no effect on hepatic expression of IL-10. Interestingly, HES pretreatment improved the CIS-induced hemato-biochemical, molecular and histopathological alterations. In conclusion, hesperidin hepato-protective effects against CIS might be mediated by its antioxidant, anti-inflammatory, and anti-apoptotic properties.

Betaine downregulates microRNA 34a expression via a p53-dependent manner in cisplatin-induced nephrotoxicity in rats.

Cisplatin-induced nephrotoxicity limits its wide application as a chemotherapeutic drug. Betaine is a natural trimethylglycine compound involved in several biological reactions. In this study, the protective effect of betaine against cisplatin-induced nephrotoxicity through modulating the expression of microRNA 34a (miRNA 34a), p53, apoptosis, and inflammation was investigated. Adult Wistar rats were divided into normal group (received vehicle); betaine group (received 250 mg betaine/kg BW/day via oral gavage from Day 1 to Day 25); cisplatin group (received a single intraperitoneal dose of cisplatin at 5 mg/kg BW on Day 21) and betaine + cisplatin group (received the same doses of betaine and cisplatin). The results demonstrated that the cisplatin group exhibited severe kidney tissue damage and an increase in blood creatinine and urea levels. Furthermore, the cisplatin group showed a significant upregulation of miRNA 34a and higher levels of phospho-p53, caspase 3, cytochrome c, NFk B, and IL-1β compared to the normal group. Remarkably, the betaine + cisplatin group showed significantly decreased blood creatinine and urea concentrations, decreased levels of miRNA 34a, phospho-p53, caspase 3, cytochrome c, NFk B, and IL-1β as well as improved kidney tissue integrity compared to the cisplatin group. In conclusion, cisplatin-induced nephrotoxicity in rats was associated with upregulation of miRNA 34a expression, apoptosis, and inflammation in p53-dependent manner. These effects were reversed by betaine administration that ultimately improved the kidney function and tissue integrity.

Coenzyme Q10 Attenuates Cisplatin-induced Nephrotoxicity Through Counteracting Oxidative Stress and Inflammation

Background: Cisplatin is an anticancer drug used in the management of solid tumors, however, dose-related nephrotoxicity is one of its major problems. Agents having antioxidants, antiinflammatory and/or antiapoptotic activities may thus represent potential therapeutic options to avoid cisplatin-induced nephrotoxicity. Among these agents, coenzyme Q10 has several pharmacological properties including antioxidant, anti-inflammatory and/or anti-apoptotic effects. Objective: The current study aimed to examine whether coenzyme Q10 could attenuate cisplatininduced nephrotoxicity or not. Methods: 24 adult rats were randomly separated into three groups (8 rats per group). The first one was the control group, rats receiving vehicle (olive oil) intraperitoneally. The second group was Cisplatin treated group, rats were receiving 13 mg/kg of Cisplatin intraperitoneally as a single dose. The third group (Cisplatin + Coenzyme Q10), rats were receiving 13 mg/kg as a single intraperitoneal dose of Cisplatin and coenzyme Q10 daily for six consecutive days (10 mg/kg intraperitoneally). Results: Cisplatin caused significant increases in serum creatinine and severe histological lesions. Cisplatin treated group also showed a significant elevation in renal malondialdehyde concentration as a marker of oxidative stress; renal tumor necrosis factor-alpha concentration as a marker of inflammation; and Kidney injury molecule -1 concentration. Coenzyme Q10 significantly attenuated cisplatininduced nephrotoxicity through lowering serum creatinine and improving nephrotoxicity histological scores. Coenzyme Q10 also significantly reduced the renal concentration of MDA, TNF-α and KIM-1 relative to cisplatin treated group. Conclusions: Coenzyme Q10 has a potential nephroprotective effect against cisplatin-induced nephrotoxicity that was demonstrated by biochemical and histopathological analysis.

MON-223 CHANGES IN MERCAPTURATES OF CYSTEINE-DISULFIDES ASSOCIATE TO ACUTE KIDNEY INJURY INDUCED BY CISPLATIN AND GENTAMICIN

Disulfide stress is a mechanism of redox signalling associated with increased formation of cysteine-disulfides (CysSSX) in inflammatory/oxidative conditions. The kidney is a primordial organ for CysSSX accumulation due to its high metabolic rate and dependence on oxidative phosphorylation to produce energy. CysSSX undergo filtration and their increased urinary levels have been associated with a decreased tubular reabsorption. They are also secreted through glutathione turnover. In addition, they are eliminated in urine in the form of mercapturates (uNAC) that are generated upon CysSSX acetylation in proximal tubular cells through the mercapturate pathway. We investigated the tubular detoxification of CysSSX in animal models of nephrotoxic-mediated acute kidney injury (AKI). Female Wistar rats weighing 200–250 g were allocated under controlled environmental conditions in individual metabolic cages, for 24-h urine samples collection. Rats were randomly divided into three groups: (1) control group (CTL), receiving daily vehicle intraperitoneal for 6 days; (2) gentamicin group (G), receiving gentamicin intraperitoneal (150 mg/kg) for 6 days; and (3) cisplatin group (CISP), receiving a single intraperitoneal dose of cisplatin (5 mg/kg). At the end of the experiment, kidneys were perfused by the aorta with saline and immediately dissected and processed. Blood and urine samples were obtained at different time points. The levels of urinary total cysteine (uCys) (CysSSX filtration+secretion) and total cysteine-glycine (uCys-Gly) (measure of glutathione turnover) and uNAC (measure of mercapturate formation) were also quantified. Hematoxylin–eosin-stained kidney sections revealed a clear tubular necrosis in both gentamicin and cisplatin-treated rats. Plasma creatinine levels increased at day 4 after cisplatin initiation (2.55±0.56 mg/dL) and at day 5 after gentamicin (3.3±0.4 mg/dL) in comparison with CTL group (0.55±0.05 mg/dL) (p<0.001). The levels of uNAC decreased 2 days after initiation of CISP (64±10 µM) worsening at day 4 (47±3 µM) in comparison with the basal state group (163±6 µM) (p<0.001). The same tendency was observed for G, despite with lower levels of uNAC excretion (basal state 97±14 µM) and only reaching significance at day 5 (37±7 µM) (p=0.044). Changes in uCys levels were coincident with serum creatinine increases and more evident for CISP (319±58 µM) than for G (53±11 µM), comparing to basal state (27±3 µM and 56±3 µM for CISP and G) (p<0.001 and p=0.039 for CISP and G). A decrease of uCysGly was observed for the CISP group at day 2 (18±2 µM) and day 4 (9±2 µM) in relation to basal state (33±3 µM) (p<0.001). No changes were observed for the G group. uNAC might represent an early biomarker of drug induced-AKI, particularly for drugs undergoing the mercapturate pathway, such as cisplatin. Moreover, CysSSX acetylation might represent the primary mechanism of detoxification of the large burden of CysSSX formed in kidney tubule upon injury, particularly when there is an impairment of CysSSX secretion (eg.CISP).

Apocynin alleviates cisplatin-induced testicular cytotoxicity by regulating oxidative stress and apoptosis in rats.

The aim of this study was to investigate possible protective effects of apocynin (APO), an NADPH oxidase (NOX2) inhibitor, on cisplatin (CIS)-induced testicular damage. Four groups of Sprague Dawley rats were used: control, APO, CIS and CIS+APO. Following a single intraperitoneal dose of CIS (7mg/kg), either dimethyl sulfoxide or APO (25mg/kg) was administered orally for 5days. Testis samples were evaluated microscopically for general histopathology and ultrastructure, proliferating and apoptotic cells, and NOX2 localization. Sperm parameters were evaluated. Malondialdehyde (MDA) and glutathione (GSH) levels and superoxide dismutase (SOD), myeloperoxidase (MPO) and 8-hydroxy-2-deoxyguanosine (8-OHdG) activities were analysed biochemically. The CIS group had a greater number of abnormal spermatozoa, atrophic seminiferous tubules, apoptotic and NOX2-immunoreactive cells; numerous large vacuole formations in the cytoplasm of germinal epithelial cells; degenerated intercellular tight junctions; higher MDA, 8-OHdG and MPO levels; decreased numbers of spermatozoa; and lower proliferative index and GSH and SOD levels. All these histologic and biochemical results were better in the CIS+APO group. CIS causes testicular damage by decreasing spermatogenic cell lines and increasing NOX2 activity and apoptosis through oxidative stress. APO prevents testicular damage, possibly by its antioxidant effects.

Oral thymoquinone administration ameliorates: the effect of cisplatin on brush border membrane enzymes, energy metabolism, and redox status in rat kidney.

Therapeutic use of cisplatin (CP), an effective anticancer drug, is limited by dose dependent nephrotoxicity. Thymoquinone (TQ), the major Nigella sativa seed oil constituent has been shown to prevent progression of various renal disorders. The present study investigates the protective effect of TQ on CP-induced nephrotoxicity. Rats were divided into six groups viz. control, CP, CPTQ1, CPTQ2, CPTQ3, and TQ alone group. Animals in CP and TQ combination groups were administered TQ (0.5, 1.5, and 3mg/kgbwt, orally) with single intraperitoneal dose of CP (6mg/kgbwt). The effect of TQ administration was determined on CP-induced alterations in various serum/urine parameters and on the enzymes of brush border membrane enzyme (BBM), carbohydrate metabolism, and antioxidant defense system in renal cortex and medulla. Oral administration of TQ in all the three doses prior to and following a single dose CP treatment caused significant recovery of serum creatinine and blood urea nitrogen levels; however, maximum recovery was seen in CPTQ2 group. TQ administration averted CP-induced decline in BBM activities, both in the cortical and medullary homogenates and in isolated BBM vesicles. TQ administration also ameliorated CP-induced impairments in renal metabolic and antioxidant status. Histopathological studies supported these biochemical findings. TQ ameliorates CP-induced oxidative damage owing to its intrinsic antioxidant properties.

Oral administration of thymoquinone mitigates the effect of cisplatin on brush border membrane enzymes, energy metabolism and antioxidant system in rat intestine

Cisplatin (CP) is a widely used chemotherapeutic agent that elicits severe gastrointestinal toxicity. Nigella sativa, a member of family Ranunculaceae, is one of the most revered medicinal plant known for its numerous health benefits. Thymoquinone (TQ), a major bioactive component derived from the volatile oil of Nigella sativa seeds, has been shown to improve gastrointestinal functions in animal models of acute gastric/intestinal injury. In view of this, the aim of the present study was to investigate the protective effect of TQ on CP induced toxicity in rat intestine and to elucidate the mechanism underlying these effects. Rats were divided into four groups viz. control, CP, TQ and CP+TQ. Animals in CP+TQ and TQ groups were orally administered TQ (1.5mg/kg bwt) with and without a single intraperitoneal dose of CP (6mg/kg bwt) respectively. The effect of TQ was determined on CP induced alterations in the activities of brush border membrane (BBM), carbohydrate metabolism, and antioxidant defense enzymes in rat intestine. TQ administration significantly mitigated CP induced decline in the specific activities of BBM marker enzymes, both in the mucosal homogenates and in the BBM vesicles (BBMV) prepared from intestinal mucosa. Furthermore, TQ administration restored the redox and metabolic status of intestinal mucosal tissue in CP treated rats. The biochemical results were supported by histopathological findings that showed extensive damage to intestine in CP treated rats and markedly preserved intestinal histoarchitecture in CP and TQ co-treated group. The biochemical and histological data suggest a protective effect of TQ against CP-induced gastrointestinal damage. Thus, TQ may have a potential for clinical application to counteract the accompanying gastrointestinal toxicity in CP chemotherapy.

Urolithin A Mitigates Cisplatin-Induced Nephrotoxicity by Inhibiting Renal Inflammation and Apoptosis in an Experimental Rat Model.

Cumulative kidney toxicity associated with cisplatin is severe and there is no clear consensus on the therapeutic management of the same. The pathogenesis involves activation of inflammatory and apoptotic pathways; therefore, regulating these pathways offers protection. Given the anti-inflammatory and antioxidant effects of urolithin A, a gut microbial metabolite of ellagic acid, our aim was to explore the potential use of urolithin A in the prevention of cisplatin-induced nephrotoxicity in an experimental rat model. For this purpose, animals received a single intraperitoneal dose of cisplatin (5 mg/kg body weight). Six hours prior to cisplatin administration, rats were orally treated with either ellagic acid or urolithin A (50 mg/kg body weight), followed by a daily dose of these compounds during the next 5 days. At the end, plasma and kidneys were collected for analysis. Cisplatin-induced kidney damage was revealed by a significant rise in the plasma creatinine levels accompanied by significant morphologic changes in tubules, T cell Ig and mucin domain-containing protein-1, ionized calcium-binding adapter molecule 1, as well as a marked increase in the number of apoptotic cells localized in tubules. Cisplatin also reduced nitric oxide synthase 3 and nuclear factor kappa-light-chain-enhancer of activated B cells resulting in regulation of various inflammatory cytokines. Urolithin A effectively attenuated cisplatin-induced kidney damage and showed significantly greater effect than its precursor ellagic acid on preserving the normal kidney architecture by downregulating the proinflammatory cytokines. In summary, urolithin A mitigates cisplatin-induced nephrotoxicity in rats by modulation of the inflammatory cascade and inhibition of the proapoptotic pathway.

PD35-12 KDM5A, A HISTONE H3K4 DEMETHYLASE, REGULATES SPERMATOGENESIS VIA ITS ACTION ON GERM CELL

INTRODUCTION AND OBJECTIVES: Cisplatin is a widely used chemotherapeutic agent for the treatment of various genitourinary tumors. Although it is a very effective, its use is limited by its renal and testicular toxicity. Mesenchymal stem cells (MSCs) are pluripotent undifferentiated cells that have the ability to differentiate and divide into another cell types and can self renew. Our aim was to investigate the possible protective role of MSCs against Cisplatin induced testicular apoptosis and damaged oxidant/antioxidant balance in rats. Furthermore, we explored the involvement of apoptotic markers in the pathogenesis of testicular toxicity and their role in monitoring treatment. METHODS: A total of 30 male Sprague Dawley rats were used for the experiment. They were divided into 3 groups: Group 1 served as control group received intraperitoneal (IP) saline, Group 2 (Cisplatin group) received a single IP dose of Cisplatin 7mg/kg and Group 3 (Stem Cells group) received the same IP single dose of Cisplatin and was administered BM-MSCs (2x10 cells) by penile vein injection 24h after the Cisplatin injection. Testicular weight and plasma testosterone level were determined along with testicular malondialdehyde (MDA) and reduced glutathione (GSH) levels as oxidative stress markers. Testicular gene expressions of Caspase-3 and mitogen activated protein kinase (MAPK) were estimated by real time-PCR. Histopathological examination for testicular tissues was also done. RESULTS: Cisplatin induced a significant reduction in testicular weights, plasma testosterone and testicular GSH levels in addition to significant elevation of testicular MDA levels and gene expressions of Caspase-3 and MAPK when compared with control group (p<0.05). Histopathology showed lower tubular diameters and depletion of germ cells, irregular small seminiferous tubules with Sertoli cells only were observed in Cisplatin group. MSCs injection significantly corrected these changes in both biochemical and histopathological parameters. CONCLUSIONS: There is a significant role of oxidative and apoptotic markers in the pathogenesis of Cisplatin induced oxidative injury in rat testis. Cisplatin treatment markedly impaired testicular function in rats through mechanisms that could be significantly salvaged with co-administration of MSCs. To our knowledge, this is the first report in the literature that address the protective role of MSCs in Cisplatin induced testicular toxicity; however, further studies are needed to validate our findings.

Evaluation of role of atorvastatin in cisplatin induced nephrotoxicity in Wistar rats

This study was carried out to investigate the ameliorative effect of Atorvastatin on Cisplatin-induced Nephrotoxicity in Wistar rats. Twenty Four (24) male rats were used for the experiment. Group I was administered per oral daily with Phosphate Buffered Saline (PBS) for 10 days. Group II was administered single intraperitoneal dose of Cisplatin 7.5mg kg body weight on fifth day, Group III was administered daily per oral 1

The protective effect of Ginkgo biloba extract against experimental cisplatin ototoxicity: animal research using distortion product otoacoustic emissions

Cisplatin, an effective therapeutic agent for various human cancers, has dose-limiting side effects of ototoxicity and nephrotoxicity. Cisplatin ototoxicity is thought to result from increased amounts of toxic free radicals or cell membrane changes leading to increased intracellular calcium content. Ginkgo biloba extract prevents lipid peroxidation, decreases intracellular free oxygen radical levels, regulates the cell membrane calcium transport mechanism and prevents cell death. This study aimed to investigate the protective effect of Ginkgo biloba extract against cisplatin-induced ototoxicity in rats. Twenty Wistar albino rats with normal hearing (confirmed by distortion product otoacoustic emission testing prior to cisplatin application) were randomly allocated to two groups. Both groups received a single intraperitoneal dose of cisplatin (12 mg/kg). Group two also received daily intraperitoneal doses of Ginkgo biloba extract (100 mg/kg) for 10 days. Distortion product otoacoustic emission measurements were repeated on days 10 and 17 and signal-to-noise ratios were compared. Compared with group one, group two had significantly better distortion product otoacoustic emission results at 3, 4, 6 and 8 kHz on days 10 and 17. These findings suggest that Ginkgo biloba extract protects the inner ear against cisplatin-induced ototoxicity.

Glycyrrhizic acid: A phytochemical with a protective role against cisplatin-induced genotoxicity and nephrotoxicity

Aims Glycyrrhizic acid (GA) is a main sweetening component of licorice roots and has been found to be associated with multiple therapeutic properties. In this study, we used GA as a protective agent against the clastogenic and nephrotoxic effects of cisplatin (CP). Main methods Mice were given a prophylactic treatment of GA orally at doses of 75 and 150 mg/kg body weight for seven consecutive days before the administration of a single intraperitoneal dose of CP at 7 mg/kg body weight. The modulatory effects of GA on CP-induced nephrotoxicity and genotoxicity were investigated by assaying oxidative stress biomarkers, lipid peroxidation, serum kidney toxicity markers, DNA fragmentation, alkaline unwinding, and micronuclei and by histopathological examination of the kidneys. Key findings A single intraperitoneal dose of cisplatin in mice enhanced renal lipid peroxidation, xanthine oxidase, and H 2O 2 generation; depleted glutathione content, activities of the anti-oxidant enzymes glutathione peroxidase, glutathione reductase, catalase, glutathione-S-transferase and quinone reductase; induced DNA strand breaks and micronucleus formation (p < 0.001); and majorly disrupted normal kidney architecture. Pretreatment with GA prevented oxidative stress by restoring the levels of antioxidant enzymes at both doses. A significant dose-dependent decrease in DNA fragmentation, micronucleus formation (p < 0.05), and the kidney toxicity markers BUN (p < 0.001), creatinine (p < 0.01), and LDH (p < 0.001) and restoration of normal kidney histology was observed. Significance Our study supports the claim that the phytochemical GA has the potential to attenuate the side effects of anticancer drug overdose.

Oral administration of caffeic acid ameliorates the effect of cisplatin on brush border membrane enzymes and antioxidant system in rat intestine

Cisplatin (CP) is a widely used antineoplastic drug that exhibits gastrointestinal toxicity. We have previously shown that administration of a single dose of CP results in a decrease in the activities of several brush border membrane (BBM) enzymes, induces oxidative stress and alters the activities of several antioxidant enzymes in the small intestine of rats. In the present study we have investigated the effect of treatment with the dietary antioxidant caffeic acid (CA) on CP induced biochemical changes in the intestine. Administration of a single intraperitoneal dose of CP alone (6 mg/kg body weight) led to a decrease in the activities of the BBM enzymes, increase in lipid peroxidation, decrease in sulfhydryl groups and changes in the activities of catalase, superoxide dismutase, glutathione peroxidase, glucose 6-phosphate dehydrogenase, glutathione reductase, glutathione S-transferase and thioredoxin reductase. Administration of two doses of CA (each of 250 mg/kg body weight), at 15 and 120 min after treatment with CP, significantly attenuated the CP-induced changes in all these parameters but the administration of CA alone had no effect. These results suggest that CA is an effective agent in reducing the effects of CP on the intestine and could prove to be useful in alleviating the gastrointestinal toxicity of this drug.

Acid sphingomyelinase deficiency protects from cisplatin-induced gastrointestinal damage

Cisplatin is one of the most effectively used chemotherapeutic agents for cancer treatment. However, in humans, important cytotoxic side effects are observed including dose-limiting renal damage and profound gastrointestinal symptomatology. The toxic responses to cisplatin in mice are similar to those in human patients. Here, we evaluated whether the acid sphingomyelinase (Asm) mediates at least some of the toxic in vivo effects of cisplatin. To this end, we determined the toxic effects of a single intraperitoneal dose of cisplatin (27 mg/kg) in wild type (Asm(+/+)) and Asm-deficient mice (Asm(-/-)). Tissue injury and apoptosis were determined histologically on hematoxylin-eosin and TUNEL (terminal deoxynucleotidyl transferase (TdT)-mediated nick end labeling) stainings 3, 12, 36 and 72 h after treatment. Our results revealed severe toxicity of cisplatin in Asm(+/+) mice with increased numbers of apoptotic cells in the thymus and small intestine. In marked contrast, Asm(-/-) mice were resistant to cisplatin and no apoptosis was observed in these organs after treatment. Moreover, cisplatin treatment primarily triggered apoptosis of endothelial cells in microvessels of intestine and thymus, an effect that was absent in mice lacking Asm. The data thus suggest that at least some toxic effects of cisplatin are mediated by the Asm in vivo resulting in early death of endothelial cells and consecutive organ damage.

Effect of cisplatin on brush border membrane enzymes and anti-oxidant system of rat intestine

Cisplatin (CP) is a widely used antineoplastic agent which exhibits gastrointestinal toxicity. The present work was done to study the effect of administration of CP on brush border membrane (BBM) enzymes and anti-oxidant system of rat intestine. Male Wistar rats were given a single intraperitoneal dose of CP (6 mg/kg body weight) and then sacrificed 1, 3, 5 and 7 days after this treatment. Control animals were given saline only. The administration of CP led to significant decline in the specific activities of BBM enzymes both in the mucosal homogenates and isolated membrane vesicles. Kinetic studies showed that the V max of the enzymes was decreased in BBM vesicles from CP treated rats while the K m remained unchanged. The activities of catalase, Cu–Zn superoxide dismutase, glucose 6-phosphate dehydrogenase and glutathione reductase decreased while the activities of glutathione S-transferase and thioredoxin reductase increased in CP treated animals compared to the control group. Lipid peroxidation and total sulfhydryl groups were also altered upon CP treatment indicating the generation of oxidative stress. The maximum changes in all the parameters studied above were 3 days after administration of CP and then recovery took place on days 5 and 7. Thus, the administration of CP leads to significant alterations in the activities of BBM enzymes and the anti-oxidant status of rat intestine.

The Effect of MGN-3 on Cisplatin and Doxorubicin Induced Toxicity in the Rat

ABSTRACT MGN-3 (BioBran(r)) is derived from rice bran and is produced by the partial hydrolysis of the water soluble hemicellulose fraction of rice bran by carbohydrases derived from Lentius edodes mycelia. It is a biological response modifier producing an increase in natural killer cell activity in immunocompromised patient. The aim of the study was to evaluate orally administered MGN-3 against gross pathological changes and weight loss produced by a single intraperitoneal dose of cisplatin or doxorubicin by daily oral dosing of 5 or 50 mg/kg MGN-3. Male Sprague-Dawley rats received either vehicle or MGN-3 prior to and after a single dose of cis-platinum or doxorubicin. Rats were observed for clinical signs daily for 11 days and body weights were recorded every other day. All animals were euthanized and necropsied on Day 11. Lethality was observed only in rats receiving cisplatin (50% with cisplatin alone reduced to 10% in rats receiving MGN-3 5 mg/kg, and 40% after MGN-3 50 mg/kg). Rats receiving MGN-3 ...