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Öğe Activation of TRESK background potassium channels by cloxyquin exerts protective effects against excitotoxic-induced brain injury and neuroinflammation in neonatal rats(Elseiver, 2022) Dilek, Mustafa; Kılınç, Yasemin Baranoğlu; Kılınç, Erkan; Torun, İbrahim Ethem; Saylan, Aslıhan; Düzcü, Selma ErdoğanWe investigated effects of activation of TRESK channels by selective activator cloxyquin on excitotoxic-induced brain injury and neuroinflammation involving brain mast cells and inflammatory cytokines in neonatal rats. Three different doses of cloxyquin (0.2, 1 and 5 mg/kg) were studied in ibotenate-induced perinatal brain injury (PBI) in P5 rat-pups. Cerebral lesions and mast cells in coronal brain sections were evaluated. Concentrations of activin A, IL-1 beta, IL-6 and IL-10 in brain homogenates were measured using ELISA. Cloxyquin dose-dependently exerted protective effects against excitotoxic-induced neonatal brain injury and neuroinflammation. TRESK channels may be a promising new target for the treatment of PBIs.Öğe Activation of TRESK channels ameliorates pain and neurogenic inflammation in a nitroglycerin-induced migraine model in rats(Wiley, 2023) Torun, İbrahim Ethem; Kılınç, Yasemin Baranoğlu; Kılınç, Erkan; Töre, FatmaCloxyquin; Mast cell; Migraine; Neurogenic; Inflammation; TRESK Background Potassium ChannelsÖğe Anti-inflammatory potential of liraglutide, a glucagon-like peptide-1 receptor agonist, in rats with peripheral acute inflammation(Springer, 2022) Mert, İrem; Çetinkaya, Ayhan; Gürler, Müjgan; Türel, Canan Akünal; Çelik, Hümeyra; Torun, İbrahim Ethem; Türel, İdrisThe present study aimed to explore the possible anti-inflammatory actions of liraglutide (LRG), a glucagon-like peptide-1 (GLP-1) receptor agonist, and to compare with tramadol (TR) or LRG, and TR combination treatment by investigating the inflammatory signs such as pain hypersensitivity, edema, and fever in carrageenan (CG)-induced acute peripheral inflammation model in rats. The levels of several biomarkers for inflammatory status, angiogenesis, and oxidative stress were also measured in inflamed tissues. CG induced inflammation in the paws of rats identified by hypersensitivities, redness, edema and fever. LRG, significantly improved the hypersensitivity to mechanical (from 4 to 35.5 g) or cold (from 5 to 44.2 s) stimuli, reduced the edema (paw mass, from 2.54 to 1.85 g), and fever (paw temperature, from 33.6 to 27.3 degrees C). LRG dramatically suppressed the inflammatory signs when compared to those of TR. In addition, co-administration of TR and LRG resulted in further reduction of sensitivity to mechanical and cold stimuli. Anti-inflammatory potential of LRG altered depending on their inhibitory effects in the biomarkers of inflamed paws. Consequently, the suppressive actions of LRG in the inflammation induced hypersensitivities, edema, and fever, indicating that these drugs have significant anti-inflammatory potential with anti-hypersensitivities, anti-edema, and anti-pyretic effects. LRG with anti-inflammatory actions may be a highly promising therapeutic option for the management of inflammatory conditions or inflammatory-related various diseases.Öğe The antiinflammatory and electrophysiological effects of fingolimod on penicillin-induced rats(Associação Arquivos de Neuro-Psiquiatria, 2022) Türel, Canan Akünal; Çelik, Hümeyra; Torun, İbrahim Ethem; Çetinkaya, Ayhan; Türel, İdrisBackground The fact that inflammation triggers epileptic seizures brings to mind the antiepileptic properties of anti-inflammatory drugs.Objective To investigate the electrophysiological and anti-inflammatory effects of fingolimod on an experimental penicillin-induced acute epileptic seizure model in rats.Methods Thirty-two male Wistar rats were divided into four groups: control (penicillin), positive control (penicillin + diazepam [5 mg/kg]), drug (penicillin + fingolimod [0.3 mg/kg]) and synergy group (penicillin + diazepam + fingolimod). The animals were anesthetized with urethane, and epileptiform activity was induced by intracortical injection of penicillin (500,000 IU). After electrophysiological recording for 125 minutes, IL-1 beta, TNF-alpha, and IL-6 were evaluated by ELISA in the serum of sacrificed animals.Results During the experiment, animal deaths occurred in the synergy group due to the synergistic negative chronotropic effect of diazepam and fingolimod. Although not statistically significant, fingolimod caused a slight decrease in spike-wave activity and spike amplitudes in the acute seizure model induced by penicillin ( p > 0.05). Fingolimod decreased serum IL-1 beta ( p < 0.05); fingolimod and diazepam together reduced IL-6 ( p < 0.05), but no change was observed in serum TNF-alpha values.Conclusion Even in acute use, the spike-wave and amplitude values of fingolimod decrease with diazepam, anticonvulsant and anti-inflammatory effects of fingolimod will be more prominent in chronic applications and central tissue evaluations. In addition, concomitant use of fingolimod and diazepam is considered to be contraindicated due to the synergistic negative inotropic effect.Öğe Capsaicin attenuates excitotoxic-induced neonatal brain injury and brain mast cell-mediated neuroinflammation in newborn rats(Elsevier Ireland Ltd, 2023) Kılınç, Yasemin Baranoğlu; Dilek, Mustafa; Kılınç, Erkan; Torun, İbrahim Ethem; Şaylan, Aslıhan; Düzcü, Selma ErdoğanExcitotoxicity and neuroinflammation are key contributors to perinatal brain injuries. Capsaicin, an active ingredient of chili peppers, is a potent exogenous agonist for transient receptor potential vanilloid 1 receptors. Although the neuroprotective and anti-inflammatory effects of capsaicin are well-documented, its effects on excitotoxic-induced neonatal brain injury and neuroinflammation have not previously been investigated. The aim of this study was to investigate the effects of capsaicin on brain damage, brain mast cells, and inflammatory mediators in a model of ibotenate-induced excitotoxic brain injury in neonatal rats. P5 rat-pups were intraperitoneally injected with vehicle, 0.2-, 1-, and 5-mg/kg doses of capsaicin, or the NMDA (N-methyl-D-aspartate) receptor antagonist MK-801 (dizocilpine), 30 min before intracerebral injection of 10 mu g ibotenate. The naive-control group received no substance administration. The rat pups were sacrificed one or five days after ibotenate injection. Levels of activin A and interleukin (IL)-1 beta, IL-6, and IL-10 in brain tissue were measured using the enzyme-linked immunosorbent assay method. Cortex and white matter thicknesses, white matter lesion size, and mast cells were evaluated in brain sections stained with cresyl-violet or toluidineblue.Capsaicin improved ibotenate-induced white matter lesions and cerebral white and gray matter thicknesses in a dose-dependent manner. In addition, it suppressed the degranulation and increased number of brain mast cells induced by ibotenate. Capsaicin also reduced the excitotoxic-induced production of neuronal survival factor activin A and of the pro-inflammatory cytokines IL-1 beta, and IL-6 in brain tissue. However, IL-10 levels were not altered by the treatments. MK-801, as a positive control, reversed all these ibotenate-induced changes, further confirming the success of the model. Our findings provide, for the first time, evidence for the therapeutic effects of capsaicin against excitotoxicinduced neonatal brain injury and brain mast cell-mediated neuroinflammation. Capsaicin may therefore be a promising candidate in the prevention and/or reduction of neonatal brain damage.Öğe Cloxyquinin sıçanlarda in-vivo ve ex-vivo deneysel modellerde migrendeki ağrı ve nörojenik enflamasyon üzerine etkileri(Bolu Abant İzzet Baysal Üniversitesi, 2022) Torun, İbrahim Ethem; Kılınç, ErkanSunulan çalışmada, TRESK kanalları aktivasyonunun in-vivo ve ex-vivo modeller kullanılarak ağrı davranışı ve migren ağrısından sorumlu mekanizmalar üzerine etkilerinin araştırılması amaçlanmıştır. İn-vivo migren modeli nitrogliserinin (NTG) intraperitoneal enjeksiyonu ile oluşturuldu. NTG enjeksiyonundan 75 dakika sonra gruplara NTG ve diğer ilaçların çözücüsü, TRESK aktivatörü cloxyquinin üç farklı dozu (1, 10 ve 50 mg/kg), TRESK inhibitörü A2764 (10 mg/kg), sumatriptan (1 mg/kg) ayrı ve/veya birlikte uygulandı. Ex-vivo hemiskull, trigeminal gangliyon ve beyin sapı preparatlarında CGRP salımı kapsaisin ile indüklendi ve in-vivo grupta test edilen ilaçların CGRP salımı üzerine direk etkisi araştırıldı. Mekanik hiperaljezi von-Frey testi ile serum, trigeminal gangliyon, ex-vivo CGRP ve beyin sapı CGRP ve c-Fos konsantrasyonları ELISA ile meningeal mast hücrelerinin degranülasyonu ve sayısı toluidine-blue boyaması ile belirlendi. İn-vivo veriler one-way ANOVA ile ex-vivo veriler ise tekrarlı ölçümler ANOVA ile analiz edildi. İn-vivo modelde, cloxyquin doza bağlı olarak NTG ile indüklenen mekanik hiperaljeziyi, c-fos ekpresyonunu, CGRP salımını, meningeal mast hücre aktivasyonunu ve sayısını azalttı (p<0,05). TRESK inhibitörü A2764 cloxyquinin etkilerini tersine çevirerek bu etkilere TRESK kanal aktivasyonunun aracılık ettiğini doğruladı (p<0,05). Ex-vivo preparatlarda cloxyquin kapsaisin ile uyarılmış CGRP salımını azaltırken (p<0,05), bazal CGRP salımı üzerine bir etkisi olmadı. A2764 cloxyquinin etkilerini tersine çevirdi (p<0,01) ve CGRP salımını kolaylaştırdı. Sumatriptan, NTG ve kapsaisin kaynaklı etkileri iyileştirirken (p<0,05) cloxyquin sumatriptanın etkisini güçlendirdi (p<0,05). Cloxyquin doza bağlı olarak migren modelinde ağrı davranışını ve nörojenik enflamasyonun bileşenleri olan artmış CGRP ve c-Fos düzeylerini ve mast hücre sayı ve aktivasyonunu azaltmaktadır. Bu sonuçlar TRESK kanallarının migren tedavisinde umut vadeden yeni bir hedef olabileceğini önermektedir.Öğe The effects of certain TRP channels and voltage-gated KCNQ/Kv7 channel opener retigabine on calcitonin gene-related peptide release in the trigeminovascular system(Sage Publications Ltd, 2022) Çıtak, Arzu; Kılınç, Erkan; Torun, İbrahim Ethem; Ankaralı, Seyit; Dağıstan, Yaşar; Yoldaş, HamitBackground Calcitonin gene-related peptide release in trigeminovascular system is a pivotal component of neurogenic inflammation underlying migraine pathophysiology. Transient receptor potential channels and voltage-gated KCNQ/Kv7 potassium channels expressed throughout trigeminovascular system are important targets for modulation of calcitonin gene-related peptide release. We investigated the effects of certain transient receptor potential (TRP) channels the vanilloid 1 and 4 (TRPV1 and TRPV4), the ankyrin 1 (TRPA1), and metastatin type 8 (TRPM8), and voltage-gated potassium channel (Kv7) opener retigabine on calcitonin gene-related peptide release from peripheral (dura mater and trigeminal ganglion) and central (trigeminal nucleus caudalis) trigeminal components of rats. Methods The experiments were carried out using well-established in-vitro preparations (hemiskull, trigeminal ganglion and trigeminal nucleus caudalis) from male Wistar rats. Agonists and antagonists of TRPV1, TRPV4, TRPA1 and TRPM8 channels, and also retigabine were tested on the in-vitro release of calcitonin gene-related peptide. Calcitonin gene-related peptide concentrations were measured using enzyme-linked immunosorbent assay. Results Agonists of these transient receptor potential channels induced calcitonin gene-related peptide release from hemiskull, trigeminal ganglion and trigeminal nucleus caudalis, respectively. The transient receptor potential channels-induced calcitonin gene-related peptide releases were blocked by their specific antagonists and reduced by retigabine. Retigabine also decreased basal calcitonin gene-related peptide releases in all preparations. Conclusion Our findings suggest that favorable antagonists of these transient receptor potential channels, or Kv7 channel opener retigabine may be effective in migraine therapy by inhibiting neurogenic inflammation that requires calcitonin gene-related peptide release.Öğe Endogenous and exogenous serotonin, but not sumatriptan, ameliorate seizures and neuroinflammation in the pentylenetetrazole-induced seizure model in rats(Assoc Arquivos Neuro- Psiquiatria, 2022) Torun, İbrahim Ethem; Kılınç, Yasemin Baranoğlu; Kılınç, ErkanBackground: Epilepsy has neuropsychiatric comorbidities such as depression, bipolar disorder, and anxiety. Drugs that target epilepsy may also be useful for its neuropsychiatric comorbidities. Objective: To investigate the effects of serotonergic modulation on pro-inflammatory cytokines and the seizures in pentylenetetrazole (PTZ)-induced seizure model in rats. Methods: Male Wistar rats were injected intraperitoneally with serotonin, selective serotonin reuptake inhibitor fluoxetine, 5-HT1B/D receptor agonist sumatriptan, or saline 30 min prior to PTZ treatment. Behavioral seizures were assessed by the Racine's scale. Concentrations of IL-1 beta, IL-6, and TNF-a in serum and brain tissue were determined by ELISA. Results: Serotonin and fluoxetine, but not sumatriptan, alleviated PTZ-induced seizures by prolonging onset times of myoclonic-jerk and generalized tonic-clonic seizures. The anti-seizure effect of fluoxetine was greater than that of serotonin. Likewise, serotonin and fluoxetine, but not sumatriptan, reduced PTZ-induced increases in the levels of IL-1 beta and IL-6 in both serum and brain tissue. None of the administered drugs including PTZ affected TNF-a concentrations. Conclusions: Our findings suggest that endogenous and exogenous serotonin exhibits anticonvulsant effects by suppressing the neuroinflammation. It seems that 5-HT1B/D receptors do not mediate anticonvulsant and anti-neuroinflammatory effects of serotonin.Öğe Esculetin alleviates pentylenetetrazole-induced seizures, cognitive impairment and pro-inflammatory cytokines and suppresses penicillin-induced epileptiform activity in rats(Pergamon-Elsevier Science Ltd, 2023) Danış, Ayşegül; Kılınç, Yasemin Baranoğlu; Torun, İbrahim Ethem; Hancı, Fatma; Kılınç, Erkan; Ankaralı, HandanAims: To investigate the effects of different doses of esculetin on epileptiform activity, behavioral seizures, memory impairment, and cortical and hippocampal NF-Kappa B, as a mediator of pro-inflammatory gene induction, and pro-inflammatory cytokines in penicillin-and pentylenetetrazole(PTZ)-induced seizure models in rats. Main methods: Different doses of esculetin (5, 10, and 20 mg/kg), and diazepam (5 mg/kg) as a positive control, were tested in penicillin-and pentylenetetrazole(PTZ)-induced seizure models. In the PTZ model, cognitive function, behavioral seizures, and cortical and hippocampal pro-inflammatory biomarkers and survival factor was evaluated. In the penicillin model, the frequency and amplitude of electrophysiological epileptiform activity were assessed. Key findings: In the PTZ model, the 10 mg/kg esculetin displayed anticonvulsant effects by extending onset-times of myoclonic-jerk and generalized tonic-clonic seizure, and by diminishing seizure severity and duration of generalized tonic-clonic seizure. It also ameliorated PTZ-induced cognitive impairment, and cortical and hip-pocampal activin-A, IL-1 beta, IL-6 and NF-Kappa B levels. In the penicillin model, the 10 mg/kg esculetin decreased the frequency of spikes without changing the amplitude of spikes. As a positive-control, diazepam reversed all changes induced by both PTZ and penicillin. Significance: Esculetin exhibits anticonvulsant and memory-improving effects by alleviating the behavioral and electrophysiological characteristics of epileptic seizures. Additionally, esculetin exerts anti-neuroinflammatory actions in the PTZ-induced seizures model. Thus, esculetin may be a multi-targeted promising agent with anti-convulsant and anti-neuroinflammatory effects in the treatment of epilepsy.Öğe Long-term dietary probiotic intake ameliorates pentylenetetrazole-Induced epileptic seizures by reducing oxidative stress in rats(Wiley, 2019) Kılınç, Erkan; Ankaralı, Seyit; Ayhan, Didem; Ankaralı, Handan; Torun, İbrahim Ethem; Çetinkaya, Ayhan[No Abstract Available]Öğe Mast cell activation alleviates pentylenetetrazole-induced epileptic seizures via serotonin in rats(KARGER, 2021) Kılınç, Erkan; Torun, İbrahim Ethem; Çetinkaya, Ayhan; Töre, FatmaMast cell activation alleviates pentylenetetrazole-induced epileptic seizures via serotonin in ratsÖğe Mast cell activation ameliorates pentylenetetrazole-induced seizures in rats: the potential role for serotonin(Blackwell Publishing Ltd, 2021) Kılınç, Erkan; Torun, İbrahim Ethem; Çetinkaya, Ayhan; Töre, FatmaNeuroinflammation plays a key role in the pathogenesis of epilepsy, but the underlying mechanisms are not well understood. Mast cells are multifunctional immune cells that are also activated by stress. The effects of activated mast cells on epileptogenesis are not yet known. This study investigated the effects and mechanisms of compound 48/80-stimulated mast cell activation on pentylenetetrazole-induced epileptic seizures in rats. Male Wistar rats were separated into seven groups (n = 12). Group-1(NS+PTZ) received intraperitoneal saline solution, while groups 2(C-48/80+PTZ-1), 3(C-48/80+PTZ-2), and 4(C-48/80+PTZ-3) received compound-48/80 at doses of 0.5, 1, and 2 mg/kg, respectively, 30 min before 45 mg/kg pentylenetetrazole administration. Similarly, Group-5(Cr+C-48/80+PTZ) received 10 mg/kg cromolyn plus 2 mg/kg compound-48/80 before pentylenetetrazole, and Group-6(MC Dep+C-48/80+PTZ) was exposed to a mast cell-depletion process, and then received 2 mg/kg compound-48/80. Group-7(5-HT+PTZ) received 10 mg/kg serotonin. Seizure stages were evaluated using Racine's scale. Compound-48/80 at 2 mg/kg induced anticonvulsive effects against pentylenetetrazole-induced seizures by extending onset-times of both myoclonic-jerk and generalized tonic–clonic seizures (p = 0.0001), and by shortening the duration of generalized tonic–clonic seizure (p = 0.008). These effects were reversed by cromolyn (p = 0.0001). These effects were not observed in mast cell-depleted rats. Similarly to compound 48/80, serotonin also exhibited anticonvulsive effects against seizures (p < 0.05). Compound 48/80 acts as an anticonvulsant by activating mast cells in a dose-dependent manner. The anticonvulsive effects of mast cell activation may be mediated by serotonin. Mast cell activation may therefore provide protective activity against seizures under appropriate circumstances.Öğe Receptor mechanisms mediating the anti-neuroinflammatory effects of endocannabinoid system modulation in a rat model of migraine(Wiley, 2020) Kılınç, Erkan; Ankaralı, Seyit; Torun, İbrahim Ethem; Dağıstan, YaşarCalcitonin gene-related peptide (CGRP), substance P and dural mast cells are main contributors in neurogenic inflammation underlying migraine pathophysiology. Modulation of endocannabinoid system attenuates migraine pain, but its mechanisms of action remain unclear. We investigated receptor mechanisms mediating anti-neuroinflammatory effects of endocannabinoid system modulation in in vivo migraine model and ex vivo hemiskull preparations in rats. To induce acute model of migraine, a single dose of nitroglycerin was intraperitoneally administered to male rats. Moreover, isolated ex vivo rat hemiskulls were prepared to study CGRP and substance P release from meningeal trigeminal afferents. We used methanandamide (cannabinoid agonist), rimonabant (cannabinoid receptor-1 CB1 antagonist), SR144528 (CB2 antagonist) and capsazepine (transient receptor potential vanilloid-1 TRPV1 antagonist) to explore effects of endocannabinoid system modulation on the neurogenic inflammation, and possible involvement of CB1, CB2 and TRPV1 receptors during endocannabinoid effects. Methanandamide attenuated nitroglycerin-induced CGRP increments in in vivo plasma, trigeminal ganglia and brainstem and also in ex vivo hemiskull preparations. Methanandamide also alleviated enhanced number and degranulation of dural mast cells induced by nitroglycerin. Rimonabant, but not capsazepine or SR144528, reversed the attenuating effects of methanandamide on CGRP release in both in vivo and ex vivo experiments. Additionally, SR144528, but not rimonabant or capsazepine, reversed the attenuating effects of methanandamide on dural mast cells. However, neither nitroglycerin nor methanandamide changed substance P levels in both in vivo and ex vivo experiments. Methanandamide modulates CGRP release in migraine-related structures via CB1 receptors and inhibits the degranulation of dural mast cells through CB2 receptors. Selective ligands targeting CB1 and CB2 receptors may provide novel and effective treatment strategies against migraine.
