Oytun Erbas

Exenatide reduces TNF-α expression and improves hippocampal neuron numbers and memory in streptozotocin treated rats.

Recent studies suggest a possible link between type 2 diabetes and Alzheimers disease (AD). Glucogan-like peptide 1 (GLP-1) facilitates insulin release from pancreas under hyperglycemic conditions. In addition to its metabolic effects, GLP-1 and its long-lasting analogs, including exenatide can stimulate neurogenesis and improve cognition in rodent AD model. The aim of the present study was to investigate the effects of exenatide on hippocampal cellularity, cognitive performance and inflammation response in a rat model of AD. Fourteen rats were used to create AD model using intracerebroventricular (ICV) streptozotocin (STZ) infusion while 7 rats were administered 0.9% NaCl only (sham-operated group). Following stereotaxic surgery, STZ received rats were randomly distributed into two groups, and treated with either saline or exenatide 20 µgr/kg/day through intraperitoneally for two weeks. Then, cognitive performance (passive avoidance learning), brain tumor necrosis factor alpha (TNF-α) levels, choline acetyltransferase (ChAT) activity and hippocampal neuronal count were determined. While the brain TNF-α levels were significantly high in the saline-treated STZ group, exenatide treatment suppressed the increase in TNF-α levels. Saline-treated STZ group showed reduced ChAT activity compared to sham group. However, exenatide significantly preserved brain ChAT activity. The cognitive performance was also impaired in saline group while exenatide improved memory in rats. Moreover, exenatide treatment significantly prevented the decrease in hippocampal neurons. Overall, the results of the present study clearly indicated exenatide might have beneficial effects on impaired cognitive performance and hippocampal neuronal viability in AD by suppressing the inflammation response and increasing cholinergic activity.

Montelukast Inhibits Pentylenetetrazol-Induced Seizures in Rats

Background Montelukast is an antiinflammatory drug with an antioxidant property. In this study, we aimed to reveal whether montelukast has a preventive effect against seizures and post-seizure oxidative stress in pentylenetetrazol (PTZ)-induced seizures in rats. Material/Methods Of the 48 male Sprague-Dawley rats used in the study, 24 were assigned to EEG recordings (group A) and 24 were assigned to behavioral studies (group B). In group A, the electrodes were implanted on dura over the left frontal cortex for EEG recording. After 10 days, in group A, i.p. saline, 25, 50, or 100 mg/kg montelukast+35 mg/kg PTZ was administered to the rats. EEG was recorded and spike percentage was evaluated. In group B, i.p. saline, 25, 50, or 100 mg/kg montelukast+70 mg/kg PTZ was administered to the rats. Racine’s Convulsion Scale (RCS) and onset times of first myoclonic jerk (FMJ) was used to evaluate the seizures. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined in the brain tissue of animals. Results Animals treated with 50 or 100 mg/kg montelukast had significantly lower RCS and significantly increased FMJ onset time compared to the saline-treated animals. Moreover, groups given 25, 50, or 100 mg/kg montelukast had significantly lower MDA and higher SOD levels compared to the saline-treated group. The differences were more pronounced in the 100 mg/kg montelukast-pretreated group (p<0.001). Conclusions Montelukast showed anticonvulsant action and led to amelioration of oxidative stress markers in PTZ-induced seizures in rats.

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.

Protective effect of edaravone against manganese-induced toxicity in cultured rat astrocytes

Manganese (Mn), a trace metal, is essential for maintaining the normal regulation of many biochemical and cellular processes. However, accumulation of Mn due to excessive environmental exposure leads to neurological impairment, referred to as manganism. Edaravone (EDA) is a potent free radical scavenger that has been clinically shown to reduce the neuronal injury after cerebral ischemia. In the present study, we aimed to examine the protective effects of EDA against Mn toxicity in astrocyte cultures. Astrocyte cultures were prepared from cerebral cortices of newborn Sprague-Dawley rats. The experiments were performed between 16 and 18 days of cultures. Astrocytes were treated in DMEM medium containing Mn (1-1000μM) for 24h to test Mn toxicity. In order to assess the effect of EDA, cells were pre-treated with different doses of EDA (10, 100 and 1000μM) 6h before Mn treatment. Cell viability (MTT), apoptotic cell death (Hoechst test) and lipid peroxide levels were evaluated in cultures. Our results showed that Mn significantly and dose-dependently reduced cell viability in astrocyte cultures. The apoptotic cell death and lipid peroxides were significantly higher in Mn treated cultures. Treatment of astrocytes with EDA successfully suppressed oxidative stress and cell death due to Mn exposure. The findings of the present study suggest that Mn cytotoxicity is mainly associated with ROS generation and apoptotic cell death. Besides, EDA may have beneficial effects against Mn toxicity. However, further studies are needed to elucidate the molecular mechanisms underlying protective effect of EDA.

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.

Protection by Edaravone, a Radical Scavenger, against Manganese-Induced Neurotoxicity in Rats

Manganese (Mn) is a required element for biological systems; however, its excessive exposure may lead to a neurological syndrome known as manganism. The aim of the present study was to assess the toxic effects of subacute exposure of Mn by measuring weight gain, motor performance, and biochemical parameters (complex I activity, lipid peroxides, and protein carbonyls) in brain mitochondria in rats. We also examined whether edaravone (EDA), a radical scavenger, exerts protective effects against Mn‐induced neurotoxicity. In addition, we evaluated the accumulation of Mn in brain regions using magnetic resonance imaging. Mn‐exposed rats revealed significantly impaired motor performance, weight loss, and Mn accumulation in particular brain area. Lipid peroxides and protein carbonyls were significantly increased in Mn‐exposed rats, whereas complex I activity was found to be decreased. EDA treatment significantly prevented mitochondrial oxidative damage and improved motor performance. These findings suggested that EDA might serve as a clinically effective agent against Mn‐induced neurotoxicity.

Exogenously administered adenosine attenuates renal damage in streptozotocin-induced diabetic rats.

Abstract Background: Diabetic nephropathy (DNP) is one of the most serious complications of diabetes mellitus (DM). In the present study, we investigated the potential of adenosine as a therapeutic candidate for preventing DNP. Methods: Twenty-one adult male rats were included in the study. Fourteen rats were administered a single dose of 60 mg/kg streptozotocin (STZ) to induce diabetes. Seven rats served as normal control group. Diabetic rats were randomly divided into two groups: one group was treated with 1 mL/kg saline/day (DM + saline) and the other group was treated with 5 mg/kg/day adenosine (DM + adenosine) for 6 weeks. After 6 weeks, biochemical parameters including urea, creatinine, blood urea nitrogen (BUN), kidney injury molecule-1 (KIM-1) and tumor necrosis factor-α (TNF-α) were measured in plasma samples. Also, kidneys were removed for histopathological assessment. Results: Both of plasma KIM-1 and TNF-α levels were significantly higher in DM + saline group compared to controls. However, treatment of diabetic rats with adenosine significantly decreased the plasma KIM-1 and TNF-α levels compared to DM + saline group. Significant histopathological changes were observed in diabetic rats whereas adenosine treatment effectively prevented these changes. Conclusions: The findings of the present study suggest that adenosine may be a useful therapeutic agent for preventing DNP.

Effect of platelet-rich plasma on reconstruction with nerve autografts

Despite advances in understanding of peripheral nerve injuries and regeneration and advances in surgical techniques, successful outcomes cannot be guaranteed after reconstructive surgery. Platelet‐rich plasma (PRP) has been reported to have positive effects on nerve regeneration, as well as on tissue healing. The present study was designed to evaluate the effect of PRP on nerve‐grafted defects. Sprague–Dawley rats were divided into four surgery groups (n = 7 in each). A 1‐cm long nerve defect was created in the upper thigh and then reconstructed using a nerve autograft in all groups. The wet muscle weights, electromyographic findings, and histomorphologic changes were evaluated 10 weeks later. As shown by both the electromyographic (p < 0.001) and histomorphologic findings (p < 0.001), PRP had more positive effects on nerve gap reconstruction in Group 3 then Group 4 as compared to the control groups. The present study is novel in that it evaluated the regeneration effect of PRP on a large nerve defect reconstructed with a nerve graft rather than primary repair. The results are encouraging for further experimental studies on the role of PRP in nerve healing.

Neuroprotective effects of octreotide on diabetic neuropathy in rats

The purpose of the present study is to investigate the possible healing effects of octreotide (OCT) on motor performance, electrophysiological and histopathological findings of diabetic neuropathy in a rat model of diabetes mellitus (DM). To induce diabetes, rats were administered a single dose (60mg/kg) of streptozotocin (STZ). Diabetic rats were treated either with saline (1ml/kg/day, n=7) or OCT (0.1mg/kg/day, n=7) for four weeks. Seven rats served as control group and received no treatment. At the end of the study, electromyography (EMG), gross motor function (inclined plate test), general histology and the perineural thickness of sciatic nerve were evaluated. At the end of study, weight loss was significantly lower in OCT treated rats than that of saline treated ones (p<0.001). Electrophysiologically, compound muscle action potential (CMAP) amplitudes of the saline treated DM group were significantly reduced than those of controls (p<0.0001). Also, distal latency and CMAP durations were significantly prolonged in saline treated DM group (p<0.05) compared to control. However, treatment of diabetic rats with OCT significantly counteracted these alterations in EMG. Furthermore, OCT significantly improved the motor performance scores in diabetic rats (p<0.05). Histomorphometric assessment of the sciatic nerve demonstrated a significant reduction in perineural thickness in OCT treated group compared to saline group. In conclusion, OCT possesses beneficial effects against STZ-induced diabetic neuropathy, which promisingly support the use of OCT as a neuroprotective agent in patients with diabetic neuropathy.