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Öğe Akut ketamin uygulamasının kognitif fonksiyonlar üzerine etkilerinin araştırılması(Dicle Üniversitesi, Sağlık Bilimleri Enstitüsü, 2018) Uyar, Emre; Erdinç, MeralAmaç: Major Depresif Bozukluk tedavisinde kullanılan klasik ajanların etkilerinin belli bir periyod sonrasında baĢlaması ve vakaların önemli bir kısmında etkisiz kalmaları, yeni ve hızlı-etkili terapötik yaklaĢımlara ihtiyaç duyulmasına sebep olmaktadır. Literatürde, subanestezik tek-doz ketamin uygulamasının, hızlı ve güçlü antidepresan-benzeri etkiler oluĢturduğu, tekrarlanan yüksek-doz uygulamaların ise kognitif fonksiyon bozukluklarına neden olduğu belirtilmektedir. Antidepresan etki oluĢumuna, serotonerjik aĢırımda güçlenme ve AMPA reseptör aktivasyonunu içeren çeĢitli mekanizmaların katkı sağladığı vurgulanmaktadır. Bu çalıĢmada, subanestezik dozda ketamin'in tekrarlanan uygulamaları ile emosyonel bellek süreçleri (edinme, pekiĢtirme ve geri çağırma) üzerine oluĢan etkilerin incelenmesi; akut ketamin uygulamasının antidepresan etkinliğinde serotonerjik sistemin ve AMPA reseptörlerinin rollerinin araĢtırılması planlanmıĢtır. Gereç ve Yöntem: Bu amaçla deneklerin, methiothepin ile serotonin reseptör antagonizması veya p-klorofenil alanin ile serotonin deplesyonu suretiyle serotonerjik aktiviteleri, GYKI-52466 ile de AMPA reseptörleri baskılanmıĢır. Antidepresan kontrol grubu olarak fluoksetin kullanılmıĢ ve ketamin ile kombinasyonunun etkileri değerlendirilmiĢtir. Psikofarmakolojik incelemeler; zorunlu yüzme, açık alan, yükseltilmiĢ artı labirenti ve pasif sakınma test düzenekleriyle gerçekleĢtirilmiĢtir. Lipid peroksidasyonları, beyin malondialdehit seviyeleri incelenerek değerlendirilmiĢtir. Ek-4 xvi Beyin kesitlerinde kaspaz-3 ekspresyon seviyeleri incelenmiĢ ve histopatolojik değerlendirmeler yapılmıĢtır. Bulgular: Tekrarlanan ketamin uygulamalarıyla emosyonel bellek süreç performanslarında, kaspaz-3 ekspresyon ve malondialdehit seviyelerinde anlamlı farklılık gözlemlenmemiĢtir. Buna karĢın, ketamin uygulanan grupların beyin kesitlerinde gerçekleĢtirilen histopatolojik incelemelerde kısmi nörodejeneratif bulgular tespit edilmiĢtir. Subanestezik tek-doz ketamin uygulaması ile lokomotor aktivite etkilenmeksizin hızlı antidepresan-benzeri etkiler oluĢtuğu gözlemlenmiĢtir. Serotonerjik aktivitenin baskılanması ve AMPA reseptörlerinin antagonize edilmesi durumlarında ketamin'in antidepresan-benzeri etki oluĢturmakta baĢarısız olduğu anlaĢılmıĢtır. Sonuç: Kullandığımız subanestezik dozda ketamin'in tekrarlanan uygulamalarıyla beyinde kısmi nörodejenerasyonu iĢaret eden bulgular saptanmıĢ, oluĢan bu dejenerasyonun davranıĢ deneyleri ile incelenen emosyonel bellek süreçlerini etkileyecek boyutta olmadığı anlaĢılmıĢtır. GerçekleĢtirilecek ileri çalıĢmalar, ketamin'in antidepresan etki mekanizmasının ve glutamaterjik sistemin depresyondaki rolünün aydınlatılmasına olanak sağlayacaktır.Öğe Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems(Taylor and Francis Ltd., 2019) Erdinç, Meral Alper; Uyar, Emre; Kelle, İlker; Akkoç, HasanOBJECTIVE: In pain management, alternative medications are necessary due to the development of tolerance to traditional opioid analgesics. Literature data suggest that N-methyl-D-aspartate (NMDA) receptor antagonizing drugs can induce antinociception, and can reduce the opioid requirement. Ketamine is a non-competitive NMDA receptor antagonist drug and has well-known antinociceptive properties. The drug acts not only on NMDA receptors but also has effects on the monoaminergic system and non-NMDA glutamatergic receptors which have vital roles in the regulation of pain. This study was conducted to investigate the serotonergic and glutamatergic involvement in low-dose ketamine (20 mg/kg) analgesia in mice. METHOD: The effects of serotonin were suppressed with two different ways; either the serotonin was depleted with p-chlorophenylalanine (pCPA, 150 mg/kg/d; 4 days) or the serotonin receptors were blocked with methiothepin (0.1 mg/kg), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors were antagonized with GYKI-52466 (20 mg/kg). Fluoxetine (20 mg/kg; 7 days) was used to increase the serotoninergic activity. We used a hotplate (HP) test to measure pain reaction latencies. Furthermore, we tested sustained analgesic effects of ketamine for six consecutive times (1-hour break between each test). RESULTS: In our experiment, ketamine treatment increased pain reaction latencies, yet it failed to increase the latencies when combined with antiserotonergic drugs, e.g. pCPA and methiothepin. The latencies were increased with AMPA receptor blockade, yet ketamine did not increase the analgesic effect of the AMPA receptor antagonist, i.e. GYKI-52466. In consecutive tests, ketamine was effective for 5 h, and the peak effect was seen at the 3rd-hour test. CONCLUSION: Our data suggest that the activity of the serotonergic system and AMPA receptors are necessary for ketamine to produce antinociceptive effects. In pain management, ketamine can offer an alternative option to traditional analgesics and may be useful to reduce opioid tolerance.Öğe A case-control study on depression, anxiety, and belief in sexual myths in trans women(Frontiers Media S.A., 2023) Uyar, Betül; Yücel, İlyas; Uyar, Emre; Budak, Elif Ateş; Kelle, İlker; Bülbüloğlu, SemraObjective: The purpose of our study was to investigate depression, anxiety, and belief in sexual myths in trans women. Methods: This is a prospective case-control study. The case group included 60 trans women who were referred to the Medical Biology and Genetics Department from various clinics of the research and training hospital where this study was conducted. The control group consisted of 60 healthy male individuals who presented to the same hospital for routine health follow-ups and collecting documents showing their health. In data collection, we used a Personal Information Form, the Sexual Myths Scale, and the Beck Depression and Anxiety Inventories. The IBM Statistical Package for the Social Sciences 25.0 was used to analyze the data. Results: In the case group, 26.7% of the participants were sex workers, and all were single. While 46.7% of the participants in the case group were living with their families, 66.7% were smokers, and 13.3% were receiving hormone treatment. All 60 participants in the control group were also single. The participants in the control group had higher levels of believing sexual myths and lower levels of anxiety and depression than those in the case group (p = 0.000). The mean scores of the participants in the control group in the Sexual Orientation and Sexual Violence subscales of the Sexual Myths Scale were higher than the mean scores of those in the case group (p < 0.05). Conclusion: The trans women who participated in this study had higher levels of anxiety and depression and lower levels of believing sexual myths than the control group. The mental health of trans women can be disrupted due to various treatments they are exposed to in society such as stigma, discrimination, and violence. Their higher anxiety and depression levels in this study could be explained by this exposure. This exposure could also have led to their lower total scores in the Sexual Myths Scale, as well as lower scores in the Sexual Violence and Sexual Orientation subscales.Öğe Deneysel diyabetin neden olduğu depresyon tedavisinde minosiklin ve minosiklin+metformin kullanımı(Ankara Üniversitesi Eczacılık Fakültesi, 2022) Çamçi, Merve İnci; Erdinç, Meral; Uyar, Emre; Kelle, İlkerAmaç: Minosiklin, santral sinir sistemine geçebilen, ikinci kuşak tetrasiklin grubu bir antibiyotiktir. Minosiklinin anti-inflamatuar, mikroglial aktivasyonu azaltma, anti-apoptotik, antioksidan özellikleri olduğu bilinmektedir. Son yıllarda diyabet ve depresyon arasında çift yönlü bir ilişki olduğunun ve fizyopatolojilerinde ortak yolaklardan birinin inflamasyon olduğunun ileri sürülmesi ile minosiklinin depresyon üzerine etkileri çalışılmaya başlanmıştır. Bu çalışmada minosiklinin tek başına ve diyabet tedavisinde kullanılan metformin ile kombinasyonu şeklinde kullanımının, diyabet ile ilişkili depresyon üzerine etkilerinin ortaya konması amaçlandı. Gereç ve Yöntem: Farelerde insandakine benzer tip 2 diyabet modeli oluşturmak için 4 haftalık yüksek kalorili diyetin ardından ardışık beş gün, günde 1 defa streptozotosin (50mg/kg) uygulandı, uygulamadan 1 hafta sonra açlık kan glukoz düzeyi 200 mg/dl’nin üzerinde olan deneklerde diyabetin oluştuğu kabul edilip deneye dahil edildi. Streptozotosin (STZ) enjeksiyonundan iki hafta sonra minosiklin (40mg/kg), fluoksetin (20mg/kg) ve metformin (200mg/kg) 7 gün süre ile günde bir defa uyguladı. İlaç uygulamaları tamamlandıktan sonra; lokomotor aktivitenin belirlenmesi için açık alan testi, depresyon düzeyinin belirlenmesi için zorunlu yüzme testi yapıldı. Sonuç ve Tartışma: Diyabetin ve uygulanan ilaçların lokomotor aktivitede anlamlı bir değişiklik oluşturmadığı, minosiklin ve minosiklin-metformin kombinasyonunun ise depresyon tedavisinde en az fluoksetin kadar etkili olduğu sonucuna varıldı. Antidepresan etkinin kısa sürede başlamasının hastanın tedaviye uyuncu ve diyabetin prognozu açısından oldukça önemli olduğu bilinmektedir. Bu nedenle de minosiklin uygulamasının gösterdiği antidepresan etki üzerine yapılan çalışmalar derinleştirilmeli, etkinin mekanizması araştırılmalıdır.Öğe The Effects of Ethyl Pyruvate on Behavioral and BiochemicalParameters in Immobilization Stress-Induced Mice(2021) Akkoc, Hasan; Uyar, Emre; Abul, Mihrab; Dönmezdil, SüleymanObjective: Ethyl pyruvate (EP) is a molecule with antioxidant, anti-inflammatory, and anti-apoptotic features. The present study investigates EP's effects on behavioral and biochemical alterations induced by immobilization (IM) stress. Methods: In this outcome, 45 male BALB/c mice were separated into five groups [CONT (control), IM, IM+EP, EP, IM+F (fluoxetine)]. IM applied groups had 6 hours of immobilization stress procedure a day for a week. EP (50 mg/day) and fluoxetine (5 mg/day) were applied to the mice intraperitoneally. After the stress induction protocol, passive avoidance, open field (OF), and forced swimming tests (FST) were executed. After behavioral tests, brain tissues were obtained for biochemical investigations. Results: Immobilization application increased immobility times in the FST and decreased the total distance moved and the center time in the OF test. Immobile times were reduced with fluoxetine and EP applied groups compared with the IM group due to decreased learned helplessness. The IM group had decreased brain-derived neurotrophic factor (BDNF), superoxide dismutase, and glutathione peroxidase levels, which were increased with EP applications.Conclusion: These results show that EP generates antidepressant-like effects with decreasing oxidation and increasing BDNF levels.Öğe The effects of melatonin, fluoxetine and their combinations on stress induced behavioral and cognitive impairments in mice(Ankara Üniversitesi Eczacılık Fakültesi, 2023) Çamçi, Merve İnci; Erdinç, Meral; Kelle, İlker; Uyar, Emre; Erdinç, LeventObjective: Melatonin (Mel) is a hormone with anti-depressant and anti-oxidant features. It is well known that melatonin protects brain cells from reactive oxygen species and that the brain's high oxygen consumption and lipid content make it particularly vulnerable to oxidative stress caused by prolonged stress. This study aims to investigate the effects of melatonin, fluoxetine and their combinations on emotional memory, depression, and anxiety-like behavioral changes induced by immobilization (Imb) stress. Material and Method: 48 male Balb/c mice were divided into eight groups: Cnt (control), Imb, Imb+Mlt, Imb+Flx (fluoxetine), Imb+Mlt+Flx, Mlt, Flx and Mlt+Flx. For seven days in a row, the mice underwent daily immobilization stress for 6 hours. Mice were treated with Mlt (10 mg/kg) and Flx (20 mg/kg). All animals were subjected to the behavioral tests; forced swimming test (FST), open field test (OFT), elevated plus maze (EPM), passive avoidance test (PAT) and hot plate (HP) test. After all behavioral tests, brain tissues were obtained for malondialdehyde level analysis. Result and Discussion: OFT test data showed the time spent in the central zone and the number of entrances to the central area were significantly lower in the Imb group compared to the Cnt group, these were higher in the Imb+Flx, Imb+Mlt, Imb+Mlt+Flx groups compared to the Imb group. Also, according to the data obtained from FST, immobile time was significantly higher in the Imb group compared to the Cnt group, it was lower in the Imb+Flx, Imb+Mlt, Imb+Mlt+Flx groups compared to the Imb group. Besides, it was demonstrated that the emotional memory index was statistically higher in the Imb group compared to the Cnt group, and the increasing of memory index returned to normal in the Imb+Mlt and Imb+Mlt+Flx groups with PAT. And also, lipid peroxidation level, which increased in the Imb group, decreased significantly in the Imb+Flx, Imb+Mlt, and Imb+Mlt+Flx groups. As a result, it was observed that melatonin has anti-depressant, anxiolytic, antioxidant effects and normalized emotional memory. Also, melatonin, fluoxetine and their combinations exert similar effects in the present study.Öğe Effects of Sublethal Doses of Thiacloprid, a Neonicotinoid Insecticide, on Learning and Memory Performance of Mice(Asian Network Scientific Information-Ansinet, 2020) Akkoc, Hasan; Acar, Abdullah; Toprak, Gulten; Uyar, EmreBackground and Objective: Thiacloprid (THI), a neonicotinoid insecticide, currently one of the most preferred insecticides worldwide. Although they are claimed to be less hazardous on mammals, late studies revealed the harmful effects of this kind of insecticides. However, there are few studies examining the effect of THI on learning and memory performance in the literature. This study was conducted to investigate the effects of sublethal doses of THI on learning and memory functions and to determine the effect of the protocol on biochemical parameters. Materials and Methods: In this outcome, 50, 100 and 200 mg kg(-1) THI were administered by oral gavage for 3 weeks in mice (n:7). At the end of this process, a novel object recognition (NOR) and passive avoidance (PA) tests were conducted to measure learning and memory functions. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) levels were measured biochemically. Results: In the NOR test, reductions in the discrimination index values were observed with THI applications. The step-through latencies of the mice to enter the dark compartment in the retention trial of the PA test was reduced similarly in THI applied groups. The biochemical investigations revealed that BDNF and GPx levels in the brain tissue were significantly reduced in all groups compared to the control group, while a significant reduction in NGF levels was observed only in 200 mg kg(-1) applied group. There was no significant difference in SOD and CAT levels between test groups. Conclusion: These results indicated that sublethal, chronic THI application degenerates the learning and memory functions with affecting BDNF, NGF and GPx levels.Öğe Exenatide Treatment Exerts Anxiolytic- and Antidepressant-Like Effects and Reverses Neuropathy in a Mouse Model of Type-2 Diabetes(Int Scientific Information, Inc, 2014) Celikyurt, Ipek Komsuoglu; Mutlu, Oguz; Ulak, Guner; Uyar, Emre; Bektas, Emine; Akar, Furuzan Yildiz; Erden, FarukBackground: Comorbid neurobehavioral disturbances and type-2 diabetes mellitus (T2DM) warrant immediate research attention. Exenatide, which is a potent and selective agonist for the glucagon-like peptide-1 (GLP-1), is used in the treatment of T2DM. Exenatide displays a multitude of effects in the central nervous system. The aim of this study was to investigate the anxiolytic- and antidepressant-like effects and analgesic effects of exenatide in a type-2 diabetic mouse model. Material/Methods: Modified elevated plus-maze test for anxiolytic- like, forced swimming test for depression-like behavior and hotplate test for neuropathy were used as behavioral tasks. Behavioral parameters were investigated in a streptozocin - (100 mg/kg, i.p.) and nicotinamide - (240 mg/kg, i.p.) induced type-2 diabetic mouse model. Exenatide (0.1 mu g/kg, s.c., twice daily) was administered for 2 weeks. Vehicle (control), diabetic, and exenatide-treated diabetic mice were tested. Results: Our results confirm that exenatide exerts anxiolytic- and antidepressant-like effects and might be effective in diabetic neuropathy in a diabetic mouse model. Conclusions: Exenatide may be a good candidate as a treatment option for depression, anxiety, and neuropathy in patients with type-2 diabetes.Öğe İn vivo sıçan kalbinde oluşturulan iskemi reperfüzyon hasarında Rosuvastatin'in koruyucu etkisinin iskemik önkoşullama ile karşılaştırılması(2015) Uyar, Emreİskemi sonrası reperfüzyonun yol açtığı ağır oksidatif stres ciddi işlevsel ve yapısal hasara yol açamaktadır. Bu hasardan başlıca serbest oksijen radikalleri sorumlu tutulmaktadır. Son yıllarada farklı organlarda yapılan çalışmalarda reperfüzyon kaynaklı hasara karşı iskemik önkoşullama gibi yöntemlerin yanı sıra birçok antioksidan maddenin koruyucu etkileri gösterilmiştir. Statin bileşikleri arasında yer alan rosuvastatinin pleiotropik etkileri ile reperfüzyon döneminde izlenen oksidatif strese karşı antioksidan ve antienflamatuar etkinliğiyle kardiyak hasarı azaltmada yararlı bulunmuştur. Bu çalışmada sol koroner arter ligasyonu ile miyokard iskemisi oluşturulan kalplerde, rosuvastatin ile gerçekleştirilen farmakolojik önkoşullamanın koruyucu etkisi, iskemik önkoşulama ile karşılaştırıldı. Bu amaçla, kullanılan erkek wistar albino sıçanlar; Sham opere grubu, İskemi Reperfüzyon (İR) grubu (30 dk iskemi, 120 dk reperfüzyon), İskemik Önkoşullama (İÖK) grubu (3 siklus halinde 5 dk. iskemiyi takiben 5 dk. Reperfüzyon) ve Farmakolojik Önkoşullama (FÖK) grubu (10 mg/kg rosuvastatin, iv infüzyon şeklinde) olmak üzere 4 gruba ayrıldı. Tüm gruplarda stabilizasyonun 10. dakikasında, iskeminin sonunda, reperfüzyonun 60. ve 120. dakikalarında kreatin kinaz-miyokard bandı (CK-MB) düzeyleri ölçümü için kan örneği alındı ve alınan miktar kadar vücut sıcaklığına getirilmiş serum fizyolojik verildi. Tüm protokol boyunca ratlarda stabilizasyonun 10. dakikasında, iskeminin sonunda, Reperfüzyonun 60. ve 120. dakikalarında 3 er tekrar şeklinde arteriyel tansiyon ve nabız ölçümü yapıldı. Deney protokolünün sonunda nekroz alanı tayini için kalplere evans mavisi ve 2,3,5-Trifeniltetrazolyum klorür (TTC) boyası ile muamele edildi. Deneyler sonucuında, iskemi reperfüzyon grubuna göre CK-MB düzeylerinde iskemi sonunda, reperfüzyonun 60. ve 120. dakikalarında anlamlı şekilde düşüş izlendi (p<0.05). Ayrıca, iskemi sonunda farmakolojik önkoşullama grubundaki CK-MB düzeyindeki azalmanın iskemik önkoşullama grubuna göre anlamlı şekilde farklı olduğu gözlendi (p<0.05). Nekroz alanlarındaki değişimler açısından yapılan karşılaştırmada, iskemik önkoşullama grubunda, gerek ağırlık ve gerekse hacim açısından iskemi reperfüzyon grubuna göre düşük değerler izlenirken (p<0.01), farmakolojik önkoşullama grubunda nekroz alanı boyutlarının en düşük değerleri aldığı gözlendi (p<0.01). Sonuç olarak, rosuvastatin ile yapılan farmakolojik önkoşullamanın, iskemi reperfüzyon hasarına karşı, iskemik önkoşullamadan daha etkili ve koruyucu olduğu görüldü. Anahtar kelimeler: İskemi Reperfüzyon Hasarı, İskemik Önkoşullama, Farmakolojik Önkoşullama, Rosuvastatin, Oksidatif stres, Antioksidan etkilerÖğe Investigating the Effects of Trolox on Behaviour and Biochemical Parameters in Mice Exposed to Immobilization Stress(Asian Network Scientific Information-Ansinet, 2019) Toprak, Gulten; Akkoc, Hasan; Uyar, EmreBackground and Objective: Stress is known to play a causal role in several neuropsychiatric disorders. Trolox has been reported to show potent antioxidant activity against reactive oxygen species. The aim of this study was to investigate the effect of trolox on the behaviour and biochemical parameters of mice exposed to immobilization stress. Materials and Methods: The mice were subjected to 6 h of immobilization stress daily for 7 consecutive days. The 48 mice were randomly divided into 6 groups with 8 mice each: (I) Control, (II) Immobilization (IM), (III) Immobilization+Trolox (IM+T), (IV) Immobilization+Fluoxetine (IM+F), (V) Immobilization+Trolox+Fluoxetine (IM+T+F) and (VI) Trolox (T). At the end of day 7, open field test (OFT) and forced swimming test (FST) were performed to assess the locomotor activity and anxiety-like behaviour in mice. After the completion of these tests, brain tissue samples were removed for biochemical analysis. Results:The OFT and FST results indicated that the incidences of anxiety-like and depression-like behaviour were significantly lower in the IM+T group compared to the IM group. A significant improvement was observed in the groups treated with trolox for the catalase, total oxidant status, total antioxidant status and oxidative stress index values deteriorated by immobilization. Conclusion:The results implicated that antioxidant molecules such as trolox can lead to favourable outcomes in the treatment of oxidative damage either in isolation or in combination with classic treatment methods.Öğe Investigation of the effects of Trpc4/5 inhibitor M084 in experimental alzheimer’s-likedementia model(Kırşehir Ahi Evran Üniversitesi, 2022) Güneş, Ali; Akkoç, Hasan; Uyar, EmrePurpose: This study aimed to research the effects of N-butyl-1H]-benzimidazole-2-amine (M084) on cognitive functions in an experimental Alzheimer-like dementia model.Materials and Methods: In our study, male rats were divided into five groups (n:8). The control (C) had 1 ml 0.9% saline solution administered intraperitoneally (i.p.) for 14 days. Scopolamine (S) was administered intraperitoneally with 1 ml 0.9% saline solution for the first 7 days, followed by 3 mg/kg scopolamine on days 8-14.Scopolamine+M084 (SM) was administered i.p. dissolved in 1 ml 0.9% saline solution for the first 7 days, followed by 3 mg/kg scopolamine on days 8-14 and 20 mg/kg M084 on days 10-14. M084 (M) was administered i.p. 20 mg/kg M084 in a single daily dose from days 0-14. Positive control (D) had 5 mg/kg donepezil administrations on days 0-14 and 3 mg/kg scopolamine on days 8-14.On days 14 and 15 of the study, passive avoidance, novel object recognition, and modified elevated plus maze tests were performed.Results: In the passive avoidance test, transfer latencies were significantly lower in group S compared to group C. In the modified elevated plus maze test, the passing time to either closed arms on the 2nd-day test was significantly higher in group S compared to groups C and D. In the novel object recognition test, the values for groups C, SM, D, and other groups were significantly higher compared to group S.Conclusion: In conclusion, in an Alzheimer-like dementia model, M084 provided positive results for visual memory; however, it was ineffective for other memory types.Öğe Involvement of necroptosıs and apoptosıs ın protectıve effects of cyclosporın a on ischemıa-reperfusıon injury in rat kıdney(Springer, 2025) Ozgen, Zeynep Erdogmus; Erdinc, Meral; Kaya, Meryem Seyda; Aktar, Fesih; Ozekinci, Selver Ozsener; Erdinc, Levent; Uyar, EmreWe aimed to investigate the protective effects of low dose cyclosporin A (CsA) on ischemia-reperfusion (IR) injury in rat the kidney and on the apoptotic and necroptotic mechanisms involved. 1. Control group (received a single intraperitoneal (i.p.) dose of 1 ml sterile saline 15 min before the surgical procedure), 2. IR group (was subjected to 30 min of bilateral kidney ischemia followed by 90 min of reperfusion; and received a single i.p. dose of 1 ml sterile saline 15 min before the IR procedure, 3. IR + CsA group (received a single i.p. dose of 3 mg/kg CsA 15 min before the IR procedure. Renal functions (renal perfusion pressures, and serum urea-creatinine levels), kidney histological scores, MDA levels, and TNF-alpha, caspase-3, RIP1, RIP3, MLKL, CaMKII and CypD protein expressions were also measured. Renal perfusion pressures (PP), serum urea and creatinine levels, renal tissue MDA levels, and the protein expression levels of TNF-alpha, caspase-3, RIP1, RIP3, MLKL, CAMKII and CypD were significantly increased in the IR group compared to the control group (p < 0.05), Additionally, there were significant decreases in all the parameters in the IR + CsA group compared to those in the IR group (p < 0.05). Furthermore, histopathological analyses revealed significantly higher kidney injury scores in the IR group compared to the control group, and low dose CsA treatment improved the injury. A single low dose of CsA injection 15 min before IR, demonstrated a protective effect on bilateral renal IR injury and a reduction in apoptotic and necroptopic markers which is resulted in improvement of renal functions.Öğe The Involvement of the Serotonergic System in Ketamine and Fluoxetine Combination-induced Cognitive Impairments in Mice(Ataturk Univ, 2024) Uyar, Emre; Erdinc, Meral; Kelle, Lker; Erdinc, Levent; Seker, Ugur; Nergiz, YusufBackground: Gluta mater gic N-methyl-D-aspartate (NMDA) receptors play vital roles in memory formation. Changes in the activity of these receptors influence memory processes. Ketamine is a noncompetitive NMDA receptor antagonist drug with promising mood-altering and pain-reducing effects ff ects in low doses. These effects ff ects are believed to be related to altered serotonergic transmission. Methods: The present study investigated the involvement of the serotonergic system in low-dose ketamine administrations' effects ff ects on memory acquisition, consolidation, and retrieval processes. Sixty-four male BALB/c mice were used in this experiment and separated into 8t groups. Mice were treated subchronically with a selective serotonin reuptake inhibitor, fluoxetine, and a serotonin depletion agent, p-chlorophenylalanine (pCPA). A serotonin antagonist, methiothepin, and ketamine were acutely administered 60 minutes before or after the behavioral tests. A passive avoidance (PA) test measured emotional memory acquisition, consolidation, and retrieval processes. Hippocampi malondialdehyde (MDA) levels were analyzed, and histopathological examinations were performed. Results: Ketamine alone did not significantly affect ff ect memory encoding processes in the PA test, while the ketamine-fluoxetine combination disrupted memory consolidation. Fluoxetine negatively affected ff ected the memory acquisition process, which was normalized during the consolidation and retrieval trials. Drug applications did not significantly alter hippocampal MDA levels. In all ketamine-applied groups, histopathologic alterations were evident. Conclusion: Low-dose ketamine administration induces neurodegeneration, and it also impairs memory functions when combined with fluoxetine, indicating increased serotonergic transmission may be involved in the memory-impairing and neurotoxic effects ff ects of ketamine.Öğe The M1/M2 Macrophage Polarization and Hepatoprotective Activity of Quercetin in Cyclophosphamide-Induced Experimental Liver Toxicity(Wiley, 2025) Seker, Ugur; Uyar, Emre; Gokdemir, Gul Sahika; Kavak, Deniz Evrim; Irtegun-Kandemir, SevgiBackground: Chemotherapy drugs may lead to hepatic injury, which is considered one of the limitations of these drugs. Objectives: The aim of this study was to evaluate the effect of quercetin (QUE) on M1/M2 macrophage polarization and hepatoprotective effect in cyclophosphamide (CTX)-induced liver toxicity. Methods: Twenty-four mice were divided into four groups (Control, QUE, CTX, CTX + QUE). The CTX and CTX + QUE groups received 200 mg/kg CTX. The animals in the QUE and CTX + QUE groups received 50 mg/kg QUE. All animals were sacrificed, and serum and liver samples were used for laboratory analyses. Results: Examinations indicated that CTX exposure led to disruption of liver functions and morphological degenerations. Tissue pro-apoptotic Bax and caspase 3, pro-inflammatory TNF-alpha and IL-1 beta, transcription factor NF-kappa B, and M1 macrophage polarization marker CD86 were upregulated significant (p < 0.05) in this group. In addition, CTX exposure led to significantly (p < 0.05) upregulation of the Bax/Bcl-2 mRNA ratio and DNA fragmentations. The PCNA-positive hepatic cell ratio and anti-apoptotic Bcl-2 expression are remarkably suppressed (p < 0.05). Immunohistochemical analyses are also indicated that M2 macrophage polarization marker CD163 is slightly but remarkably (p < 0.05) downregulated in the CTX group compared to the Control and QUE groups. The morphological and biochemical disruptions were alleviated in QUE-treated animals in the CTX + QUE group. Liver function test results, apoptosis, inflammatory, transcription factor NF-kappa B, regeneration/proliferation, and apoptotic index results in this group were similar (p > 0.05) to the control and QUE groups. The M1 cell surface marker expression of CD86 is significantly (p < 0.05) downregulated, and M2 macrophage polarization marker expression of CD163 is upregulated significantly (p < 0.05) compared to the CTX group. Conclusions: This study indicates that QUE has the potential to downregulate CTX-induced hepatic injury and regulate M1/M2 macrophage polarization to the M2 side, which indirectly demonstrates activation of anti-inflammatory signalling and tissue repair.Öğe QbD application for a fixed-dose combination with biowaiver potential: Evaluations of In vitro and In vivo applications(Springer, 2022) Yaşın, Diren Sarısaltık; Uslu, Abdullah; Uyar, Emre; Erdinç, Meral; Teksin, Zeynep ŞafakPurpose The purpose of this study was to use the quality by design (QbD) approach to design a directly compressed fixed-dose combination (FDC) tablet comprising amlodipine besylate and enalapril maleate with biowaiver potential in alignment with the Biopharmaceutical Classification System (BCS). Methods As a result of the risk assessment, the amounts of the formulation components such as disintegrant, binder, and lubricant were selected as critical material attributes, and the processes of blending and lubrication were accepted as critical process parameters in a screening design of Plackett-Burman. These factors were evaluated based on the statistical significance of their impact on the drug product's content uniformity, assay, friability, disintegration, and dissolution. The most significant factors determined with the use of Pareto charts and half-normal graphs were the amount of lubricant and disintegrant and blending time, all of which were subsequently optimized using Box-Behnken Design. The optimum formulation was evaluated with in vitro quality tests and in vivo blood pressure-lowering efficacy tests, the results of which were compared to the individual references in rats. Results As a result of the optimization process, a design space was established for the critical factors. FDC product showed quality and dissolution profiles similar to those of the references. Combination therapy was superior to individual drugs in rats (p < 0.05). Conclusion It was concluded that an FDC product eligible for BCS-based biowaiver can be developed systematically by using the QbD concept. It was demonstrated that using scanning designs prior to optimization can reduce the number of unnecessary experiments and yield more reliable results in less time.Öğe Risperidone and ethyl pyruvate have protective effects against ketamine-induced cognitive impairments in mice(Verduci Publisher, 2022) Kelle, İlker; Eriman, H.; Erdi̇nç, Meral Alper; Uyar, EmreOBJECTIVE: Ketamine, an N-methyl D-aspartic acid receptor antagonist drug, is reported to produce memory disruptions. The aim of this study was to investigate the protective effects of ethyl pyruvate (EP), a pyruvic acid derivative, and risperidone, an atypical anti-psychotic drug, against ketamine-induced cognitive disturbances. MATERIALS AND METHODS: A passive-avoidance test, a novel object recognition test, and a modified elevated plus maze test were used to assess memory functions. Hippocampal malondialdehyde (MDA) levels were measured to determine the oxidation levels. RESULTS: Ketamine applications produced memory deficits in all tests and insignificantly increased MDA levels, which were alleviated by risperidone, EP, and combination treatments. CONCLUSIONS: Increased oxidative stress and neurotransmission imbalance can be responsible for ketamine-induced memory disruptions. With its antioxidant effects, EP may be helpful to reduce cognitive impairments related to schizophrenia either alone or in combination with antipsychotics.Öğe Trolox is more successful than allopurinol to reduce degenerative effects of testicular ischemia/reperfusion injury in rats(Elsevier Sci Ltd, 2020) Seker, Ugur; Nergiz, Yusuf; Aktas, Ayfer; Akkus, Murat; Ozmen, Mehmet Ferit; Uyar, Emre; Soker, SevdaIntroduction Reperfusion surgery following testicular ischemia is a reproductive health threatening status and may result with organ dysfunction in men. The high level of reactive oxygen species (ROS) and cease of blood flow to the testis are the most important reasons of this testicular injury. Until today, numerous experimental studies reported that antioxidants might be efficient to alleviate oxidative stress induced organ dysfunction. For this purpose, in this study, we have investigated the protective effects of xanthine oxidase (XO) inhibitor, allopurinol, and ROS scavenger, trolox, in a comparative perspective in testicular ischemia reperfusion injury subjected rats. Materials and methods Twenty-eight adult male Sprague Dawley rats were divided into four groups of seven animals in each; control, ischemia/reperfusion (I/R), allopurinol and trolox. The rats in control group did not receive any application. Animals in I/R, allopurinol and trolox groups were subjected to 2 h testicular reperfusion injury following 5 h ischemia. Intraperitoneally (i.p.) 1 ml isotonic, 200 mg/kg allopurinol and 50 mg/kg trolox were administered to the animals in these groups 30 min prior reperfusion. At the end of experiment, all animals were sacrificed and blood serum malondialdehyde (MDA) levels were measured. Histological sections were obtained from the testis and stained with hematoxylin and eosin (H&E), proliferating cell nuclear antigen (PCNA) and cleaved caspase-3. Apoptotic index was evaluated with TUNEL Assay. Results Severe morphological degenerations, increased serum MDA, cleaved caspase-3 and TUNEL Assay positivity rate, but reduced PCNA positivity rate was observed in ischemia and reperfusion group. Morphological degenerations, MDA level, apoptotic index and PCNA positive cell rate were slightly alleviated in allopurinol administered animals compared with ischemia and reperfusion group. Protection with trolox was more successful and the results of the analysis were similar to the control group. Discussion Ischemia that leading to testicular torsion is a reproductive health affecting problem and current surgical treatment methods might be insufficient to recover testis. Various types of ROS generating mechanisms in cell are limiting protective potency of allopurinol, and cocktail administration of different ROS inhibitors might be more effective. However, our results indicate that free radical scavenger trolox might be a candidate drug to alleviate degenerative effects of testicular ischemia reperfusion injury. Conclusions This is the first study that demonstrates antioxidant trolox was more successful than XO inhibitor allopurinol to protect testis against ischemia and reperfusion injury in rats. [GRAPHICS]
