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Öğe Agomelatine pretreatment prevents development of hyperglycemia and hypoinsulinemia in streptozotocin-induced diabetes in mice(Wiley, 2019) Ozcan, Mete; Canpolat, Sinan; Bulmus, Ozgur; Ulker, Nazife; Tektemur, Ahmet; Tekin, Suat; Ozcan, SibelThe main objective of this study was to investigate potential effectiveness of agomelatine pretreatment in the prevention of diabetes itself and encephalopathy, with a focus on brain tissue oxidative stress and inflammatory processes in streptozotocin (STZ)-induced diabetic mice. Interleukine-1 beta (IL-1 beta) and TACR1 (NK1), which is a tachykinine receptor, were used for the investigation of inflammation in the brain regions including raphe nucleus, periaqueductal gyrus (PAG), amygdala, and nucleus accumbens. The effects of agomelatine on total antioxidant capacity were also evaluated. In the in vitro part of the study, the effects of agomelatine on cell viability were investigated in dorsal root ganglion (DRG) neurons. Fasting blood glucose levels were measured 72 h after STZ injection to determine the diabetic condition. Agomelatine pretreatment prevented both hyperglycemia and hypoinsulinemia in STZ-treated mice. When STZ was injected to induce diabetes in mice, neither hyperglycemia nor hypoinsulinemia was developed in agomelatine pretreated mice and 6 weeks after development of diabetes, agomelatine treatment significantly decreased levels of IL-1 beta mRNA in raphe nucleus and nucleus accumbens. TACR1 mRNA levels were lower in raphe nucleus, PAG, and amygdala of agomelatine-treated diabetic mice. The increase in total antioxidant capacity after agomelatine administration may responsible for its beneficial effect in the prevention of diabetes. We showed that agomelatine reversed high glucose-induced cell viability decreases in DRG neurons. Both the antihyperglycemic and antioxidant effects of agomelatine might have contributed to the DRG neuron viability improvement. In conclusion, agomelatine seems to both prevent development of diabetes and reverse the encephalopathic changes caused by diabetes.Öğe Effect of Spexin on Cell Viability in a Diabetic Neuropathy Model: An in vitro Study(Wiley, 2025) Bahar, Mehmet Refik; Orhan, Seval Ulku; Ozcan, Mete; Tekin, Suat[No abstract available]Öğe Effects of Meteorin-Like Protein on Pain in an Experimental Diabetes Model(Wiley, 2023) Yuksel, Furkan; Tekin, Suat; Ozcan, Mete; Sandal, Suleyman[Abstract Not Available]Öğe Effects of Peripheral Administration of Kisspeptin on Pubertal Maturation and Serum Leptin Levels in Female Rats(Ortadogu Ad Pres & Publ Co, 2011) Alcin, Ergul; Ozcan, Mete; Ayar, Ahmet; Yilmaz, Bayram; Turkoz, Yusuf; Kelestimur, HalukObjective: The aim of this study was to investigate the effects of exogenous kisspeptin on pubertal maturation in immature female rats. Material and Methods: Wistar female rats were weaned when they were 21 days old. The rats were divided into two groups. Controls (n=10) received saline only (1 ml/kg). Experimental rats (n=9) were intraperitoneally injected with daily 100 nmol kisspeptin-10 between 09.00h-10.00h a.m. starting from the day 26. Body weight and food intake were daily determined, and vaginal opening (VO) was daily monitored starting from day 26. The animals were decapitated when the first diestrus was determined by vaginal smears. Upon decapitation, serum was separated and stored at -20 degrees C until measurement of leptin, luteinizing hormone (LH) and estradiol. Uterus and ovaries were dissected out and weighed. Results: Intraperitoneal injection of 100 nmol kisspeptin-10 did not change median VO ages. There were no differences in food intake, and percentages of body weight change, between control and kisspeptin groups during the experimental period. Kisspeptin administration elicited significant (P<0.01) increases in uterus weight over control values. Serum leptin levels were significantly lower (P<0.05) in kisspeptin-treated group compared to vehicle group. Kisspeptin administration increased (P<0.05) serum LH and estradiol levels. Conclusion: Chronic peripheral administration of kisspeptin-10 does not advance puberty onset as estimated from the date of vaginal opening, but potentiates other conventional indices of maturation of reproductive axis such as elevated uterine weight and increased serum levels of LH and estradiol.Öğe Fibroblast growth factor-21: Preserving cell viability in diabetic neuropathy through the AKT/PI3K cellular pathway(2024) Tekin, Suat; Ozcan, Mete; Bulut, Ferah; Orhan, Seval ÜlküAim: This study aims to investigate the potential neuroprotective effects of fibroblast growth factor-21 (FGF21) on dorsal root ganglion (DRG) neurons under high glucose (HG) conditions, mimicking diabetic neuropathy. Specifically, we hypothesize that FGF21 enhances cell viability and reduces glucose-induced neuronal death via the activation of the phosphatidyl-inositol-3-kinase (PI3K)/AKT signaling pathway. Materials and Methods: DRG neurons were cultured from 1-day-old to 2-day-old Wistar rats and exposed to HG concentrations to simulate diabetic conditions. Various concentrations of FGF21 were administered to the DRG neurons. Cell viability was assessed using the MTT assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide), a widely used enzymatic method for determining cellular metabolic activity. The involvement of the PI3K/AKT signaling pathway in mediating the effects of FGF21 was also examined through biochemical assays and pathway inhibitors. Results: Administration of FGF21 to DRG neurons exposed to HG conditions significantly protected cell viability and reduced glucose-induced neuronal death (p<0.05). The protective effects of FGF21 were found to be dose-dependent, with higher concentrations showing more pronounced benefits. Furthermore, the activation of the PI3K/AKT signaling pathway was confirmed to play a crucial role in the neuroprotective mechanism of FGF21, as inhibition of this pathway attenuated the protective effects. Conclusion: This study demonstrates for the first time that FGF21 has a neuroprotective effect on DRG neuron survival in a diabetic neuropathy model. By activating the PI3K/AKT signaling pathway, FGF21 helps maintain cell viability and reduces glucoserelated neuronal death. These findings provide a promising basis for the development of new therapeutic strategies for the treatment of diabetic neuropathy, leveraging the neuroprotective properties of FGF21.Öğe Investigation of the Effects of Meteorin-Like Protein in a Model of Neuropathy Induced by Sciatic Nerve Injury(Wiley, 2023) Tekin, Suat; Yuksel, Furkan; Ozcan, Mete; Sandal, Suleyman[Abstract Not Available]Öğe Investigation of the Effects of Saxagliptin in In Vitro and In Vivo Models of Diabetic Neuropathy(Wiley, 2025) Oz, Samet; Orhan, Seval Ulku; Taslidere, Asli; Ozcan, Mete; Tekin, SuatDiabetic neuropathy (DN), one of the most common microvascular complications of diabetes, is a condition involving complex pathophysiological mechanisms such as oxidative stress, inflammation, apoptosis, primarily resulting from chronic hyperglycemia. This study aimed to evaluate potential effects of Saxagliptin (Sax), a DPP-4 enzyme inhibitor, on in vitro and in vivo models of DN. Dorsal root ganglion neurons isolated from 1 to 2-day-old Wistar Albino rats were exposed to a high-glucose environment for 24 h to induce in vitro DN model. In this model, effects of Sax on cell viability and associated intracellular signaling pathways were investigated. In the in vivo model, streptozotocin-induced diabetic mice were divided into four groups: control, DN, DN+Sax-2, DN+Sax-10 (n = 10). For 15 days, DN group received 0.9% isotonic sodium chloride, while DN+Sax-2 and DN+Sax-10 groups were administered Sax orally via gavage at doses of 2 and 10 mg/kg, respectively, with concurrent nociceptive behavioral testing. At end of experiment, animals were decapitated, biochemical and histological analyses were performed on collected blood and pancreatic tissues. Sax, significantly increased cell viability via phosphoinositide 3-kinase pathway (p < 0.05). Compared to DN group, Sax-treated groups showed improvements in mechanical allodynia and thermal hyperalgesia; increased levels of superoxide dismutase, catalase, glutathione, total antioxidant status, interleukin-10; decreased levels of malondialdehyde, interleukin-1 beta, interleukin-6 (p < 0.05). Additionally, caspase-3 expression in pancreatic tissue was suppressed, and histopathological damage was markedly reduced (p < 0.0001). These findings suggest that Sax suppresses inflammation, inhibits oxidative damage and apoptosis, thereby reducing hyperalgesia, and may have therapeutic effects against DN.Öğe Kisspeptin antagonist prevents RF9-induced reproductive changes in female rats(Bioscientifica Ltd, 2015) Sahin, Zafer; Canpolat, Sinan; Ozcan, Mete; Ozgocer, Tuba; Kelestimur, HalukThe aim of this study was to determine the modulatory effects of peptide 234 (p234) (an antagonist of GPR54 receptors) on kisspeptin and RF9 (an RFamide-related peptide antagonist)-induced changes in reproductive functions and energy balance in female rats. Female Sprague-Dawley rats were weaned on postnatal day (pnd) 21. The animals were intracerebroventricularly cannulated under general anesthesia on pnd 23. Groups of female rats were injected with kisspeptin, RF9, p234, kisspeptin plus p234, or RF9 plus p234, daily. The experiments were ended on the day of first diestrus following pnd 60. Kisspeptin or RF9 alone advanced vaginal opening (VO), which was delayed by administration of kisspeptin antagonist alone. In the rats given kisspeptin plus p234 or RF9 plus p234, VO was not different from control rats. Kisspeptin and RF9 elicited significant elevations in circulating LH levels. Coadministrations of kisspeptin or RF9 with p234 decreased LH levels significantly. The use of p234 alone did not cause any significant change in LH secretion. Kisspeptin decreased both food intake and body weight while RF9 decreased only food intake without affecting body weight. The effects of kisspeptin on energy balance were also reversed by central administration of p234. In conclusion, kisspeptin antagonist, p234, modulates the effects of kisspeptin on reproductive functions and energy balance, whereas RF9 seems to exert only its effects on reproductive functions by means of GPR54 signaling in female rats.Öğe Kisspeptin-10 elicits triphasic cytosolic calcium responses in immortalized GT1-7 GnRH neurones(Elsevier Ireland Ltd, 2011) Ozcan, Mete; Alcin, Ergul; Ayar, Ahmet; Yilmaz, Bayram; Sandal, Suleyman; Kelestimur, HalukKisspeptins, which are alternatively called as metastin since they were originally identified as products of metastasis suppressor gene KiSS-1, are the natural ligands for the G protein-coupled receptor 54 (GPR54). Kisspeptins are the most potent activators of hypothalamic-pituitary-gonadal (HPG) axis reported to date. The pulsatile pattern of GnRH release, which results in the intermittent release of gonadotropic hormones from the pituitary, has a critical importance for reproductive function but the factors responsible from this release pattern are not known. Therefore, the pattern of kisspeptin-induced intracellular signaling and the role of PKC in the intracellular signaling cascade were investigated by fluorescence calcium imaging using the immortalized GnRH-secreting GT1-7 hypothalamic neurons. Kisspeptin-10 caused a triphasic change characterized by an initial small increase followed by a significant decrease and increase in intracellular free calcium concentrations ([Ca2+](i)). The changes in [Ca2+](i) were significantly attenuated by pre-treatment with protein kinase C inhibitor. The compatibility of appeared mirrored-patterns of kisspeptin-10-induced changes in [Ca2+](i) concentrations in these neurons and GnRH secretion confirm the importance of intracellular calcium flux downstream from GPR54 through PKC signaling pathway. (C) 2011 Elsevier Ireland Ltd. All rights reserved.Öğe Melatonin elicits protein kinase C-mediated calcium response in immortalized GT1-7 GnRH neurons(Elsevier Science Bv, 2012) Kelestimur, Haluk; Ozcan, Mete; Kacar, Emine; Alcin, Ergul; Yilmaz, Bayram; Ayar, AhmetMelatonin is suggested to have effects on hypothalamic-pituitary-gonadal (HPG) axis. The pulsatile pattern of GnRH release, which results in the intermittent release of gonadotropic hormones from the pituitary, has a critical importance for reproductive function but the factors responsible from this release pattern are not known. Calcium is a second messenger involved in hormone release. Therefore, investigation of the effects of melatonin on intracellular free calcium levels ([Ca2+](i)) would provide critical information on hormone release in immortalized GnRH neurons. The pattern of melatonin-induced intracellular calcium signaling was investigated by fluorescence calcium imaging using the immortalized GnRH-secreting GT1-7 hypothalamic neurons. Melatonin caused a significant increase in [Ca2+](i), which was greatly blocked by luzindole, a melatonin antagonist, or attenuated by pre-treatment with protein kinase C inhibitor. This study suggests that melatonin seems to have a direct effect on GnRH neurons. (C) 2011 Elsevier B.V. All rights reserved.Öğe Meteorin-Like Protein Reduces Oxidative Damage in Diabetic Mice(Wiley, 2023) Yuksel, Furkan; Tekin, Suat; Ozcan, Mete; Tekin, Cigdem[Abstract Not Available]Öğe Oxytocin activates calcium signaling in rat sensory neurons through a protein kinase C-dependent mechanism(Springer, 2014) Ayar, Ahmet; Ozcan, Mete; Alcin, Ergul; Serhatlioglu, Ihsan; Ozcan, Sibel; Kutlu, Selim; Kelestimur, HalukIn addition to its well-known effects on parturition and lactation, oxytocin (OT) plays an important role in modulation of pain and nociceptive transmission. But, the mechanism of this effect is unclear. To address the possible role of OT on pain modulation at the peripheral level, the effects of OT on intracellular calcium levels ([Ca2+](i)) in rat dorsal root ganglion (DRG) neurons were investigated by using an in vitro calcium imaging system. DRG neurons were grown in primary culture following enzymatic and mechanical dissociation of ganglia from 1- or 2-day-old neonatal Wistar rats. Using the fura-2-based calcium imaging technique, the effects of OT on [Ca2+](i) and role of the protein kinase C (PKC)-mediated pathway in OT effect were assessed. OT caused a significant increase in basal levels of [Ca2+](i) after application at the doses of 30 nM (n=34, p<0.01), 100 nM (n=41, p<0.001) and 300 nM (n=46, p<0.001). The stimulatory effect of OT (300 nM) on [Ca2+](i) was persistent in Ca2+-free conditions (n=56, p<0.01). Chelerythrine chloride, a PKC inhibitor, significantly reduced the OT-induced increase in [Ca2+](i) (n=28, p<0.001). We demonstrated that OT activates intracellular calcium signaling in cultured rat primary sensory neurons in a dose-and PKC-dependent mechanism. The finding of the role of OT in peripheral pain modification may serve as a novel target for the development of new pharmacological strategies for the management of pain.Öğe The Effects of Meteorin-Like Protein on Diabetic Neuropathy: In Vivo and In Vitro Model Studies(Wiley, 2025) Yuksel, Furkan; Taslidere, Asli; Ozcan, Mete; Tekin, Cigdem; Tekin, SuatDiabetes is a disease characterized by insulin metabolism, and diabetic neuropathy (DN) develops as a result of prolonged hyperglycemia. Meteorin-like protein (Metrnl), which has been found to regulate insulin resistance in conducted studies, is thought to be therapeutic for type-2 diabetes. This study was conducted to investigate the efficacy of Metrnl on In Vivo and In Vitro diabetic neuropathy model. In study, 40 normoglycemic male Balb-C mice were divided into 4 groups (n = 10). Except for control, all groups received a single intraperitoneal (ip) injection of streptozotocin (STZ). After 72 h, blood glucose level was measured and animals above 250 mg/dL were considered diabetic. 14-day experiments were initiated 21 days after the onset of diabetes. Every day for 14 days, 0.9% isotonic sodium chloride was administered to DN group, and 2-4 mu g/kg/day ip Metrnl was administered to treatment groups, and nociceptive behavior tests were performed simultaneously. End of experiment, animals were decapitated, and pancreatic tissues were collected. Dorsal root ganglion (DRG) isolated from Wistar Albino rats aged 1-2 days were exposed to high glucose for 24 , and the effect of Metrnl on cell viability and cellular pathway it utilizes were determined. It was observed that Metrnl injection increased the pain threshold (p < 0.05), improved oxidative stress parameters (p < 0.05), and restored histopathological damage of the pancreas (p < 0.05) compared to the DN group. Furthermore, Metrnl was detected to increase cell viability by utilizing mitogen-activated protein kinase pathway in DRG (p < 0.05). These findings suggest that Metrnl has neuroprotective and analgesic efficacy and ameliorates oxidative damage and histopathologic status of pancreas.
