Dose-Dependent Effect of Hydrogen Sulfide in Cyclophosphamide-Induced Hepatotoxicity in Rats.

BACKGROUND: Cyclophosphamide is a commonly used anticancer and immunosuppressive agent; however, hepatotoxicity is one of its severe toxicities. Hydrogen sulfide is a gaseous signaling molecule that plays crucial regulatory roles in various physiological functions. This study aimed to evaluate the hepatoprotective effect of hydrogen sulfide against cyclo phosp hamid e-ind uced hepatic damage in rats. METHODS: Hepatotoxicity was induced by the single intraperitoneal administration of cyclophosphamide (200 mg/kg). Sprague-Dawley rats were treated by hydrogen sulfide donor, sodium hydrosulfide (25, 50, and 100 µmol/kg, intraperitoneal) 7 days before and 7 days after the administration of a single intraperitoneal injection of cyclophosphamide (200 mg/kg). Cyclo phosp hamide-ind uced hepatotoxicity was evaluated by serum and tissue biochemical and histopathological assessments. The levels of hydrogen sulfide, nitric oxide, cyclic guanosine monophosphate, interleukin 6, and interleukin 10 in liver homogenates were also determined by ELISA. One-way analysis of variance and Kruskal-Wallis tests were used as statistical analyses. RESULTS: Cyclophosphamide increased liver function enzymes (alanine aminotransferase and aspartate aminotransferase), immunoreactivity to caspase-3 and Apaf-1, and proinflammatory cytokines. Cyclophosphamide also induced histopathological alterations including pycnotic nucleus with eosinophilic cytoplasm, increased sinusoidal dilatation, congestion, and edema. Hydrogen sulfide cotreatment significantly reduced cyclo phosp hamid e-ind uced inflammation, histological alterations, and apoptosis in the liver. 50 mg/kg sodium hydrosulfide was more effective against cyclo phosp hamid e-ind uced hepatotoxicity. CONCLUSION: In conclusion, hydrogen sulfide with its anti-inflammatory and anti-apoptotic effects seems to be beneficial as an adjunct to cyclophosphamide treatment to reduce cyclo phosp hamid e-ind uced hepatotoxicity and thereby can be suggested as a promising agent to increase the therapeutic efficacy of cyclophosphamide.

Research Into the Effect of Proton Pump Inhibitors on Lungs and Leukocytes.

BACKGROUND: Proton pump inhibitors (PPI) are the most commonly used medication in the world. They are prescribed as an effective treatment choice for gastrointestinal system diseases linked to hyperacidity, especially. Additionally, non-indication and unnecessary use are very common. Many publications in recent times have reported significant side effects. However, there are insufficient studies about the mechanism for these side effects. METHODS: Twenty-four Wistar albino rats were used in this study. Rats were divided into 3 groups of control, group-administered H2 receptor blockers and a group-administered PPI. Medications were administered for 30 days intraperitoneal. After 30 days, rats were euthanized and lung tissue was obtained. Lung was stained for immunohistochemical catalase, superoxide dismutase, Glutathione peroxidase, myeloperoxidase, and toluidine blue and investigated with a light microscope. Transmission electron microscopy (TEM) was used to investigate lung tissues and neutrophil leukocytes. Additionally, lung tissue had biochemical hydrogen peroxide (H2O2) levels researched. RESULTS: H2O2 amounts, produced by lysosomes with important duties for neutrophil functions in lung tissues, were found to be statistically significantly reduced in the group-administered PPI. Results from investigations of specimens obtained with immunohistochemical staining observed increases in antioxidant amounts in the PPI group. Investigation with TEM identified more inflammation findings in the lung tissue from the group-administered PPI compared to the control group and the group-administered H2 receptors. CONCLUSION: In conclusion, we identified long-term PPI use disrupts neutrophil leukocyte functions in the lung. All clinicians should be much more careful about PPI use.

Cisplatin decreases HOXA13 and alphaVBeta3 integrin levels in the uterus.

OBJECTIVE: To examine the effects of cisplatin on uterine histology and implantation molecules and the possible protective role of recombinant Klotho administration on uterine histology and uterine receptivity in mice exposed to cisplatin. MATERIALS AND METHODS: This study was conducted using thirty-two adult female mice assigned to four groups with 8 mice in each group. Saline was given to the 1st group, cisplatin to the 2nd group, recombinant mouse Klotho to the 3rd group and recombinant mouse Klotho plus cisplatin to the 4th group. Uterine tissues were examined for damage histologically and immunobiologically for the uterine receptivity markers HOXA13 and alphaVBeta3 integrin. RESULTS: Apoptosis, degeneration, decrease in uterine thickness and uterine absence of gland scores were higher in the cisplatin group (3rd group) compared to the saline group (1st group) (cisplatin vs. saline p < 0.0001 for all parameters). In the recombinant Klotho plus cisplatin group (4th group), scores of apoptosis, degeneration, reduction in uterine thickness and uterine absence of gland were lower than the group receiving only cisplatin (cisplatin plus recombinant Klotho vs cisplatin, p = 0.006 for apoptosis; p = 0.017 for degeneration; p = 0.011 for the reduction in uterine thickness; p = 0.002 for the absence of gland). However, HOXA13 and alphaVBeta3 integrin staining levels were not different between the cisplatin group (group 3) and the cisplatin plus recombinant Klotho group (group 4) (p = 0.980 and p = 0.762, respectively.) CONCLUSION: Cisplatin has adverse effects on the uterus. Administration of recombinant Klotho was found to attenuate the cisplatin-induced damage but failed to preserve levels of the implantation molecules HOXA13 and alphaVbeta3. Further studies examining the effect of cisplatin toxicity using other implantation markers along with functional studies are needed.

Protective and therapeutic effect of hydrogen sulfide on hemorrhagic cystitis and testis dysfunction induced with cyclophosphamide

Backround/aim: Cyclophosphamide (CP) is a drug used for treatment of many malignant diseases. However, it can cause serious side effects such as hemorrhagic cystitis and male infertility. Hydrogen sulfide (H2S) is a gaseous mediator and is suggested to have antioxidant, antiinflammatory, and antiapoptotic effects. In this study, dose-dependent effects of H2S donor sodium hydrosulfide (NaHS) on cyclophosphamide-induced hemorrhagic cystitis and testicular dysfunction were investigated in rats. Material and methods: Rats were divided into 5 groups (n = 8): control, CP, NaHS25 µmol/kg, NaHS50 µmol/kg, and NaHS100 µmol/ kg. After treatment for 7 days intraperitoneally (ip), a single ip dose of CP 200 mg/kg was given on the 8th day. Then, treatment was continued for 7 days. In bladder and testicular tissues, IL 6, IL 10, cGMP, NO, H2S, FSH, LH, and testosterone levels were measured by ELISA. Histopathological examination with H&E staining, as well as immunohistochemical staining for acrolein in bladder and caspase-3 and APAF-1 in testis were performed. Results: NaHS prevented the increased IL 6 and IL 10 values induced by CP as well as prevented the decrease in cGMP values associated with CP. There was no significant change in FSH values, but the LH value, which increased with CP, decreased with 25, 50, and 100 µmol/kg NaHS. In contrast, testosterone decreased in the CP group and increased in the treatment groups. NaHS was effective in many biochemical and histopathological parameters at 25 and 50 µmol/kg doses, and this effect decreased at 100 µmol/kg dose. Conclusion: H2S has a protective and therapeutic effect on hemorrhagic cystitis and testicular dysfunction induced by cyclophosphamide. It can be suggested that H2S is a promising molecule in facilitating cancer treatment.

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

AIM: To investigate whether recombinant klotho given concomitantly with cisplatin is effective in preventing cisplatin-induced ovarian damage. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Do Resveratrol and Dehydroepiandrosterone Increase Diminished Ovarian Reserve?

OBJECTIVE: In this study, the aim is to observe changes induced by dehydroepiandrosterone (DHEA) and resveratrol (RES) in diminished ovarian follicles that was induced by 4-vinylcyclohexenediepoxide (VCD). MATERIALS AND METHODS: Twenty four Wistar albino female rats were divided into 3 groups: control, DHEA and RES. Unilateral oophorectomy was performed in control group to remove the right ovary of 4 rats and the left ovary of 4 rats. After administration of 160 mg/kg VCD, remaining ovaries were removed. Following the same VCD treatment, in DHEA and RES groups, 60 mg/kg DHEA and 20 mg/kg RES were given for 45 days respectively and residual ovaries were removed. Hematoxylin-eosin and TUNEL staining were performed. Follicle stimulating hormone (FSH), estradiol (E2) and anti-mullerian hormone (AMH) values were measured. RESULTS: In control group, VCD-induced apoptosis in follicles increased the TUNEL-positive cell counts (p<0.001) with decreased number of follicles. On the other hand, DHEA significantly increased all three follicle types in the ovaries and decreased apoptosis (p<0.001). The decreased follicle number in all three follicle types after VCD treatment were found to be significantly increased after RES treatment (p<0.001). Apoptosis in the follicles was significantly decreased by RES administration (p<0.001). FSH values were found to be increased with VCD and to reach control values with DHEA and RES. E2 values significantly decreased with VCD, but significantly increased with RES and DHEA. CONCLUSION: Both DHEA and RES may improve VCD-induced diminished ovarian reserve. DHEA and RES increased the number of primary, primordial and growing follicles, with no significant difference between them.

Bone Marrow Mesenchymal Stem Cell Transplantation Enhances Nerve Regeneration in a Rat Model of Hindlimb Replantation.

BACKGROUND: Successful limb replantation must be based not only on the viability of the amputated part but also on satisfactory long-term functional recovery. Once the vascular, skeletal, and soft-tissue problems have been taken care of, nerve recovery becomes the ultimate limiting factor. Unfortunately, nerve regeneration after limb replantation is impaired by several consequences. The authors tested the hypothesis that bone marrow mesenchymal stem cells could improve nerve regeneration outcomes in an experimental model of limb replantation. METHODS: Twenty rats underwent replantation after total hindlimb amputation. Animals were subdivided into two groups: a replanted but nontreated control group and a replanted and bone marrow mesenchymal stem cell-transplanted group. Three months after surgery, nerve regeneration was assessed using functional, electrophysiologic, histomorphologic, and immunohistochemical analyses. RESULTS: Bone marrow mesenchymal stem cell-treated animals showed significantly better sciatic functional index levels and higher compound muscle action potential amplitudes in comparison with the controls. Histomorphometric analysis revealed that the number of regenerating axons was approximately two-fold greater in the treated nerves. In addition, the mean g-ratio of these axons was within the optimal range. Immunohistochemical assessment revealed that expression of S-100 and myelin basic protein in the treated nerves was significantly higher than in controls. Correspondingly, the expression levels of anti-protein gene product 9.5 and vesicular acetylcholine transporter in motor endplates were also significantly higher. Finally, muscles in the bone marrow mesenchymal stem cell-transplanted group showed significantly larger average fiber areas. CONCLUSION: The authors' findings demonstrate that it is possible to improve the degree of nerve regeneration after limb replantation by bone marrow mesenchymal stem cell transplantation.

Effects of hydrogen sulfide on acetaminophen-induced acute renal toxicity in rats.

INTRODUCTION AND AIM: Hydrogen sulfide (H2S) is an endogenously produced gas-structure mediator. It is proposed to have antioxidant, anti-inflammatory and antiapoptotic effects. Acetaminophen (N-acetyl-P-aminophenol; APAP) is an antipyretic and analgesic medication known as paracetamol. When taken at therapeutic doses there are few side-effects, but at high doses APAP can cause clear liver and kidney damage in humans and experimental animals. In this study, the effects of the H2S donor of sodium hydrosulfide (NaHS) on acute renal toxicity induced by APAP in rats were researched in comparison with N-acetyl cysteine (NAC). METHOD: Rats were divided into six groups (n = 7) as control. APAP, APAP + NAC, APAP + NaHS 25 µmol/kg, NaHS 50 µmol/kg and NaHS 100 µmol/kg. After oral dose of 2 g/kg APAP, NAC and NaHS were administered via the i.p. route for 7 days. In renal homogenates, KIM-1 (Kidney Injury Molecule-1), NGAL (neutrophil gelatinase-associated lipocalin), TNF-α and TGFß levels were measured with the ELISA method for tissue injury and inflammation. In renal tissue, oxidative stress levels were identified by spectrophotometric measurement of TAS and TOS. Histopathologic investigation of renal tissue used caspase 3 staining for apoptotic changes, Masson trichrome and H&E staining for variations occurring in glomerular and tubular systems. RESULTS: NaHS lowered KIM-1, NGAL, TNF-α, TGF-ß and TOS levels elevated in renal tissue linked to APAP and increased TAS values. NaHS prevented apoptosis in the kidney and was identified to ensure histologic amelioration in glomerular and tubular structures. NaHS at 50 µmol/kg dose was more effective, with the effect reduced with 100 µmol/kg dose. CONCLUSION: H2S shows protective effect against acute renal injury linked to APAP. This protective effect reduces with high doses of H2S. The anti-inflammatory and antioxidant activity of H2S may play a role in the renoprotective effect.

Comparative Analysis of Mesenchymal Stem Cells from Bone Marrow, Adipose Tissue, and Dental Pulp as Sources of Cell Therapy for Zone of Stasis Burns.

Introduction: The implantation of mesenchymal stem cells (MSCs) has been shown to exert benefits for the survival of the zone-of-stasis. However, the clinical experience indicates the importance of selecting the right source and type of stem cells. Therefore, we planned the current study to perform a quantitative comparison of MSCs isolated from three different sources to provide information useful in selection of the optimal source and to see whether critical mechanisms are conserved between different populations. Methods: The protective effects of MSCs derived from bone marrow, adipose tissue and dental pulp were compared in a rat model of thermal trauma. The stasis zones were evaluated 72 h after the burn using histochemistry, immunohistochemistry and biochemistry. Results: Gross evaluation of burn wounds revealed that the differences between the mean percentages of the calculated necrotic areas weren't statistically significant. Semi-quantitative grading of the histopathological findings revealed that there were no significant differences between damage scores. Immunohistochemical assessment of apoptotic and necrotic cell deaths revealed that the differences between the mean numbers of apoptotic and necrotic cells weren't statistically significant. Myeloperoxidase activity was found to be significantly lower in the adipose tissue group. Biochemical and immunohistochemical assessment of tissue malondialdehyde revealed that the differences between the groups weren't statistically significant. Finally, the number of neo-vessels in the dental pulp group was found to be significantly higher. Conclusion: Our findings suggest that bone marrow, adipose tissue and dental pulp may serve as a universal donor MSC source for the prevention of burn wound progression.

Prevention of Burn Wound Progression by Mesenchymal Stem Cell Transplantation: Deeper Insights Into Underlying Mechanisms.

INTRODUCTION: Burns are dynamic wounds that may present a progressive expansion of necrosis into the initially viable zone of stasis. Therefore, salvage of this zone is a major subject of focus in burn research. The beneficial effects of mesenchymal stem cells (MSCs) on the survival of the zone of stasis have been previously documented. However, many gaps still exist in our knowledge regarding the underlying protective mechanisms. Hence, this study was designed to evaluate the pathophysiological basis of MSCs in the prevention of burn wound progression. METHODS: Wistar rats received thermal trauma on the back according to the "comb burn" model. Animals were randomly divided into sham, control, and stem cell groups with sacrifice and analysis at 72 hours after the burn. The stasis zones were evaluated using histochemistry, immunohistochemistry, biochemistry, real-time polymerase chain reaction assay, and scintigraphy to evaluate the underlying mechanisms. RESULTS: Gross evaluation of burn wounds revealed that vital tissue percentage of the zone of stasis was significantly higher in the stem cell group. Semiquantitative grading of the histopathologic findings showed that MSCs alleviated burn-induced histomorphological alterations in the zone of stasis. According to CC3a staining and expression analysis of Bax (B-cell leukemia 2-associated X) and Bcl-2 (B-cell leukemia 2) genes, MSCs attenuated increases in apoptosis postburn. In addition, these transplants showed an immunomodulatory effect that involves reduced neutrophilic infiltration, down-regulation of proinflammatory cytokines (tumor necrosis factor α, interleukin 1ß [IL-1ß], and IL-6), and up-regulation of the anti-inflammatory cytokine IL-10 in the zone of stasis. Burn-induced oxidative stress was significantly relieved with MSCs, as shown by increased levels of malondialdehyde, whereas the expression and activity of the antioxidant enzyme superoxide dismutase were increased. Finally, MSC-treated interspaces had enhanced vascular density with higher expression levels for vascular endothelial growth factor A, platelet-derived growth factor, fibroblast growth factor, and transforming growth factor ß. Gamma camera images documented better tissue perfusion in animals treated with MSCs. CONCLUSIONS: The protective effects of MSCs are mediated by the inhibition of apoptosis through immunomodulatory, antioxidative, and angiogenic actions.

Protective role of resveratrol on testicular germ cells in mice with testicular toxicity.

OBJECTIVE: The aim of the present study was to investigate the possible beneficial effects of resveratrol in mice subjected to vinyl cyclohexene dieposide (VCD) -induced testicular toxicity. MATERIAL AND METHODS: A total of thirty- six Swiss albino male mice aged 28-days were used in the present study. The study was composed of two stages where mice which received or did not receive VCD (320 mg/kg/day) were administered resveratrol. The animals were assigned into control and resveratrol-treated groups in the first stage and into groups of VCD- and VCD+resveratrol-treated groups in the second stage. At the end of the experiments, relative testicular weight (TW/BW) and dry/wet weight of testis (TDW/TWW) were calculated. Histological analysis by hematoxylin and eosin (H&E) staining and immunohistochemical staining by BAX and Bcl-2 were performed. Serum testosterone, LH and FSH levels were measured by a commercially available ELISA kit. RESULTS: Resveratrol caused a dose-dependent increase in TW/BW and decrease in TDW/TWW (p<0.05). Resveratrol at a dose of 20 mg/kg resulted in an improvement in testosterone, LH and FSH levels in mice with VCD-induced testicular toxicity (p<0.001). Resveratrol also improved apoptotic index and epithelial cell height of testicular seminipherous tubuli significantly after VCD exposure (p<0.001). CONCLUSION: Results of the present study suggest that resveratrol can be used as a protective and/or therapeutic agent particularly for cases with male infertility caused by testicular toxicity.

The Role of Cyclooxygenase Enzymes in the Effects of Losartan and Lisinopril on the Contractions of Rat Thoracic Aorta.

OBJECTIVE: It was suggested that prostaglandins which are synthesized by cyclooxygenase (COX) enzymes contribute to the actions of angiotensin-converting enzyme (ACE) inhibition and angiotensin AT1 receptor antagonism and there is an interaction between ACE signaling pathway and COX enzymes. We aim to investigate the role of COX enzymes in the effects of losartan, an angiotensin II (Ang II) receptor antagonist or lisinopril, an ACE inhibitor, on the contractions of rat thoracic aorta in isolated tissue bath. MATERIALS AND METHODS: Responses of losartan (10-6, 10-5, 10-4 M), lisinopril (10-6, 10-5, 10-4 M), and non-selective COX inhibitor dipyrone (10-4, 7 × 10-4, 2 × 10-3 M) alone to the contractions induced by phenylephrine (Phe) (10-7 M), potassium chloride (KCl) (6 × 10-2 M), Ang II (10-8 M) and responses of losartan or lisinopril in combination with dipyrone to the contractions induced by Phe or KCl were recorded. RESULTS: When used alone, dipyrone and losartan inhibited Phe, KCl, and Ang II-induced contractions, whereas lisinopril inhibited only Phe and Ang II-induced contractions. Inhibition of COX enzymes (COX-3, COX-3 + COX-1, COX-1+ COX-2 + COX-3 by dipyrone 10-4, 7 × 10-4, 2 × 10-3 M, respectively) augmented the relaxant effects of losartan or lisinopril. Also, dipyrone potentiated the effect of lisinopril on KCl-induced contractions. CONCLUSION: We suggest that dipyrone increases the smooth-muscle relaxing effects of losartan or lisinopril and that COX enzyme inhibition may have a role in the enhancement of this relaxation.

Enhancement of vascular endothelial growth factor's angiogenic capacity by the therapeutic modulation of notch signalling improves tram flap survival in rats submitted to nicotine.

BACKGROUND: Smoke of cigarettes, and specifically nicotine, has been shown to diminish pedicled transverse rectus abdominis musculocutaneous (TRAM) flap survival. Considering that Notch signalling through its ligand Delta-like 4 (Dll4) functions as anti-angiogenic factor by inhibiting the pro-angiogenic effects of vascular endothelial growth factor (VEGF), it is hypothesised that inhibition of the Notch would promote angiogenesis and increase TRAM flap survival in rats submitted to nicotine. METHODS: Twenty rats were treated with nicotine for 28 days preoperatively. Thereafter, a pedicled TRAM flap was created in all animals. The Notch inhibitor N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine-t-butyl-ester was administered in animals of the treatment group. Animals in the control group were given the same amount of solvent. Five days after the surgery, viable flap areas were determined. Skin samples were evaluated for VEGF and Dll4 mRNA levels. Immunohistochemical analysis was used for the assessment of endothelial Dll4 expression. Vascular density was determined histologically. Plasma levels of VEGF and Dll4 were measured. RESULTS: A significant improvement in TRAM flap surviving area was observed in the treatment group (53.50 ± 14.25%) compared with the controls (32.20 ± 9.15%). Immunohistochemical analysis revealed a significant increase in the number of Dll4 stained vessels in animals of the treatment group (9.2 ± 1.6) in comparison with the controls (5.7 ± 1.9). VEGF mRNA levels (0.22 ± 0.08) in the treatment group were significantly lower than those in the control group (0.36 ± 0.09). CONCLUSION: Notch inhibition significantly improved TRAM flap survival in animals exposed to nicotine by promoting VEGF-induced angiogenesis.

The Notch Signaling System Is Involved in the Regulation of Reparative Angiogenesis in the Zone of Stasis.

The Notch pathway ligand Delta-like 4 (Dll4) functions as an antiangiogenic factor, inhibiting vascular endothelial growth factor (VEGF)-induced angiogenesis. This function is documented in tumor and embryonic vasculature. However, its implication in burn wounds remains unexplored. Our objective was to explore the involvement of the Notch in the healing of zone of stasis burns. We hypothesized that anti-Dll4 therapy would prevent progressive necrosis in the stasis zone by promoting angiogenesis. Burns were created in 21 rats using the comb burn model. The Notch inhibitor N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine-t-butyl-ester was administered in the treatment group. Controls were given the same amount of solvent. Seven days after the burn, skin samples were evaluated for VEGF and Dll4 gene expressions. Immunohistochemical analysis was used for the assessment of vascular density, endothelial Dll4 expression, and apoptosis count. Histologic grading of tissue damage was performed. Circulating levels of VEGF and Dll4 were determined. VEGF and Dll4 mRNA levels were found to be simultaneously induced after the burn. In the treatment group, a significant increase in the number of vessels was observed. However, gross evaluation documented an expansion of necrosis to the zone of stasis with marked activation of apoptosis. Histologic assessment showed that the resultant vascular overgrowth was accompanied by extensive edema and abundant infiltration of leukocytes. We provide evidence for the involvement of Notch in the regulation of angiogenesis in zone of stasis burns.

Interaction of sertraline and nimodipine on some behavioural tests in rats.

BACKGROUND: Intracellular calcium contributes to the development of affective disorders. Also, calcium channel inhibitors influence the activity of many neurotransmitters and exert antidepressant and anxiolytic properties. OBJECTIVES: The aim of this study was to examine the effects of sertraline on anxiety and depressive behaviors and the role of nimodipine, a calcium channel antagonist, on these effects. MATERIAL AND METHODS: Forced swimming and elevated plus maze tests were used to assess depression and anxiety respectively in rats. Sertraline (10 mg/kg) was administered repeatedly for 7 days both alone and in combination with single (0.5 mg/kg) and repeated (0.5 mg/kg/7 days) nimodipine administrations. RESULTS: Both repeated sertraline (S) and its combination with single nimodipine administration (S + N) significantly decreased the immobility time compared to control. The combination of (S) with repeated doses of nimodipine (N/7d), significantly increased the immobility time compared to (S) and (S + N). Single dose of nimodipine (N) significantly increased the immobility time compared to (S) and (S + N), and decreased the number of divings compared to control. There was no significant difference between groups in terms of struggle and the time spent in closed arms of the elevated plus maze. CONCLUSIONS: There was no interaction between a single dose of sertraline and nimodipine when administered in combination, while repeated nimodipine administration reversed the antidepressant-like effect of sertraline. We suggest that L-type calcium channels are involved in the antidepressant-like effect of sertraline. Neither single nor repeated nimodipine administration had a significant effect on both depressive behaviour and anxiety. We also propose that there is no interaction between the effects of sertraline and nimodipine on anxitey behavior.

Effects of tadalafil on hemorrhagic cystitis and testicular dysfunction induced by cyclophosphamide in rats.

INTRODUCTION: The protective and/or therapeutic potential of tadalafil (TDL) on cyclophosphamide (CP)-induced hemorrhagic cystitis (HC) and testicular dysfunction in rats was evaluated. MATERIALS AND METHODS: The animals except from the control group were divided into four groups and treated with saline, or 1, 5 or 10 mg/kg TDL orally (CP, TDL1, TDL5 and TDL10 groups, respectively) before and after CP injection. Body and organ weights, sperm count, cGMP, nitric oxide (NO), IL-6 and IL-10 levels in serum and bladder tissue, and serum testosterone (T), LH and FSH levels were determined. The histological analysis of bladder and testis was performed and the number of apoptotic cells was determined. RESULTS AND CONCLUSION: The CP group had decreased cGMP and NO levels in the bladder, serum T level (p < 0.05) and sperm count (p < 0.001) and higher IL-6 levels in serum and bladder (p < 0.01). Treatment with TDL resulted in increased cGMP (p < 0.001), NO (p < 0.05) and serum T (p < 0.05) levels. Histological analysis of the CP group showed severe HC in bladder and testicular damage. TDL-treated animals showed a dose-dependent improvement in all of these histological impairments. In conclusion, a selective inhibitor of phosphodiesterase-5 enzyme, TDL, showed a protective and/or therapeutic effect on CP-induced HC and testicular dysfunction in rats.