Cisplatin-induced Ovarian Damage Research Articles

WITHDRAWN: Metformin mitigates cisplatin-induced ovarian damage through inhibiting the pyroptosis of granulosa cells via ROS/TXNIP/NLRP3 signaling pathway.

This paper was originally published in Aging Advance Online Publications on March 14, 2024. In compliance with Aging's withdrawal policy, the paper was withdrawn in its entirety. It will not appear in Aging internal or any external indexes or archives.

Does resveratrol reduce cisplatin-induced ovarian damage?

The objective of this study was to investigate the protectiveness of resveratrol on cisplatin-induced damage to the ovary using experimental models. A total of 30 female Wistar-Albino rats constituted the research material. The rats were categorized into three groups: Group 1 was administered one milliliter of 0.9% NaCl solution, Group 2 was administered 7.5 mg/kg cisplatin, and Group 3 was administered 7.5 mg/kg cisplatin and 10 mg/kg resveratrol. Ovaries were extirpated in all groups and subjected to biochemical and histopathological tests. Cisplatin-induced damage to ovarian tissue was graded and scored as the total histopathological findings score. The ovarian function was assessed using immunohistochemical staining for c-kit expression. Rats' malondialdehyde, catalase, and superoxide dismutase levels were determined. The histopathological finding score was significantly higher in Group 2 than in other groups (p<0.05). The superoxide dismutase and catalase levels were significantly higher in Group 3 than in Group 2 (p<0.001 for both cases). The malondialdehyde level was significantly higher in Group 2 than in Group 3 (p<0.001). The study findings demonstrated that resveratrol reduced ovarian injury and enhanced biochemical parameters following cisplatin-induced ovary damage in experimental models.

Protective Effect and Mechanism of Melatonin on Cisplatin-Induced Ovarian Damage in Mice.

Chemotherapeutics' development has enhanced the survival rate of cancer patients; however, adverse effects of chemotherapeutics on ovarian functions cause fertility loss in female cancer patients. Cisplatin (CP), an important chemotherapeutic drug for treating solid tumors, has adversely affected ovarian function. Melatonin (MT) has been shown to have beneficial effects on ovarian function owing to its antioxidative function. In this research, an animal model was established to explore the effect of MT on CP-induced ovarian damage. Immunohistochemical analysis and Western blot were also used to explore its mechanism. This study reported that MT protects mouse ovaries from CP-induced damage. Specifically, MT significantly prevented CP-induced ovarian reserve decline by maintaining AMH and BMP15 levels. We also found that MT ameliorated CP-induced cell cycle disorders by up-regulating CDC2 expression, and inhibited CP-induced ovarian inflammation by decreasing IL-1β and IL-18 levels. Moreover, MT protected the ovary from CP-induced mitochondrial damage, as reflected by restoring mitochondria-related protein expression. Furthermore, CP caused ovarian apoptosis, as indicated by up-regulated BAX expression. MT was also shown to activate the MAPK pathway. Our results showed that MT could ameliorate ovarian damage induced by CP, implying that MT may be a viable alternative to preserve female fertility during CP chemotherapy.

Fertility protective effect of taxifolin in cisplatin-induced ovarian damage.

The aim of our study was to investigate the protective effect of taxifolin on ovarian damage and reproductive dysfunction created by cisplatin administration. A total of 36 albino Wistar female adult rats were equally divided into 3 groups as cisplatin administered only (CIS), taxifolin+cisplatin (T+C) and healthy control group (HG). Taxifolin 50 mg/kg was administered orally by gavage in the T+C (n=12) group. In the HG (n=12) and CIS (n=12) groups, the same volume of distilled water as a solvent was orally administered. One hour after administration of taxifolin or distilled water, animals in the T+C and CIS groups were injected with cisplatin at a dose of 2.5 mg/kg intraperitoneally. This procedure was repeated once a day for 14 days. Six animals from each group were sacrificed on day 15, and their ovaries were removed for histopathological and biochemical analysis. Ovarian tissue malondialdehyde (MDA), total Glutathione (tGSH), Nuclear Factor-Kappa B (NF-kB), Tumor Necrosis Factor-α (TNF-α), Interleukin 1 beta (IL-1β), and Interleukin-6 (IL-6) levels were measured. The remaining animals (n=6 in each group) were kept in the laboratory with mature male rats for two months to breed. CIS administration led to an increase in inflammatory molecules and membrane lipid peroxidation products, and decreased the synthesis of antioxidant molecules. Compared to the CIS group, the ovarian tissue MDA, NF-kB, TNF-α, IL-1β and IL-6 levels were found to be significantly decreased in the T+C group (p<0.001 for all comparisons). On the other hand, the tGSH levels of the T+C group were significantly higher than the CIS group (p<0.001). Milder ovarian necrosis, fibrosis and follicle damage were detected in animals which were given taxifolin. Four out of the six rats (67%) treated with taxifolin gave birth within 27 days. We demonstrated, for the first time, that taxifolin ameliorates cisplatin-induced ovarian injury by decreasing MDA and proinflammatory cytokines and increasing the antioxidant enzyme. The fact that more than half of the animals receiving taxifolin became pregnant suggests that the cytoprotective effect of taxifolin is strong enough to preserve fertility.

Efeito protetor do kaempferol contra o dano ovariano agudo induzido pela cisplatina em um modelo murino

ABSTRACT The flavonoid kaempferol has attracted research attention as a potential adjuvant during chemotherapy. This study aimed to evaluate the protective effects of kaempferol against ovarian damage in cisplatin-treated mice. Two groups of mice received saline solution (intraperitoneal injection [i.p.]; control) or a single dose of cisplatin (5 mg/kg body weight, i.p.). Moreover, two other mice groups were pretreated with kaempferol (1 or 10 mg/kg body weight, i.p.) 30 min before of the cisplatin administration. Thereafter, their ovaries were harvested and subjected to histological (follicular morphology and activation) and fluorescence (reactive oxygen species [ROS] production, glutathione [GSH] concentration, and mitochondrial activity) analyses. Compared with cisplatin treatment alone, pretreatment with 1 mg/kg kaempferol maintained normal follicular morphology, reduced ROS production and mitochondrial damage, and enhanced GSH concentration. However, pretreatment with 10 mg/kg kaempferol did not prevent cisplatin-induced damage. The rate of primordial follicle activation was greater in mice pretreated with 1 mg/kg kaempferol than in the other treatment groups. In conclusion, pretreatment with 1 mg/kg kaempferol prevents cisplatin-induced ovarian damage and stimulates primordial follicle activation in mice.

Amburana cearensis leaf extract protects against cisplatin-induced ovarian damage through regulation of p-PTEN and p-Akt proteins in mice.

Objective(s):To evaluate the effects of Amburana cearensis leaf extract against cisplatin-induced ovarian toxicity in mice and involvement of p-PTEN and p-Akt proteins. Materials and Methods: A. cearensis ethanolic leaf extract was analyzed by high-performance liquid chromatography (HPLC). Mice were pretreated once daily for 3 days as follows: (1) the control group was pretreated with oral administration (o.p.) of saline solution, followed by intraperitoneal (IP) injection of saline solution. The other groups were pretreated (o.p.) with (2) saline solution (cisplatin group), (3) N-acetylcysteine (positive control), with (4) 50, or (5) 200 mg/kg body weight of A. cearensis extract, followed by injection of 5 mg/kg body weight (IP) of cisplatin. The ovaries were harvested and destined for histological (follicular morphology), immunohistochemistry (apoptosis and cell proliferation), and fluorescence (reactive oxygen species [ROS], glutathione concentrations [GSH], and active mitochondria) analyses. Furthermore, immunoexpression of p-PTEN and p-Akt was evaluated to elucidate a potential mechanism by which A. cearensis extract could prevent cisplatin-induced ovarian damage. Results:After HPLC analysis, protocatechuic acid was detected in the extract. The pretreatment with N-acetylcysteine or A. cearensis extract maintained the percentage of normal follicles and cell proliferation, reduced apoptosis and ROS concentrations, and increased GSH concentrations and mitochondrial activity compared with cisplatin treatment. Furthermore, pretreatment with A. cearensis extract regulated p-PTEN and p-Akt immunoexpression after cisplatin exposure. Conclusion:Pretreatment with A. cearensis extract prevented cisplatin-induced ovarian damage through its anti-oxidant actions and by modulating the expression of phosphorylated PTEN and Akt proteins.

Dose-dependent effects of ghrelin and aberrant anti-Mullerian hormone levels in the prevention of ovarian damage caused by cisplatin in Wistar-albino rats.

Ghrelin has previously been proven to have anti-inflammatory and antioxidant properties in preventing cisplatin-induced ovarian damage. The aim of this study was to evaluate the potential effects of this hormone in preventing this damage in rats using histopathological and biochemical methods. Twenty-eight Wistar-albino rats were randomly divided into four groups. While no drug was given to Group 1 (sham group), acylated ghrelin was intraperitoneally administered to Group 2 at 0.5nmol/kg and Group 3 at 2nmol/kg for 21days. Group 4 received only saline solution. On the 15th day, a single dose of 5mg/kg cisplatin was intraperitoneally administered to each rat in Groups 2, 3 and 4. Serum anti-Mullerian hormone (AMH) values were measured on days 0, 15 and 21. Then, laparotomy and bilateral oophorectomy were performed, and the ovaries were histopathologically examined. The number of primordial and primary follicles was significantly higher in Group 3 than in the saline solution + cisplatin group. In Group 4, cisplatin caused significantly higher follicle damage in the primordial, primary and secondary phases compared to the sham group. The AMH level of the SF + cisplatin group was significantly lower than that of the sham group and the high-dose ghrelin + cisplatin group, and the AMH level of the sham group was significantly higher than that of the low-dose ghrelin + cisplatin group. High-dose ghrelin was effective in preventing cisplatin-induced ovarian damage by preserving the number of primordial and primary follicles. Larger randomized studies are needed to determine the optimal dosage and duration of ghrelin.

Evaluation of protective effects of mirtazapine and mesna on cisplatin-induced ovarian damage in rats

To evaluate whether mirtazapine and mesna have protective effects on cisplatin-induced ovarian injury. A total of 32 female Wistar Albino rats were divided into 4 groups (8 rats per group) and included in the study. No medication was administered to the first group; only intervention was that their ovaries were removed and anti-mullerian hormone (AMH) values were measured. The second group received intramuscular cisplatin at a single dose of 7.5 mg/kg. The third group received a single dose of 200 mg/kg mesna intraperitoneally, and 30 minutes later, a single dose of 7.5 mg/kg intramuscular cisplatin was administered. The fourth group received oral 30 mg/kg mirtazapine, and 60 minutes later, a single dose of 7.5 mg/kg intramuscular cisplatin was administered. Oral 30 mg/kg mirtazapine was continued for ten days. Ovaries and AMH values of all groups were evaluated at the end of tenth day. In the cisplatin group when compared to normal ovarian tissue total histopathological damage score increased (p=0.037), preantral follicle count decreased (p=0.003) and AMH levels decreased (p&lt;0.001). In the cisplatin + mesna group total ovarian damage score was also increased (p=0.005), preantral and antral follicles decreased (p&lt;0.001 and p=0.001, respectively), and AMH levels decreased (p&lt;0.001). In the cisplatin + mirtazapine group, total ovarian damage score (p&lt;0.001), preantral follicle count (p=0.002) and AMH values were decreased (p&lt;0.001). It was concluded that mesna and mirtazapine were not effective in preventing ovarian damage due to cisplatin.

The effects of recombinant klotho in cisplatin-induced ovarian failure in mice.

To investigate whether recombinant klotho given concomitantly with cisplatin is effective in preventing cisplatin-induced ovarian damage. Thirty-two adult female mice were divided into four groups. Saline was given to the first group, cisplatin to the second group, recombinant mouse klotho to the third group, and recombinant mouse klotho + cisplatin to the fourth group. The removed ovarian tissues were examined and groups were compared histologically and immunohistochemical examination for antimullerian hormone (AMH), superoxide dismutase (SOD) and catalase expression were done. Glutathione peroxidase (GPx) and glutathione reductase (GR) activities were measured by ELISA. Ovarian tissue weight, primary and secondary follicle counts were higher in cisplatin + recombinant klotho group compared to cisplatin group in our study (respectively p < 0.0001, p < 0.0001, and p = 0.010). Injury scores (stromal congestion, edema and infiltration, follicular degeneration scores and edema in corpus luteum scores) were similar between cisplatin and cisplatin + recombinant klotho groups (all p > 0.05). AMH staining intensities were similar between cisplatin and cisplatin + recombinant klotho groups (p = 0.925). There was no difference between the groups in terms of SOD, GPx, and GR (p > 0.05). The recombinant klotho administered before cisplatin could partially protect the ovarian tissue from cisplatin-induced ovarian damage considering that there was no difference in histologic injury score parameters, AMH staining intensity and oxidative stress markers between cisplatin and cisplatin plus klotho groups except that klotho preserved follicules to some extent. The antioxidant mechanism of action of klotho may not be the primary protection mechanism in cisplatin induced ovarian injury.

Involvement of PTEN and FOXO3a Proteins in the Protective Activity of Protocatechuic Acid Against Cisplatin-Induced Ovarian Toxicity in Mice.

The present study evaluated the effects of protocatechuic acid (PCA) after cisplatin-induced ovarian toxicity in mice and if PTEN and FOXO3a proteins are involved in PCA action. The mice were divided into five experimental groups (five animals per group) and treated once a day for 3days as follows: (1) the control group was pretreated with oral administration (o.p.) of saline solution, followed by an intraperitoneal (i.p.) injection of saline solution. The other groups were pretreated (o.p.) with (2) saline solution (cisplatin group), (3) N-acetylcysteine (150mg/kg of body weight), or with (4) 20 or (5) 50mg/kg body weight of PCA, followed by 5mg/kg body weight (i.p.) of cisplatin. Next, the ovaries were destined to histological (morphology and activation), immunohistochemical (PCNA and cleaved caspase-3 expression), and fluorescence (reactive oxygen species [ROS], glutathione [GSH], and active mitochondria levels) analyses. Moreover, the immunoreactivity for p-PTEN and p-FOXO3a was evaluated to investigate a potential mechanism by which PCA could prevent the cisplatin-induced ovarian damage. Pretreatment with N-acetylcysteine or 20mg/kg PCA before cisplatin preserved the percentage of normal follicles and cell proliferation as observed in the control, reduced apoptosis and ROS levels, and showed higher active mitochondria and GSH levels than the cisplatin treatment (P < 0.05). Moreover, pretreatment with 20mg/kg PCA decreased cisplatin-induced p-PTEN and increased (P < 0.05) nuclear export of p-FOXO3a. In conclusion, PCA at 20mg/kg reduced apoptosis, maintained cell proliferation and mitochondrial function, reduced ROS production, and increased GSH expression likely through the involvement of PTEN and FOXO3a proteins.

Melatonin provides protection against cisplatin-induced ovarian damage and loss of fertility in mice

Research questionCan melatonin provide non-invasive ovarian protection against damage caused by cis-diamminedichloroplatinum (cisplatin) and preserve fertility in female cancer patients? And if so, what is the possible mechanism? DesignAthymic BALB/c nude tumour-bearing female mice were used to demonstrate whether melatonin affects the antineoplastic effect when co-administrated with cisplatin. Sexually mature and newborn C57BL/6 female mice were used to evaluate the potential effects of melatonin on the ovarian follicle pool, pregnancy rate and litter number in cisplatin-treated mice. The ovaries underwent immunohistochemical, TdT (terminal deoxynucleotidyl transferase)-mediated dUTP nick-end labelling (TUNEL) and gene array analysis to explore the underlying mechanism. In addition, granulosa cells were isolated to investigate the potential protective mechanism of melatonin. ResultsMelatonin not only enhanced the anti-cancer effect of cisplatin in tumour-bearing nude mice, but also reduced ovarian toxicity and preserved long-term fertility in cisplatin-treated C57BL/6 female mice. When co-administrated, melatonin was able to reduce the DNA damage and toxic effects on lipid peroxidation in the ovaries caused by cisplatin. Specifically, melatonin was able to largely restore lipid peroxidation in granulosa cells and thus prevent ovarian follicles from being depleted. ConclusionsMelatonin has the potential to be used as a chemotherapeutic adjuvant to simultaneously improve the outcome of anti-cancer treatment and preserve ovarian function during cisplatin chemotherapy. Notably, its properties of DNA protection and antioxidant effects on follicles may benefit female cancer survivors and prevent premature ovarian failure as well as fertility loss caused by chemotherapy.

Rutin prevents cisplatin-induced ovarian damage via antioxidant activity and regulation of PTEN and FOXO3a phosphorylation in mouse model

The aims of the present study were to evaluate the protective effects of rutin during cisplatin-induced ovarian toxicity in mice and to verify the possible involvement of the phosphatase and tension homolog (PTEN)/Forkhead box O3a (FOXO3a) pathway in the rutin actions. Mice received saline solution (control, 0.15 M, i.p.) or cisplatin (5 mg/Kg body weight, i.p.) or they were pretreated with N-acetylcysteine (positive control; 150 mg/Kg of body weight [p.o.]) or with rutin (10, 30 or 50 mg/Kg body weight, p.o.) before cisplatin (5 mg/Kg body weight, i.p.) once daily for 3 days. Next, the ovaries were harvested and destined to histological (follicular morphology and activation), immunohistochemical (cell proliferation and apoptosis) and fluorescence (reactive oxygen species [ROS], glutathione [GSH] and mitochondrial activity) analyses. Moreover, the expression of phosphorylated PTEN (p-PTEN) and FOXO3a (p-FOXO3a) were evaluated to investigate a molecular mechanism by which rutin would prevent the cisplatin-induced ovarian damage. The results showed that pretreatment with N-acetylcysteine or 10 mg/Kg rutin before cisplatin preserved the percentage of normal follicles and cell proliferation, reduced apoptosis and ROS levels and increased active mitochondria and GSH levels compared to the cisplatin treatment (P < 0.05). Cisplatin treatment increased p-PTEN and decreased p-FOXO3a expression in follicles, which was prevented by 10 mg/kg rutin. In conclusion, treatment with 10 mg/Kg rutin has the potential to protect the ovarian follicles against cisplatin-induced toxicity through its antioxidant effects and PTEN/FOXO3a pathway.

Protective Effects of Imatinib and Ginkgo Biloba on Cisplatin-induced Ovarian Damage in Rats

Protective Effects of Imatinib and Ginkgo Biloba on Cisplatin-induced Ovarian Damage in Rats

Investigation of the preventive effects of dehydroepiandrosterone (DHEA) and Caffeic acid phenethyl ester (CAPE) on cisplatin-induced ovarian damage in rats

ABSTRACT To investigate whether Dehydroepiandrosterone (DHEA) and Caffeic acid phenethyl ester (CAPE) had any preventive effect against the ovarian damage caused by cisplatin (CP) (cis-diamminedichloroplatinum) in rats. On the first day ovaries were removed, Anti-Müllerian hormone (AMH) was measured (Group1, n:6), in the other groups 7.5 mg/kg cisplatin was administered intraperitoneally. In Group 2 (n = 6), 0.1 ml saline, in Group 3 (n = 5), 20 umol/kg CAPE, in Group 4 (n = 7), DHEA 6 mg/kg were administered every day. On the 10th day, ovaries were removed, AMH was measured. Ovary reserve (primordial/primary/secondary/tertiary/atretic follicles, AMH), ovarian damage scores (follicular degeneration, congestion, hemorrhage, edema, inflammation) were compared. The number of tertiary follicles were statistically high in the CAPE group (p = .015), the inflammation score in the DHEA group (p = .012), AMH level (p = .009) in the control group. The lowest number of atretic follicles (AF) was in the control group, while the highest number of AF was in the DHEA group (p = .002). Significant decreases in AF were the case in the cisplatin and DHEA groups compared to the control group (p < .008). The AMH values had the highest positive correlation with the number of primordial follicles and the highest negative correlation with the number of AF. The cut off point for AMH was 1.57 ng/ml as an indicator of low ovarian reserve. Cisplatin causes total damage and increased numbers of AF on the ovary. Depending on this, AMH levels fall. These negative effects of cisplatin are not obstructed by CAPE or DHEA, and may even be increased by DHEA.

Mechanistic perspective of protective effects of resveratrol against cisplatin-induced ovarian injury in rats: emphasis on anti-inflammatory and anti-apoptotic effects.

Chemotherapeutic platinum-containing drugs are widely used to treat a variety of cancer types; however, they cause ovarian failure and infertility. The aim of this study is to investigate the molecular mechanism underlying the potential protective effect of resveratrol against cisplatin-induced ovarian damage in a rat model. Female rats were given either cisplatin (6mg/kg, i.p., once per week for two consecutive weeks) and/or resveratrol (10mg/kg, orally for 17days). Follicular development, ovarian function markers, as well as apoptotic and inflammatory markers were assessed 24h after the last resveratrol dose. Resveratrol ameliorated the marked follicular loss and the significant reduction in anti-Müllerian hormone (AMH) level triggered by cisplatin. Mechanistically, cisplatin elicited a potent inflammatory response in ovarian tissue as evidenced by the elevated expression of tumor necrosis factor, nuclear factor kappa-B, and proinflammatory enzymes. Co-treatment with resveratrol inhibited the elevation in inflammatory mediators induced by cisplatin. Further, cisplatin switched on the apoptotic machinery in ovarian tissues via increasing the expression of both cytochrome c and caspase-3 which was reversed upon resveratrol co-treatment. Resveratrol also counteracts the upregulating poly(ADP-ribose) polymerase expression which could attribute to the inflammatory and apoptotic effects of cisplatin. Resveratrol protects the ovary from cisplatin-induced toxicity through preventing the loss of the AMH-secreting granulosa cells, diminishing PARP-1 expression, and downregulating the inflammatory and apoptotic events implicated in cisplatin toxicity.

Alleviation of endoplasmic reticulum stress protects against cisplatin-induced ovarian damage

BackgroundCisplatin (CDDP), a widely used chemotherapeutic agent, can induce excessive granulosa cell apoptosis, follicle loss and even premature ovarian insufficiency (POI). However, the mechanism remains elusive, although some studies have indicated the involvement of endoplasmic reticulum stress (ERS). The aim of our study was to investigate the possible mechanism ERS in CDDP-induced granulosa cell apoptosis and follicle loss.MethodsA POI mouse model was generated by CDDP. The ovaries samples were collected and processed for isobaric tags for relative and absolute quantification analysis (iTRAQ) to screen out our interested proteins of HSPA5 and HSP90AB1, and the decline in their expression were verified by a real-time quantitative PCR and a western blotting assay. In vitro, human granulosa cells, KGN and COV434 cells were transfected with siRNA targeting HSPA5 and HSP90AB1 and then treated with CDDP, or treated with CDDP with/without CDDP+ 4-phenylbutyric acid (4-PBA) and 3-methyladenine (3-MA). The levels of ERS, autophagy and apoptosis were evaluated by western blotting, DALGreen staining and flow cytometry. In vivo, ovaries from mice that received intraperitoneal injections of saline, CDDP, CDDP+ 4-PBA and CDDP+ 3-MA were assayed by immunofluorescence, hematoxylin and eosin (H&E) staining for follicle counting, and terminal-deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining for cell apoptosis assay. The plasma hormone levels were measured by an enzyme-linked immunosorbent assay (ELISA) kit.ResultsWe have clarified the relationships between ERS, autophagy, and apoptosis in CDDP-induced granulosa cell apoptosis, both in vitro and in vivo. Alleviating ERS by inhibiting HSPA5 and HSP90AB1 attenuated CDDP-induced autophagy and apoptosis. 4-PBA treatment significantly attenuated CDDP-induced cell autophagy and apoptosis in cultured KGN and COV434 cells. However, inhibiting cell autophagy with 3-MA negligibly restored the CDDP-induced changes in ERS and apoptosis. In vivo experiments also demonstrated that treatment with 4-PBA, but not 3-MA, prevented CDDP-induced ovarian damage and hormone dysregulation.ConclusionsCDDP-induced ERS could promote autophagy and apoptosis in granulosa cells, causing excessive follicle loss and endocrine disorders. Alleviation of ERS with 4-PBA, but not of autophagy with 3-MA, protect against CDDP-induced granulosa cell apoptosis and ovarian damage. Thus, 4-PBA can be used to protect the ovary during chemotherapy in women.

Can ebselen prevent cisplatin-induced ovarian damage?

The occurrence of ovarian damage is a major shortcoming in treating tumors with cisplatin (CP). The present study investigates the beneficial effects of ebselen-a seleno-organic compound with antioxidant and antiinflammatory properties-vis-à-vis CP-induced ovarian damage. Twenty-eight adult female rats were divided into four study groups. Group 1 received no treatment. The rats in Groups 2, 3, and 4 were intraperitoneally administered CP (2mg/kg/day) twice per week, for 5weeks. Those in Group 2 received 0.3ml saline (0.9% NaCl) intraperitoneally 60min before each CP treatment, while those in Group 3 received 0.2ml dimethyl sulfoxide (DMSO) and 0.3ml saline intraperitoneally 60min before each CP treatment. The rats in Group 4 were pretreated with an intraperitoneal injection of 15mg/kg/day ebselen 60min before each CP treatment. Ovarian tissue malondialdehyde (MDA), total nitric oxide (NOx), glutathione (GSH), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), and catalase levels, as well as histopathological damage scores (HDSs) and serum antimullerian hormone (AMH) levels, were assessed. Cu/Zn-SOD and GSH levels were significantly higher, and MDA and NOx levels significantly lower, in Group 4 than in Groups 2 and 3. Pretreatment with ebselen significantly improved serum AMH levels, relative to Groups 2 and 3. Additionally, HDS values were significantly lower in Group 4 than in Groups 2 and 3. Our results from using an experimental rat model of CP chemotherapy suggest that ebselen use may ameliorate ovarian damage by preventing oxidative injury.

Dose dependent effect of resveratrol in preventing cisplatin-induced ovarian damage in rats: An experimental study

This study aimed to evaluate the effect of resveratrol in preventing cisplatin (CP) induced ovarian damage in rats. Twenty-eight female Wistar albino rats were separated into four groups. No medication was given to group 1. Over the 21-day study period, low-dose resveratrol was given to group 2, high-dose resveratrol was given to group 3, and saline was administered to group 4. On the 15th day of medication, all groups except for group 1 were treated with a single dose of CP. Serum levels of anti-Mullerian hormone (AMH) were tested at baseline and on the 15th and 21st days. All rats underwent oophorectomy one week after CP application. Primordial, primary, secondary, and tertiary follicles were counted microscopically. No significant difference was observed among the groups in mean AMH levels according to follow-up time. The numbers of primary and primordial follicles were statistically significantly higher in group 2 than in group 4 (p<0.05). The number of tertiary follicles was statistically significantly higher in group 1 than in groups 3 and 4 (p<0.05), but it was not statistically significantly different than in group 2. Resveratrol, particularly at low-doses, can prevent CP induced ovarian damage by maintaining the numbers of primordial and primary follicles. Further studies are needed to study the effect of resveratrol on human ovaries.

Melatonin protects against cisplatin-induced ovarian damage in mice via the MT1 receptor and antioxidant activity.

This study evaluated the receptor- and/or antioxidant stress-mediated mechanisms by which melatonin prevents the ovarian toxicity of cisplatin treatment. The expression of the MT1 receptor in mouse ovaries was investigated by immunohistochemistry. Pretreatment with melatonin (5, 10, or 20 mg/kg body weight, i.p.) before cisplatin (5 mg/kg body weight, i.p.) was administered to mice once daily for 3 days (phase I). The pharmacological modulation via melatonin type 1 and/or 2 receptors was analyzed by administration of receptor antagonists (luzindole: nonselective MT1/MT2 antagonist; 5 mg/kg body weight or 4-phenyl-2-propionamidotetralin: selective MT2 antagonist; 4 mg/kg body weight) once daily for 3 days, 15 min before the treatment with melatonin and cisplatin (phase II). Thereafter, the ovaries were harvested and used for histological (morphology and activation), immunohistochemical (PCNA, activated caspase-3 and bcl-2 expression), terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and fluorescence (reactive oxygen species [ROS], glutathione [GSH], and active mitochondria levels) analyses. The expression of the MT1 protein in mouse ovaries was documented. Pretreatment with 20 mg/kg melatonin before cisplatin administration preserved the normal follicular morphology and cell proliferation rate, reduced apoptosis, ROS production, mitochondrial damage and increased GSH expression, as compared to the cisplatin treatment alone. Additionally, administration of the nonselective MT1/MT2 receptor antagonist inhibited the melatonin ovarian protection from the cytotoxic effects of cisplatin. However, administration of a selective MT2 antagonist did not modify the protective effects observed at 20 mg/kg melatonin. In conclusion, pretreatment with 20 mg/kg melatonin effectively protected the ovaries against cisplatin-induced damage. Moreover, the MT1 receptor and melatonin antioxidant effects mediated this cytoprotective activity.

Protective effects of sildenafil citrate administration on cisplatin-induced ovarian damage in rats

The aim of this study is to evaluate the effects of sildenafil citrate on cisplatin-induced ovarian toxicity. Thirty-two female rats were divided into four groups. Group 1: saline control; group 2: cisplatin; group 3: sildenafil citrate; and group 4: cisplatin plus sildenafil citrate group. In groups 2 and 4, the rats were injected with 5 mg/kg cisplatin intraperitoneally (i.p.). In groups 3 and 4, the rats were injected with 1.4 mg/kg sildenafil citrate i.p. The ovaries were removed two weeks later in all groups. Histopathologic examination, follicle counting and classification were performed. The expression of anti-Müllerian hormone (AMH) was detected immunohistochemically in the ovarian tissues. Sildenafil alleviated cisplatin-induced histopathological changes in the ovarian tissue. Primordial, secondary and tertiary follicles were diminished in group 2 compared with group 1 (p < 0.05). Pretreatment with sildenafil citrate preserved primordial follicle count in group 4 compared with group 2, and the difference was statistically significant (p < 0.05). According to our results, immunoreactivity intensity of AMH was lower in group 2 compared with group 1 (92.4 ± 3.97 versus 88.8 ± 1.77) but not significantly, whereas immunoreactivity intensity of AMH was higher in group 4 compared with group 2 (88.8 ± 1.77 versus 94.1 ± 2.36; p < 0.05). Our results demonstrated that pretreatment with sildenafil citrate is beneficial for protecting the ovaries from cisplatin-induced damage. Sildenafil citrate can be a choice for fertility preservation.