Cisplatin-induced Testicular Damage Research Articles

Thymoquinone effects on autophagy, apoptosis, and oxidative stress in cisplatin-induced testicular damage in mice.

In this study, the effect of thymoquinone (TQ) on CP-induced spermatogenesis defects in mice has been investigated. Sperm parameters, serum testosterone concentration, histology, Bax/Bcl-2 ratio, and expression of autophagy-related biomarkers have been assessed. Total antioxidant capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI) in testicular tissue were examined for the evaluation of oxidative stress levels. CPhas induced histological changes and significantlyincreased the Bax/Bcl-2 ratio, decreased testosterone concentration, testicular weight, and sperm quality. CP induced oxidative stress by elevating OSIin the testicular tissue(p < 0.05).Expression of theautophagy-inducer genes (ATG7, ATG5, and Beclin-1) andratio ofLC3B/LC3Aproteinswere significantly decreased, while mTOR expression was increased in the CP group.TQ pretreatment dose-dependently decreased the Bax/Bcl-2 ratio and mTOR gene expression while increasing the expression of ATG5 and ATG7 genes, LC3B/LC3A ratio, and Beclin-1 proteins.TQ could also dose-dependently reverse the histology, testosterone level, and sperm quality of the CP-intoxicated mice. These findings show that TQ pretreatment can enhance sperm production by inducing autophagy and reducing apoptosis and oxidative stress in the CP-intoxicated mouse testicles.

Protective effect of dental pulp stem cells' conditioned medium against cisplatin-induced testicular damage in rats

Cisplatin is a highly effective chemotherapy drug used to treat most solid tumors. However, one of its side effects is testicular toxicity, which can lead to fertility abnormalities. This study investigated the effectiveness of dental pulp mesenchymal stem cells conditioned medium (DPSC-CM) on cisplatin-induced testicular toxicity. In this study, 36 eight-week-old male Wistar rats were randomly divided into three groups equally (n = 12). Group 1 control "CTR", which received normal saline (0.5 ml) intraperitoneally (i.p), group 2 "Cis" which received an intraperitoneal dose of cisplatin (7 mg/kg), and group 3 "Cis+CM" which received an i.p injection of DPSC-CM (0.5 mg/kg) after cisplatin injection. Biochemical, histomorphometric, and histopathological studies were performed on the testis. Our results exhibited that cis administration led to a decline in total body weight, testis weight, diameter, and volume. A decrease in testosterone and IL-6 serum levels, as well as a decrease in IL-6 and TNFα levels, the activity of catalase and SOD enzymes, and an increase in MDA in testicular tissue were detected. Testicular tissue damage was associated with a significant decrease in tube diameter, germinal epithelium height, number of spermatogonia and Sertoli cells, along with a noticeable increase in basement membrane thickness, and perivascular fibrosis. DMSC-CM improved all the mentioned parameters. Taken together, our results demonstrated that DMSC-CM due to its antioxidant and anti-inflammatory properties, could be effective in reversing cisplatin-induced testicular toxicity.

Mechanistic Protective Effect of Cilostazol in Cisplatin-Induced Testicular Damage via Regulation of Oxidative Stress and TNF-α/NF-κB/Caspase-3 Pathways.

Despite being a potent anticancer drug, cisplatin has limited applicability due to its adverse effects, such as testicular damage. Consequently, reducing its toxicity becomes necessary. In this study, a selective phosphodiesterase-3 inhibitor, cilostazol, which is used to treat intermittent claudication, was examined for its ability to abrogate cisplatin-induced testicular toxicity. Its ameliorative effect was compared to that of two phosphodiesterase inhibitors, tadalafil and pentoxifylline. The study also focused on the possible mechanisms involved in the proposed protective effect. Cisplatin-treated rats showed a significant decrease in sperm number and motility, serum testosterone, and testicular glutathione levels, as well as a significant elevation in malondialdehyde, total nitrite levels, and the protein expression of tumor necrosis factor-alpha, nuclear factor-kappa β, and caspase-3. These outcomes were confirmed by marked testicular architecture deterioration. Contrary to this, cilostazol, in a dose-dependent manner, showed potential protection against testicular toxicity, reversed the disrupted testicular function, and improved histological alterations through rebalancing of oxidative stress, inflammation, and apoptosis. In addition, cilostazol exerted a more pronounced protective effect in comparison to tadalafil and pentoxifylline. In conclusion, cilostazol ameliorates cisplatin-induced testicular impairment through alteration of oxidative stress, inflammation, and apoptotic pathways, offering a promising treatment for cisplatin-induced testicular damage.

Antioxidant Nanoparticles Restore Cisplatin-Induced Male Fertility Defects by Promoting MDC1-53bp1-Associated Non-Homologous DNA Repair Mechanism and Sperm Intracellular Calcium Influx.

Cisplatin, a commonly used anticancer compound, exhibits severe off-target organ toxicity. Due to its wide application in cancer treatment, the reduction of its damage to normal tissue is an imminent clinical need. Cisplatin-induced testicular oxidative stress and damage lead to male sub- or infertility. Despite earlier studies showing that the natural polyphenol extracts honokiol serve as the free radical scavenger that reduces the accumulation of intracellular free radicals, whether honokiol exhibits direct effects on the testis and sperm is unclear. Thus, the aim of the current study is to investigate the direct effects of honokiol on testicular recovery and sperm physiology. We encapsulated this polyphenol antioxidation compound into liposome-based nanoparticles (nHNK) and gave intraperitoneally to mice at a dosage of 5 mg/kg body mass every other day for consecutive 6 weeks. We showed that nHNK promotes MDC1-53bp1-associated non-homologous DNA double-strand break repair signaling pathway that minimizes cisplatin-induced DNA damage. This positive effect restores spermatogenesis and allows the restructuring of the multi-spermatogenic layers in the testis. By reducing mitochondrial oxidative damage, nHNK also protects sperm mitochondrial structure and maintains both testicular and sperm ATP production. By a yet-to-identify mechanism, nHNK restores sperm calcium influx at the sperm midpiece and tail, which is essential for sperm hypermotility and their interaction with the oocyte. Taken together, the nanoparticulated antioxidant counteracts cisplatin-induced male fertility defects and benefits patients undertaking cisplatin-based chemotherapy. These data may allow the reintroduction of cisplatin for systemic applications in patients at clinics with reduced testicular toxicity.

Creatine Chemical Exchange Saturation Transfer (Cr-CEST) Imaging Can Evaluate Cisplatin-induced Testicular Damage.

This study aimed to investigate the ability of creatine-chemical exchange saturation transfer (Cr-CEST) technique assessed through 7-T MRI to evaluate cisplatin-induced testicular damage. We used 8-10 weeks C57BL/6 mice (n = 10) that were divided into a control group (n = 5) and a cisplatin-treated group (n = 5). The cisplatin group received cisplatin at a dose of 15 mg/kg, via intraperitoneal injection, while the control group received saline. MR images of mouse testes were acquired under anesthesia 18 days after the injection using a horizontal 7-T scanner. The pulse sequence consisted of rapid acquisition with a relaxation enhancement (RARE) with magnetization transfer. The Z-spectra were collected using a 2000-ms saturation pulse at a B1 amplitude of 1.2 μT, with frequencies varying from -4.8 to +4.8 parts per million (ppm). Maps of magnetization transfer ratio with asymmetric analysis (MTRasym) were reconstructed at a Cr metabolite concentration of 1.8 ppm. The Cr-CEST effect was significantly reduced in the cisplatin-treated group compared to the control group (MTRasym of control mice vs. cisplatin-treated mice: 6.9 [6-7.5] vs. 5.2 [4-5.5], P = 0.008). Correlation analysis revealed a strong correlation between the Cr-CEST effect and the pathological score (ρ = 0.93, P < 0.001). Cr-CEST MRI can be useful for the evaluation of cisplatin-induced testicular damage in mice.

Protective effects of rivaroxaban against cisplatin-induced testicular damage in rats: Impact on oxidative stress, coagulation, and p-NF-κB/VCAM-1 signaling.

Coagulation is a main pathway in various diseases pathogenesis including testicular damage. This study evaluated rivaroxaban (RVX) protective effects in testicular impairment by cisplatin (CP). Rats were randomly allocated into five groups: Control, RVX (7mg/kg/day), CP (10mg/kg), RVX 5mg+CP and RVX 7mg+CP. Serum testosterone and testicular ALT, AST, and ALP were assessed. Testicular oxidative stress and antioxidant parameters and inflammatory indicators including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were assessed. qRT-PCR was used to determine mRNA expression of 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD), and steroidogenic acute regulatory protein (stAR). Protein expressions of p-Nuclear factor kappa B (p- NF-κB) and vascular cell adhesion protein-1 (VCAM-1) were analyzed by Western blot analysis. Tissue factor (TF) expression was immunohistochemically analyzed. Results revealed that RVX significantly increased serum testosterone and sperm count while significantly reduced IL-1β and TNF-α. It significantly decreased tissue MDA and NO contents while increased SOD and GPx. In addition, RVX attenuated CP-induced histopathological aberrations and normalized TF. It also decreased the VCAM-1 and p-NF-κB expression and showed strong expression of 3β-HSD, 17β-HSD, and stAR, indicating improvement of steroidogenesis. In conclusion, RVX counteracted testicular damage by CP via suppressing oxidative stress, inflammation, and coagulation and downregulating p-NF-κB/VCAM-1 signaling.

EFFECTS OF ETHANOLIC LEAF EXTRACT OF NEWBOULDIA LAEVIS (P. BEAUV) ON CISPLATIN-INDUCED CHANGES ON TESTICULAR AND BLOOD PARAMETERS OF WISTAR RATS

Thirty-five Wistar rats weighing 200 - 250 mg were categorized into five treatment groups- the control, saline, cisplatin, pre-cisplatin and the post-cisplatin groups, each comprising of seven rats per group, to assess the effects of ethanolic leaf extract of Newbouldia laevis on cisplatin-induced testicular damage in Wistar rats. The control group received feed mash and water ad libitum, the saline group received equal volumes of physiological saline intraperitoneally with normal feeds and water. The pre-cisplatin group was treated with 100mg/kg body weight of ethanolic leaf extract of Newbouldia laevis for twelve weeks before being treated with 8mg/kg of cisplatin intraperitoneally for five days. Sacrifice was done after another twelve weeks. Cisplatin group received 8 mg/kg body weight of cisplastin for five days without any extract treatment, but had normal feeds and water for twelve weeks before sacrifice. The post-cisplatin group had 8mg/kg body weight of cisplatin for five days before being treated with 100mg/kg of ethanolic leaf extract of Newbouldia laevis for twelve weeks before sacrifice. The extract group received only the 100mg/kg of ethanolic leaf extract of Newbouldia laevis for twelve weeks without any other treatment before sacrifice. The effects of these treatments on body weight, testicular and epididymal weight, testicular volume, total and motile sperm count, sperm motility, percentage live:dead sperm, hormonal and haematological parameters as well effects on testicular and epididymal cytoarchitecture of the Wistar rats were assessed.There were significant (p&lt;0.05) changes in body weight, testicular and epididymal weight, testicular volume, sperm, hormonal and haematological parameters in the treatments, compared to control. The pre-cisplatin treatment group showed significant (p&lt;0.05) improvement in the induced changes caused by cisplatin, compared to the post-cisplatin group. The findings of this investigation confirms the protective effects of ethanolic leaf extract of Newbouldia laevis on cisplatin-induced gonadotoxicity in male Wistar rats.

MORPHOLOGICAL EVALUATION OF CISPLATIN-INDUCED TESTICULAR DAMAGE IN WISTAR RATS

Twenty-one Wistar rats weighing 200 - 250 mg were categorized into three treatment groups- the control, saline and the cisplatin groups, each comprising of seven rats per group, to assess the effects of cisplatin-induced testicular damage in Wistar rats. The control group received feed mash and water ad libitum, the saline group received equal volumes of physiological saline intraperitoneally with normal feeds and water, while the cisplastin group received 8 mg/kg body weight of cisplastin only for five days and had normal feeds and water for twelve weeks before sacrifice. The effects of these treatments on total sperm count, sperm motility, percentage live:dead sperm and on testicular and epididymal morphology of the Wistar rats were assessed. The results revealed total sperm count in the cisplatin group as significantly different from control (p&lt;0.001), and the motile sperm count in the cisplatin group was also significantly different from control (p&lt;0.001). Also, there was a greater percentage of dead sperm and more morphologically abnormal forms in the cisplatin group, compared to control. The testicular and epididymal sections of the saline treatment showed normal progression of the spermatogenic germ cell series and normal testicular interstitium. The sections of the testes from the cisplatin group had seminiferous tubules with atrophic changes, detached basement membrane from the seminiferous epithelium, inflammed interstitium with oedema, paucity of Leydig cells, vascular congestion and haemorrhage. The epididymis showed lumen with empty or scanty spermatozoa, necrosis and haemorrhage. These findings affirms the reality of severe gonadotoxicity associated with use of cisplatin as chemotherapeutic agent, especially in the male.

Tranilast abrogates cisplatin-induced testicular and epididymal injuries: An insight into its modulatory impact on apoptosis/proliferation.

Cisplatin is a chemotherapeutic agent whose therapeutic use is greatly limited by the associated organs' toxicity and particularly, testicular toxicity. Cisplatin-induced testicular damage reported being mediated through mitochondria-mediated apoptosis, inflammation, and oxidative stress. Evidence showed that tranilast (TRN) has the ability to restore the oxidative status and modulate TRAIL/caspase-8 signaling. This led us to hypothesize that TRN could abrogate cisplatin-induced testicular and epididymal injuries via inhibiting oxidative stress and modulating proliferation and TRAIL/caspase-8/cJNK signaling. Cisplatin injection induced oligospermia and abnormalities in testicular and epididymal structure along with impaired oxidative status. TRN administration (100 or 300 mg/kg) for 7 days post-cisplatin injection preserved spermatogenesis and restored testicular and epididymal architecture, but restoration was more so in TRN300 than TRN100. This was in line with the restoration of balanced oxidative status as indicated by the increased total antioxidant capacity, glutathione and superoxide dismutase activity, and the decreased malondialdehyde content in testes (p < 0.05 vs. cisplatin). TRN increased the cell proliferation revealed by the increased expression of proliferating cell nuclear antigen in a dose-dependent manner (p < 0.05 vs. cisplatin) whereas only TRN300 decreased testicular cJNK, TRAIL, and caspase-8 expression (p < 0.05 vs. cisplatin). Moreover, TRN dose-dependently inhibited the pro-inflammatory transcription factor NF-kB and the cytokine TNF-α expressions in testes. In conclusion, TRN300 was more effective than TRN100 in alleviating cisplatin-induced testicular and epididymal injuries and in enhancing spermatogenesis. This curative effect of TRN might be mediated through its antioxidant and anti-inflammatory impacts along with its modulatory impact on cJNK/TRAIL/caspase-8 signaling favoring proliferation rather than apoptosis.

Trans-ferulic acid ameliorates cisplatin-induced testicular damage via suppression of TLR4, P38-MAPK, and ERK1/2 signaling pathways.

Testicular damage has been described as a common side effect of cisplatin (CDDP), which limits its clinical uses. Since oxidative injury and inflammatory response are the most pathological impact, estimation of natural antioxidant and anti-inflammatory agents like trans-ferulic acid (TFA) could protect against CDDP-induced testicular damage. In the current investigation, rats were assigned into four groups: normal, TFA (50 mg/kg/day, P.O), CDDP (10 mg/kg) as single intraperitoneal (I.P) injection at the end of the 5th day, and TFA+CDDP where TFA was administered 5 days before CDDP injection and 5 days after. Interestingly, TFA significantly restored testosterone levels and abrogated oxidative stress injury. Additionally, TFA effectively suppressed inflammatory cytokines. It also counteracted the inflammation via downregulation of TLR4 and IRF3, P38-MAPK, NF-κB-p65, JAK1, STAT3, ERK1, and ERK2. Besides, TFA can modulate AKT and p-AKT protein expressions. In parallel, TFA mitigated the histopathological aberration of the testis and prevented spermatogenesis disruption. On the other hand, TFA augmented the in vitro CDDP cytotoxicity on Caco-2 and MCF-7 cells. Interestingly, TFA enhanced the cytotoxic effect of CDDP via apoptosis induction in both the early and late stages of apoptosis. Collectively, TFA exhibited a potential protective effect against CDDP-induced testicular injury by inhibiting oxidative stress as well as TLR4/IRF3/INF-γ, P38-MAPK/NF-κB-p65/TNF-α, and JAK1/STAT-3/ERK1/2 inflammatory signaling pathways with enhancing its in vitro cytotoxic activity.

Protective Effect of Aloe vera Gel against Cisplatin-Induced Testicular Damage, Sperm Alteration and Oxidative stress in Rats.

Background:Cisplatin (CIS) is an effective antineoplastic drug that is used to treat various types of cancers. However, it causes side effects on the male reproductive system. The present study aimed to investigate the possible protective effects of Aloe vera (AL) gel (known as an antioxidant plant) on CIS-induced changes in rat sperm parameters, testicular structure, and oxidative stress markers.Materials and Methods: In this experimental study, forty-eight adult male rats were divided into 6 groups including: control, CIS, AL, metformin (MET), CIS+AL, and CIS+MET. CIS was used intraperitoneally at a dose of 5 mg/kg on days 7, 14, 21, and 28 of the experiment. AL gel (400 mg/kg per day) and MET (200 mg/kg per day) were administered orally for 35 days (started one week before the beginning of the experiment). Testes weight and dimensions, and morphometrical and histological alterations, activities of antioxidant enzymes including superoxide dismutase (SOD) and glutathione peroxidase (GPx), serum testosterone concentration, lipid peroxidation level, and sperm parameters were examined.Results: CIS caused a significant decrease (P<0.05) in relative weight and dimension of the testis, germinal epithelium thickness and diameter of seminiferous tubules, the numbers of testicular cells, and spermatogenesis indexes. The malondialdehyde (MDA) levels increased and antioxidant enzymes activities decreased in the CIS group compared to the control group (P<0.05). Additionally, sperm parameters (concentration, viability, motility, and normal morphology), and testosterone levels reduced significantly in CIS-treated rats (P<0.05). Also, CIS induced histopathological damages including disorganization, desquamation, atrophy, and vacuolation in the testis. However, administration of AL gel to CIS-treated rats attenuated the CIS-induced alterations, mitigated testicular oxidative stress and increased testosterone concentration.Conclusion:The results suggest that AL as a potential antioxidant plant and due to free radicals scavenging activities, has a protective effect against CIS-induced testicular alterations.

Oral supplementation of fucoxanthin-rich brown algae extract ameliorates cisplatin-induced testicular damage in hamsters

Oxidative stress is recognized as a common pathology that affects up to half of all men infertile. Fucoxanthin possesses antioxidant activity, and several investigators have reported anti-inflammatory action. This study extracted powder of Sargassum glaucescens by acetone to obtained fucoxanthin rich-brown algae extract (FXE). The objective of this study was to evaluate the ameliorative effects of fucoxanthin extract from Sargassum glaucescens on lipopolysaccharide-induced inflammation in RAW264.7 macrophage cells and its protective effects of against Cisplatin (CP)-induced reproductive damage in hamsters. Eighty male Syrian hamsters were injected with and without CP, then daily oral gavage with various concentrations of fucoxanthin for 5 days. Treatment with FXE reduced the level of reactive oxygen species and malondialdehyde in RAW 264.7 cells and the rats’ testis as well as protective effects on mitochondrial membrane potential. The FXE administration also improved testosterone level and alpha-glucosidase activity. The sperm count also increased after treated with FXE, whereas sperm abnormality was reduced. Histopathological analysis showed that FXE successfully improved the seminiferous tubules morphology. According to these findings, fucoxanthin extract from Sargassum glaucescens can be used as an alternative for the treatment of testicular damage.

Modulating Effect of Gum Arabic on Cisplatin-induced Testicular Damage in Albino Wister Rats

The current study has been designed to evaluate the impact of cisplatin on the spermatogenesis, histopathological pictures, DNA damage, and oxidative stress parameters in the testicular tissues for a long period of time. Additionally, we clarify the conservative effect of gum arabic against all of the above toxicological parameters. Twenty male Wister rats were used and divided into four equal groups (n = 5). Group 1 was used as a control negative group. Group 2 was received gum arabic (7.5 mg/kg bwt) daily in drinking water. Group 3 was administered with a single i.p. dose of cisplatin (7 mg/kg bwt). Group 4 was received both cisplatin and gum arabic. Body and testis weights, epididymal sperm analysis, blood testosterone level, testis oxidative stress markers, histopathological pictures, and immunohistochemical staining of the testicular tissues were done. Our results showed that the cisplatin administration led to a significant reduction in the body and testis weights, sperm count, sperm motility, blood testosterone level, and testicular antioxidants. Additionally, it led to a significant elevation of sperm apoptosis, testicular malondialdehyde levels, DNA damage, histopathological alteration, and caspase-3 immunostaining reactions. On the other hand, pretreatment of rats with gum arabic was improved all of the previous parameters. From our findings, we can conclude that the gum arabic could be used as an antioxidant and anti-apoptotic agent to alleviate the toxicity of cisplatin on the testis.

Cisplatin induced testicular damage through mitochondria mediated apoptosis, inflammation and oxidative stress in rats: impact of resveratrol.

The target of this study was to explore the role of mitochondria mediated apoptosis and inflammation in cisplatin-induced testicular damage and to evaluate the ameliorative effect of resveratrol. Adult male Wistar rats were randomly allocated to 4 groups. Group I (Control) received normal saline, Group II (Resveratrol) received resveratrol (50 mg/kg/day), Group III (Cisplatin) received cisplatin (7.5 mg/kg/week, i.p.) and Group IV (Resveratrol + Cisplatin) received resveratrol and cisplatin in the same regimen of treatment. Treatment with resveratrol in Groups II and IV started 48h before cisplatin injection and continued for further 4 successive weeks. Cisplatin-treated rats showed reduced body weight, absolute testes weight and sperm count, motility and viability. On the other hand, cisplatin treatment increased the percentage of sperm abnormalities. It also decreased serum testosterone level, mitochondrial membrane potential while, increased cytochrome C liberation from the mitochondria into the cytosol. The activities of caspase-3 & -9 were increased. The level of TNF-α, IL-6 and Bax were increased whereas Bcl-2 was decreased. Oxidative stress markers were found to increase with a concomitant reduction in the antioxidant enzymes and GSH levels. These results were confirmed by immunohistochemical and histopathological analysis. Contrary to all these results, there were improvements in cisplatin induced testicular damage through attenuation of mitochondria mediated apoptosis, inflammation, and oxidative stress owing to resveratrol pretreatment. Thus, resveratrol, as a potential therapeutic agent, may hold promise in preventing mitochondria mediated apoptosis and inflammation in cisplatin-induced testicular damage in rats.

The antiapoptotic and antioxidant effects of eugenol against cisplatin-induced testicular damage in the experimental model.

Testicular dysfunction or damage is among the critical side effects of chemotherapeutic drugs like cisplatin. This study was mapped out to assess the possible therapeutic effect of eugenol on cisplatin-induced testiculardamage. In this experimental study, a single dose of cisplatin (15mg/kg) was given intraperitoneally. After 72hr of cisplatin injection, rats were sacrificed and testis tissues were removed. Tissues were examined by biochemical, histopathological and immunohistochemical methods. While tissue lipid peroxidation product and apoptotic marker levels increased, antioxidant enzyme activities of testis tissue were decreased in the cisplatin group. Additionally, histopathological damage was also determined in testis tissue. Contrary to all these results, the severity of damage in the tissue was reduced histopathologically owing to eugenol treatment. The lipid peroxidation decreased andantioxidant enzyme activities increased in the eugenol treatment group. It has been determined that eugenol has a therapeutic effect on oxidative stress and apoptosis against cisplatin-induced testiculardamage.

Protective effect of mirtazapine versus ginger against cisplatin-induced testicular damage in adult male albino rats

ABSTRACTCisplatin (CP) is a chemotherapy medication used to treat different types of organs cancers. It has damaging effects on testes. Mirtazapine is an antidepressant, which is used primarily in the treatment of depression and other anxiety disorders. Ginger is a naturally growing plant with antioxidant properties. Thirty-six adult male albino rats, subdivided into six groups (six animals each) received treatment for 30 days. Group I (control) received saline solution orally; group II received mirtazapine (20 mg/kg). Group III received ginger (200 mg/kg/day), group IV received CP (7 mg/kg) IP single dose, at day 23rd, group V received mirtazapine (200 mg/day) orally till day 23rd, CP (7 mg/kg) IP at day 23rd, mirtazapine till day 30th, group VI received ginger (200 mg/Kg/day) orally till day 23rd, CP (7 mg/kg) IP at day 23rd, and then ginger at the previous dose till day 30th. This study examined the microscopic changes associated with CP and the possible testicular protective role of mirtazapine versus ginger of adult male rats. Mirtazapine and ginger resulted in cellular protection of testicular tissue as evident from microscopic changes including Sertoli cells, spermatogonia, and Leydig cells. Ginger showed to have a more protective effect than mirtazapine on testicular tissue against CP treatment.

Protective Effect of All-Trans Retinoic Acid in Cisplatin-Induced Testicular Damage in Rats

PurposeTo investigate the effects of all-trans retinoic acid (ATRA) in cisplatin (CP)-induced testicular damage in rats.Materials and MethodsTwenty-eight male Wistar rats were divided into four groups: Control, ATRA alone, ATRA+CP, and CP alone. Body weight, testicular weight, sperm count, sperm motility, percentage of abnormal sperm, total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI) in testicular tissue, and testicular histopathology were compared among groups.ResultsThe sperm count and motility significantly decreased and the percentage of abnormal sperm significantly increased in the CP group compared to the control and ATRA groups. CP+ATRA administration significantly increased the sperm count and motility, but reduced the abnormal sperm count. CP administration significantly increased TOS and OSI compared to the control group and the other groups. Administering CP+ATRA significantly decreased TOS and the OSI in testicular tissue and reduced spermatogenesis, but increased the Johnsen score.ConclusionsThe destructive effects of CP treatment on testicular tissue and spermatogenesis were reduced by administering ATRA.

Zatariamultiflora ameliorates cisplatin-induced testicular damage via suppression of oxidative stress and apoptosis in a mice model.

Objective(s):Cisplatin (CP), as an anti-neoplastic drug, causes testicular damage. Zataria multiflora Boiss (ZM), a medicinal plant, has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of ZM against CP-induced testicular toxicity.Materials and Methods:In this experimental study, thirty-two adult male mice were randomly divided into four groups. The control group received normal saline with oral gavage during 7 days; ZM group received ZM (200 mg/kg) during 7 days by gavage; CP group received CP (10 mg/kg) intraperitoneally (IP) in the 5th day of study; ZM + CP group received ZM during 7 days and CP was injected in 5th day. Sperm parameters, biochemical (MDA, GSH, and PC) levels, serum testosterone levels, and histopathological and immunohistochemical assays of testis were examined one day after the last drug treatment.Results:CP treatment caused significant damage via changed sperm parameters (sperm motility, count, viability rate, and abnormalities), increased oxidative stress (increased MDA and PC levels, and decreased GSH level), histological changes (degeneration, necrosis, arrest of spermatogenesis, congestion, and decrease in thickness of the germinal epithelium, diameter of seminiferous tubules, and Johnsen’s Score), decreased serum testosterone level, and increased caspase-3 immunoreactivity. ZM preserved spermatogenesis and mitigated the toxic effects of CP on the testis tissue. In addition, treatment with ZM significantly reduced caspase-3 immunoreactivity.Conclusion:The findings of this study suggest that ZM as a potential antioxidant compound and due to free radicals scavenging activities has a protective effect against CP-induced testicular toxicity.

Evaluation of the Protective Effect of Olive Leaf Extract on Cisplatin-Induced Testicular Damage in Rats.

In the present investigation, the effect of olive leaf extract (OLE) on testicular damage induced in rats by an intraperitoneal injection of cisplatin (cis-diamminedichloroplatinum (CDDP)) at a dose of 5 mg/kg was tested. Rats were randomly divided into 4 groups: control, CDDP, OLE, and OLE + CDDP. After 5 days of CDDP treatment, body and testicular weights, histopathological alteration, and serum male sex hormone levels were determined. In addition to the biochemical and immunohistochemical changes in the testes, CDDP caused the disorganization of germinal epithelium and apoptosis by inducing Bax and inhibiting Bcl-2 protein expression. Testicular weights, catalase, serum testosterone, testicular enzymatic (including glutathione peroxidase, glutathione reductase, and superoxide dismutase) along with nonenzymatic (glutathione) antioxidants, and levels of luteinizing and follicle-stimulating hormones were significantly reduced in addition to a significant increase in testicular malondialdehyde and nitrite/nitrate levels when compared with the control group. OLE treatment markedly attenuated both biochemical and histopathological changes. The reproductive beneficial effects of OLE were mediated, at least partly, by inducing the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway.

Induction of heme oxygenase-1 with hemin alleviates cisplatin-induced reproductive toxicity in male rats and enhances its cytotoxicity in prostate cancer cell line

Cisplatin-induced testicular damage is a major obstacle in the application of cisplatin as chemotherapeutic agent. However, it remains as one of the most widely employed anticancer agents in treating various solid tumors including prostate cancer. Since heme-oxygenase-1 (HO-1) is a cytoprotective enzyme with anti-oxidative stress, anti-inflammatory and anticancer activities, we investigated the effects of up-regulation of HO-1 by hemin and its inhibition by zinc protoporphyrin-IX (ZnPP) on cisplatin-induced testicular toxicity in adult rats. Furthermore, the anticancer effect of hemin and ZnPP, with and without cisplatin, was evaluated on human prostate cancer cell line, PC3. Results of the animal study showed that hemin reversed cisplatin-induced perturbations in sperm characteristics, normalized serum testosterone level, and ameliorated cisplatin-induced alterations in testicular and epididymal weights, and restored normal testicular architecture. Moreover, hemin increased the expression and activity of HO-1 protein and prevented cisplatin-induced testicular toxicity by virtue of its antioxidant and anti-inflammatory effects. This effect was evidenced by amelioration of testicular oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione contents, and catalase activity) and inflammatory mediators (tumor necrosis factor-α and nitric oxide synthase expressions). In contrast, administration of ZnPP (HO-1 inhibitor) did not show significant improvement against cisplatin-induced testicular toxicity. Finally, in vitro analyses showed that, hemin augmented the anticancer efficacy of cisplatin, while ZnPP inhibited its apoptotic effect in PC3 cells. In conclusion, the induction of HO-1 represents a potential therapeutic approach to protect the testicular tissue from the detrimental effects of cisplatin without repressing, but rather augmenting, its cytotoxic effects on PC3 cells.