Fatih Oltulu

Protective effect of oxytocin on ovarian ischemia-reperfusion injury in rats

Oxytocin (OT), a neurohypophysial nonapeptide, plays dual role as a neurotransmitter/neuromodulator and a hormone. It has also well known protective properties against ischemia/reperfusion organ damage. This study investigated the effect of OT on experimentally induced ovarian torsion/de-torsion ischemia/reperfusion (I/R) injury in rats. Sprague-Dawley rats were assigned to five treatment groups (n=7/group): Group 1, sham-operated; Group 2, torsion; Group 3, 80 IU/kg of OT administration 30 min prior to torsion; Group 4, torsion/de-torsion; and Group 5, torsion followed by 80 IU/kg of OT administration 30 min prior to de-torsion. OT administration significantly decreased the tissue malondialdehyde (MDA) levels in both the torsion and OT group (Group 3), and torsion/de-torsion OT group (Group 5) in comparison with the torsion-only group (Group 2) and torsion/de-torsion group (Group 4). Histopathological finding scores including follicular degeneration, edema, hemorrhage, vascular congestion, and infiltration by inflammatory cells were found to be significantly decreased in the torsion and OT group (Group 3), and torsion/de-torsion OT group (Group 5) when compared with the torsion-only group (Group 2) and torsion/de-torsion group (Group 4). In conclusion, these results, verified with histopathologic evaluation and biochemical assays, suggest a probable protective role for OT in ischemia and I/R injury in rat ovaries.

Amelioration of rotenone-induced dopaminergic cell death in the striatum by oxytocin treatment

Oxytocin (OT) is essentially associated with uterine contraction during parturition and milk ejection reflex. Although several studies implicate the role of OT in anti-inflammatory, anti-oxidative and anti-apoptotic pathways, there is a lack of data with regard to the protective effects of oxytocin in neurodegenerative models such as Parkinsons disease (PD). The present study was undertaken to investigate the neuroprotective effects of oxytocin (OT) on rotenone-induced PD in rats. Twenty adult Sprague-Dawley rats were injected with rotenone (3 μg/μl in DMSO) or vehicle (1 μl DMSO) into the left substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) under stereotaxic surgery, and PD model was assessed by rotational test ten days after drug infusion. The valid PD rats were randomly divided into two groups; Group 1 (n=7) and Group 2 (n=7) were administered saline (1 ml/kg/day, i.p.) and oxytocin (160 μg/kg/day, i.p.) through 20 days, respectively. The effects of OT treatment were evaluated by behavioral, histological and immunohistochemical parameters. Apomorphine-induced stereotypic rotations in PD rats were significantly inhibited by OT treatment (p<0.05). In addition, immunohistochemical studies clearly demonstrated the suppression of Bax, caspase-3, caspase-8 and elevation of Bcl-2 and tyrosine hydroxylase immunoexpression in OT-treated rats compared to saline group. Our findings suggest that oxytocin may have cytoprotective and restorative effects on dopaminergic neurons against rotenone-induced injury. The underlying mechanism may be associated with the inhibition of apoptotic pathways.

The effects of sunitinib on endometriosis

Abstract The aim of the present study was to evaluate the effect of sunitinib on endometriotic implants and adhesions in a rat endometriosis model. An experimental endometriosis model was created in 21 rats. These rats were randomly divided into three groups: Group 1 (control group, 7 rats) was given no medication; Group 2 (sunitinib group, 7 rats) was given 3 mg/kg per day of oral sunitinib; and Group 3 (danazol group, 7 rats) was given 7.2 mg/kg per day of oral danazol. The volume of endometriotic implants was calculated. The extent and severity of adhesions were evaluated. The groups were compared by the Students t-test, analysis of variance (ANOVA) and the Mann–Whitney U test. There was no statistically significant difference in the mean volume of endometriotic implants before medication between three groups. The volume of implants and extent, severity, total score of adhesions were significantly decreased after medication in Group 2 and Group 3. We noted that the volume of the endometriotic implants and adhesion formation were decreased both after sunitinib and danazol treatment. As a result, sunitinib seems to be effective for endometriotic peritoneal lesions. The effects of sunitinib in rat models give hope for improving the treatment of human endometriosis and prevention of pain symptoms.

Montelukast prevents ischaemia/reperfusion-induced ovarian damage in rats

OBJECTIVE To investigate the efficacy of montelukast for prevention of ischaemia/reperfusion (I/R) injury in rat ovary. STUDY DESIGN Twenty-four female adult rats were included in the study. I/R injury was induced by CO2 pneumoperitoneum in a laparoscopic rat model. The rats were divided at random into three groups: the sham group was subjected to catheter insertion but was not subjected to pneumoperitoneum; the saline group was subjected to 60 min of pneumoperitoneum and 30 min of reperfusion, with 1 mg/kg physiological saline administered 10 min before pneumoperitoneum; and the montelukast group was subjected to 60 min of pneumoperitoneum and 30 min of reperfusion, with 20mg/kg montelukast administered 10 min before pneumoperitoneum. Damage to ovarian tissue was scored by histopathological evaluation. Caspase-3 expression was determined immunohistochemically. Ovarian tissue levels of malondialdehyde and glutathione, and plasma total antioxidant capacity were measured biochemically. RESULTS In comparison with the sham group, ovarian sections in the montelukast group had higher scores for follicular degeneration and oedema (p<0.001). Montelukast treatment prevented tissue damage in ovaries, and this result was significant. Caspase-3 expression was only observed in ovarian surface epithelium in the saline and montelukast groups. However, the mean caspase-3 expression score was higher in the saline group than the montelukast group (p<0.001). Tissue levels of malondialdehyde were higher in the montelukast group than the sham group, but plasma total antioxidant capacity and tissue levels of glutathione were significantly lower. Pretreatment with montelukast reduced lipid peroxidation (p<0.005) and improved antioxidant status in rats (p<0.001). CONCLUSION Montelukast is effective for the prevention of I/R-induced damage in rat ovary.

Ovarian failure in diabetic rat model: Nuclear factor-kappaB, oxidative stress, and pentraxin-3

OBJECTIVE The aim of the present study was to investigate the effects of diabetes mellitus (DM) on ovarian reserve and injury by considering laboratory and histopathological parameters in rat models. MATERIALS AND METHODS An experimental DM model was created in 16 rats. Eight rats with normal blood glucose levels were included in the control group. Diabetic rats were divided randomly into two groups: nontreated and resveratrol-treated groups. Histopathological examination and nuclear factor (NF)-κB immunoexpression level determination were performed. Plasma malondialdehyde, glutathione, pentraxin-3, and anti-Müllerian hormone levels were measured. Relations between the variables were compared by Student t test, analysis of variance, and Mann-Whitney U and χ(2) tests. RESULTS We found statistically significantly lower glutathione and anti-Müllerian hormone levels, and higher malondialdehyde and pentraxin-3 levels in nontreated diabetic group when compared with the control and resveratrol-treated diabetic groups. Stromal degeneration, follicle degeneration, stromal fibrosis scores, and NF-κB immunoexpression levels were significantly higher in nontreated diabetic rats. Primordial and primary follicle counts were significantly lower in the nontreated diabetic group when compared with the control and resveratrol-treated groups. There was no statistically significant difference in secondary and tertiary follicles between these groups. CONCLUSION These findings provide strong evidence that the ovarian follicle pool in nontreated diabetic rats is affected in the early stages of the follicle development process. We precluded negative effects of DM on ovaries by inhibiting the NF-κB pathway with resveratrol. We thought that the NF-κB pathway plays a role in the pathophysiology of ovarian failure in diabetic rats. Further studies should evaluate this precise mechanism that leads to a decline in the anti-Müllerian hormone levels. In addition, the relationship between this abnormality and reproductive function in diabetic patients should be analyzed further.

Attenuation of Ischemia/Reperfusion- Induced Ovarian Damage in Rats: Does Edaravone Offer Protection?

Aim: The aim of this study was to investigate whether prophylactic treatment with edaravone prevents ischemia/reperfusion (I/R)-induced ovarian damage during pneumoperitoneum in an experimental rat model. Methods: Twenty-eight female Sprague Dawley rats were allocated randomly to 4 groups. The sham group (group 1) was only subjected to catheter insertion, not to pneumoperitoneum. Group 2 received a 1 mg/kg dose of 0.9% sodium chloride by the intraperitoneal route for 10 min before pneumoperitoneum. Groups 3 and 4 received 6 and 12 mg/kg edaravone, respectively, by the intraperitoneal route for 10 min before pneumoperitoneum. After 60 min of pneumoperitoneum, the gas was deflated. Immediately after the reperfusion period, both ovaries were excised for histological scoring, caspase-3 immunohistochemistry and biochemical evaluation including glutathione (GSH) and malondialdehyde (MDA) levels. Also, total antioxidant capacity (TAC) was measured in plasma samples to evaluate the antioxidant effect of edaravone. Results: Ovarian sections in the saline group revealed higher scores for follicular degeneration and edema (p < 0.0001) when compared with the sham group. Administration of different doses of edaravone in rats significantly prevented degenerative changes in the ovary (p < 0.0001). Caspase-3 expression was only detected in the ovarian surface epithelium in all groups, and there was a significant difference between the treatment groups and the saline group (p < 0.0001). Treatment of rats with edaravone reduced caspase-3 expression in a dose-dependent manner. Moreover, biochemical measurements of oxidative stress markers (MDA, GSH and TAC) revealed that prophylactic edaravone treatment attenuated oxidative stress induced by I/R injury. Conclusion: These results indicate that prophylactic treatment with edaravone prevents I/R-induced ovarian damage during pneumoperitoneum in an experimental rat model.

Neuroprotective effects of chronic administration of levetiracetam in a rat model of diabetic neuropathy

OBJECTIVE Diabetic neuropathy (DNP) is a frequent and serious complication of diabetes mellitus (DM) that leads to progressive and length-dependent loss of peripheral nerve axons. The purpose of the present study is to assess the neuroprotective effects of levetiracetam (LEV) on DNP in a streptozotocin (STZ)-induced DM model in rats. METHODS Adult Sprague-Dawley rats were administered with STZ (60mg/kg) to induce diabetes. DNP was confirmed by electromyography (EMG) and motor function test on 21st day following STZ injection. Study groups were assigned as follows; Group 1: Naïve control (n=8), Group 2: DM+1mL/kg saline (n=12), Group 3: DM+300mg/kg LEV (n=10), Group 4: DM+600mg/kg LEV (n=10). LEV was administered i.p. for 30 consecutive days. Then, EMG, motor function test, biochemical analysis (plasma lipid peroxides and total anti-oxidant capacity), histological and immunohistochemical analysis of sciatic nerves (TUNEL assay, bax, caspase 3, caspase 8 and NGF) were performed to evaluate the efficacy of LEV. RESULTS Treatment of diabetic rats with LEV significantly attenuated the inflammation and fibrosis in sciatic nerves and prevented electrophysiological alterations. Immunohistochemistry of sciatic nerves showed a considerable increase in bax, caspase 3 and caspase 8 and a decrease in NGF expression in saline-treated rats whereas LEV significantly suppressed apoptosis markers and prevented the reduction in NGF expression. Besides, LEV considerably reduced plasma lipid peroxides and increased total anti-oxidant capacity in diabetic rats. CONCLUSIONS The results of the present study suggest that LEV may have therapeutic effects in DNP through modulation of anti-oxidant and anti-apoptotic pathways.

The antioxidant role of agomelatine and gallic acid on oxidative stress in STZ induced type I diabetic rat testes

Diabetes is a multisystem disorder and its effects are observed on the reproductive system. One of the main causes of testicular tissue damage is diabetes-induced overproduction of reactive oxygen species and glycated end products. The main objectives of this study were to investigate the possible effects of agomelatine (AG) and gallic acid (GA) in suppressing oxidative stress in Type I diabetes induced testicular damage. A total of 28 adult male rats were included in the study. Diabetes was induced by intraperitoneal injection of streptozocin (STZ, 55mg/kg) to 21 rats, which were then randomly assigned to 3 groups; 1mL saline solution was given to the diabetes+saline group by oral gavage, 20mg/kg/day oral AG was given to the diabetes+AG group, and 20mg/kg/day oral GA was given to the diabetes+GA group for 4 weeks. Tumor necrosis factor α (TNFα), nitric oxide synthase 2 (NOS2), fibronectin and vascular endothelial growth factor (VEGF) were used for the investigation of inflammation, fibrosis and vascular structures. The terminal-deoxynucleoitidyl-transferase mediated nick end-labeling assay (TUNEL) was used to detect apoptosis. Testicular tissue total antioxidant capacity values were tested by biochemical analysis. AG treatment showed an improvement on biochemical parameters and histopathological appearance on the rat testes. GA showed dose-related regenerative effects on biochemical parameters. Histologically, a minimal healing effect was determined on the testes damage. In conclusion, it was observed that AG is a potentially beneficial agent for reducing testicular damage by decreasing oxidative stress level. However, GA was seen to have a poor therapeutic effect.

Therapeutic effect of sunitinib on diabetes mellitus related ovarian injury: an experimental rat model study.

Abstract The aim of our study is to investigate the effect of sunitinib on diabetes mellitus related-ovarian injury and fibrosis in rat models. An experimental diabetes mellitus model was created in 16 rats, and eight rats with normal blood glucose levels were included in control group (Group-1). The diabetic rats were divided into two groups:diabetic control group (water given) – Group-2 and sunitinib treatment group – Group-3. After four weeks, bilateral oophorectomy was performed and ovaries were examined histologically. The groups were compared by Student’s t-test, analysis of variance (ANOVA) and Mann–Whitney’s U-test. There was a significant increase in no-medication (water given) diabetic rat’s ovary (Group-2) in terms of follicular degeneration, stromal degeneration, stromal fibrosis and NF-kappaB immune-expression compared with control group normal rats’ ovary (Group-1) (p < 0.0001). Stromal degeneration (p = 0.04), stromal fibrosis (p = 0.01), follicular degeneration (p = 0.02), NF-kappaB immune-expression (p = 0.001) significantly decreased in sunitinib-treated diabetic rat’s ovary (Group-3) when compared with no-medication (water given) diabetic rat’s ovary (Group-2) (p < 0.05). When we used sunitinib in the treatment of diabetic rats, ovarian injury, fibrosis and NF-kappaB immunoexpression decreased significantly. The effects of sunitinib in rat models give hope to the improved treatment of premature ovarian failure due to diabetes mellitus in humans.

Oxytocin provides protection against diabetic polyneuropathy in rats.

Abstract Purpose: The aim of the present study is to investigate the protective effects of oxytocin (OT) on diabetic neuropathy (DNP) in rats. Materials and methods: Eighteen rats were used to induce diabetes using single dose streptozotocin (STZ, 60 mg/kg). Diabetic DNP was verified by electromyography (EMG) and motor function test on 21st day following STZ injection. Six rats served as naïve control group and received no drug (n = 6). Following EMG, diabetic rats were randomly divided into three groups and administered with either 1 ml/kg saline or 80 μg/kg OT or 160 μg/kg OT intraperitoneally for four weeks. Then, EMG, motor function test, biochemical analysis (plasma lipid peroxides and glutathione), histological, and immunohistochemical analysis of sciatic nerves (bax, caspase 3, caspase 9, and NGF) were performed. Results: Diabetic rats developed neuropathy, which was apparent from decreased compound muscle action potentials amplitudes and prolonged distal latency in saline-treated rats (p < 0.001) whereas 160 μg/kg OT significantly improved EMG findings. OT treatment significantly lessened the thickening of perineural fibrosis when compared with saline group (p < 0.001). Besides, OT significantly reduced plasma lipid peroxides (p < 0.05) and increased glutathione levels in diabetic rats (p < 0.001). The sciatic nerves of saline-treated rats showed considerable increase in bax, caspase 3 and caspase 8 expressions (p < 0.001) while OT treatment significantly suppressed these apoptosis markers. Also, OT improved NGF expression in diabetic rats compared to saline group. Conclusion: Present results demonstrate that OT appears to alleviate harmful effects of hyperglycemia on peripheral neurons by suppressing inflammation, oxidative stress and apoptotic pathways.