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Öğe 5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice(Pergamon-Elsevier Science Ltd, 2012) Ulugol, Ahmet; Oltulu, Cagatay; Gunduz, Ozgur; Citak, Cihad; Carrara, Roberto; Shaqaqi, Mohammad Reza; Mansilla Sanchez, AliciaThe role of 5-HT7 receptors in the nociceptive processing received most attention during the last few years. The involvement of 5-HT7 receptors in nerve injury-induced neuropathic pain states have been reported only recently; however, there are no reports on its contribution in diabetic neuropathic pain. We therefore planned to investigate the effect of 5-HT7 receptor activation on the changes of nociceptive threshold in diabetic mice. Diabetes was induced by a single intraperitoneal injection of streptozocin (150 mg/kg, i.p.). The nociceptive responses in normal and diabetic animals were tested in the hot-plate and tail-flick assays. Both hot-plate and tail-flick latencies significantly shortened at 1-3/4 weeks (thermal hyperalgesia) and prolonged at 6-7 weeks (thermal hypoalgesia) after streptozocin administration. At the dose of 10 mg/kg, systemic injections of AS-19, a selective 5-HT7 receptor agonist, reduced thermal hyperalgesia at early stage of diabetes, but did not influence thermal hypoalgesia at late stage. Co-administration of SB-258719, a selective 5-HT7 receptor antagonist, at a dose that had no effect on its own (10 mg/kg), reversed the anti-hyperalgesic effect of AS-19. Our results indicate that systemic administration of 5-HT7 receptor agonists may have clinical utility in treating diabetic neuropathic pain. (C) 2012 Elsevier Inc. All rights reserved.Öğe Anti-allodynic and anti-hyperalgesic effects of ceftriaxone in streptozocin-induced diabetic rats(Elsevier Ireland Ltd, 2011) Gunduz, Ozgur; Oltulu, Cagatay; Buldum, Dilek; Guven, Rabia; Ulugol, AhmetGlutamate is the principal excitatory neurotransmitter in the central nervous system. Recent evidence suggests that beta lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Moreover, these antibiotics have been shown to prevent the development of tolerance and dependence to opioids, and reduce visceral and nerve injury-induced neuropathic nociceptive responses. The aim of this study is to observe the effect of a beta lactam antibiotic, ceftriaxone, on mechanical allodynia and mechanical hyperalgesia in diabetic rats. Diabetes was produced with the injection of a single dose of streptozocin (50 mg/kg, i.p.) and this procedure resulted in neuropathic pain behaviors in the hindpaws. Mechanical allodynia was detected with an electronic aesthesiometer, and mechanical hyperalgesia was studied using the method of Randall-Selitto. With its higher doses, ceftriaxone (100, 200 mg/kg, i.p.) reduced both mechanical allodynia and hyperalgesia. Dihydrokainic acid (10 mg/kg, i.p.), a selective GLT-1 transporter inhibitor, reversed the anti-allodynic and anti-hyperalgesic effects of ceftriaxone, at doses that produced no effect on its own. Our results indicate that ceftriaxone exerts an antinociceptive effect in streptozocin-induced diabetic rats and GLT-1 activation by beta lactam antibiotics may be a promising option in the treatment of diabetic neuropathy. (C) 2011 Elsevier Ireland Ltd. All rights reserved.Öğe Determination of sildenafil and tadalafil adulteration by LC-MS/MS and 23 elements by ICP-MS in food supplements(Istanbul Univ, Fac Pharmacy, 2023) Oltulu, Cagatay; Celik, Saffet; Dasman, MustafaBackground and Aims: Since the increasing prevalence of erectile dysfunction disease, the use of phosphodiesterase type 5 (PDE-5) inhibitors is widespread in the current era. The first and the most known molecule of PDE-5 inhibitors is sildenafil. It is widely used in the market. The second and more developed one is tadalafil. It is known that these substances are found in sexual stimulant food supplements as adulteration. In addition, food supplements can contain metals that can cause haz-ardous activity by accumulating. In our study, 11 randomly chosen sexual stimulant known products are studied which were bought from different stores in Edirne. Methods: Adulteration with sildenafil and tadalafil was determined by LC-MS/MS because of the enhanced accuracy and precision, general applicability, and higher selectivity. Also, the determination of 23 metals, including known heavy metals, was made with ICP-MS. Results: In the study, 7 of 11 samples detected at least 1 compound of sildenafil (up to 92.44 mg in one serving) or tadalafil (up to 23.62 mg in one serving). Neither of the samples exceeded the limits of metal daily intakes that are shown in Table 4.Conclusion: In past studies, adulteration was determined in food supplements, and it is still detected today. The results we obtained are engrossing for the regulations of sexual stimulant food supplement sales. Their additional effects on total daily intake raise health concerns. The data obtained from this study will contribute to inform consumers and health professionals about the status of food supplements in the market.Öğe The Effect of Intrauterine Antipsychotic Drug Exposure on Learning and Memory in Adult Rats(Kure Iletisim Grubu A S, 2016) Oltulu, Cagatay; Karadag, Cetin HakanObjective: The effects of antipsychotic drugs, of whose different classes can be used in the treatment of patients with resistant to schizophrenia, on the fetus and the benefits of the treatment to the mother should be taken into consideration before making a decision about initiating treatment. This study aimed to examine the effects of prenatal exposure to various antipsychotic agents on learning and memory in adult rats. Method: In this study, antipsychotic drugs from different chemical classes (2 mg/kg haloperidol, 100 mg/kg thioridazine, 200 mg/kg sulpiride, 20 mg/kg chlorprothixene, 40 mg/kg clozapine, 10 mg/kg fluphenazine, 20 mg/kg chlorpromazine) and water for the control group were administered to pregnant Sprague-Dawley dams through gavage during the pregnancy period. In total, 16 groups were created and tested in the Morris water maze by dividing offspring of eight mother rats into male and female rat groups (n=10) on postpartum day 60. Learning was tested with hidden platform task and memory was tested with probe test. Results: It has been observed that learning was impaired in the male and female groups that received haloperidol, sulpiride, chlorprothixene, clozapine, and chlorpromazine, as well as in the female groups receiving fluphenazine and thioridazine. Thigmotaxis is the time spent on 10 cm perimeter of the walls of the pool. Thigmotaxis values of all groups were still higher except for the male group of thioridazine on fifth day. Conclusion: These results show that when prenatal exposure to antipsychotics occurs, it causes impairment in the realization of task of finding escape platform properly, rather than affecting learning and memory functions, specifically in their adulthood so that high thigmotaxis may be the reason for deterioration in escape latency parameter.Öğe Effects of in vitro Amitriptyline, Fluoxetine, Tranylcypromine and Venlafaxine on Saphenous Vein Grafts(Soc Brasil Cirurgia Cardiovasc, 2019) Akinci, Melek; Karadag, Cetin Hakan; Huseyin, Serhat; Oltulu, Cagatay; Canbaz, Suat; Gunduz, Ozgur; Topuz, Ruhan DenizObjective: In this study, we aimed to examine the effects of amitriptyline, fluoxetine, tranylcypromine and venlafaxine on saphenous vein grafts in coronary artery bypass graft surgeries. Methods: 59 patients (40 males and 19 females; mean age 65.1 years, distribution: 45-84 years) who had coronary artery bypass graft surgery between February 2014 and May 2016 were included in the study. After the saphenous vein grafts with intact and denuded endothelium were precontracted with 3x10(-6)M phenylephrine, amitriptyline, fluoxetine and tranylcypromine were cumulatively added to isolated organ baths in the range of 10(-11)-3x10(-5)M, while venlafaxine was added in the range of 10(-9)-3x10(-5)M. Then, the antidepressant-induced relaxation responses were recorded isometrically. Results: While the relaxation response of amitriptyline at -6.42 (Log M) was 74.6%, the response at -6.32 (Log M) was 75.5%. While the relaxation response at -6.46 (Log M) of fluoxetine was 68.02%, the response at -6.02 (Log M) was 72.12%. While the relaxation response of tranylcypromine at -7.53 (Log M) was 61.13%, the response at -7.23 (Log M) was 65.53%. While the relaxation response of venlafaxine at -6.21 (Log M) was 29.98%, the response at -5.90 (Log M) was 32.96%. Conclusion: The maximum relaxation at minimum and maximum therapeutic concentrations was obtained with amitriptyline, fluoxetine and tranylcypromine, and the minimum relaxation was obtained with venlafaxine. The relaxation responses were independent of the endothelium.Öğe Enhanced Cytotoxic Activity of 6-Mercaptopurine-Loaded Solid Lipid Nanoparticles in Hepatic Cancer Treatment(Mary Ann Liebert, Inc, 2023) Ergin, Ahmet Dogan; Oltulu, Cagatay; Koc, Buesra6-Mercaptopurine (6-MCP) is an antiproliferative purine analog used in acute lymphoblastic leukemia, non-Hodgkin lymphoma, and inflammatory bowel disease (Crohn's disease, ulcerative colitis). Although 6-MCP has the great therapeutic potential for cancer and immunosuppressant-related diseases, 6-MCP is not readily soluble in water, presents a high first-pass effect, short half-life (0.5-1.5 h), and implies a low bioavailability (16%). On the contrary, solid lipid nanoparticles (SLNs) are prepared from solid lipids at room temperature and body temperature. In this study, SLNs were prepared w/o/w double emulsion-solvent evaporation method using Precirol ATO5 as matrix lipid. In the emulsion stabilization, surfactant (Tween 80) and polymeric stabilizer (polyvinyl alcohol [PVA]) were used. Two group formulations using Tween 80 and PVA were compared in terms of particle size, polydispersity index, zeta potential encapsulation efficiency%, and process yield%. Differential calorimetric analysis and release properties were examined for optimum formulation, and release kinetics were calculated. According to studies, sustained release was obtained with SLNs by the Korsmayer-Peppas kinetic model. The in vitro cytotoxicity studies were performed on the hepatocarcinoma (HEP3G) cell line. According to the results, successful SLN formulations were produced, and PVA was found best stabilizer. Optimum formulation exhibited significantly higher cytotoxic effects on HEP3G than on pure 6-MCP. These results demonstrated that solid lipid nanodrug delivery systems have great potential for formulation of 6-MCP.Öğe Evaluation of Genotoxicity Risk in Health Care Workers Exposed to Antineoplastic Drugs(Marmara Univ, Inst Health Sciences, 2019) Oltulu, Cagatay; Yesil Devecioglu, Tugce; Akinci, Melek; Olmez, Sevcan Gul Akgun; Obeidin, Serra Vildan Akgul; Beceren, AyferObjective: DNA damage that can be caused by workplace exposure to antineoplastic drugs in health workers has been shown in many scientific studies. It is aimed to evaluate whether the risk of genotoxicity in health workers decreases after the regulations and measures taken by national and international health authorities in our work. Methods: For this purpose, DNA damage was assessed by using alkaline comet technique in lymphocytes isolated from blood samples of health workers (n=29) who were involved in preparing and/or administering antineoplastic agent at Trakya University Health Research and Application Center and compared with the control group (n=30). Also, those who prepare and/or administer antineoplastic agents; (n=16) and manual (n=13) preparations. Results: As a result of the evaluation, there was no statistically significant difference between health personnel and control group in preparing and / or administering antineoplastic agent (p>0,05, Mann-Whitney U) and there was no difference in the genotoxic risk between preparation forms. Furthermore, when the exposed control group was assessed for DNA damage as smokers and nonsmokers, there was no statistically significant difference in terms of DNA damage (p>0.05). Conclusion: At the center where our samples were taken, the resulting measures resulted in the control of the risk of genotoxicity due to occupational exposure to antineoplastic agents.Öğe Evaluation of the cytotoxic effect of titanium dioxide nanoparticles in human embryonic lung cells(Tubitak Scientific & Technological Research Council Turkey, 2023) Afsar, Olkan; Oltulu, CagatayBackground/aim: Titanium dioxide nanoparticles are widely used in a variety of products, including sunscreens, paints, and ceramics. However, their increasing use has raised concerns about their potential health risks. Titanium dioxide nanoparticles have been shown to have the ability to enter the bloodstream and accumulate in various tissues, reaching the fetus via the placenta. The aim of this study was to investigate the cytotoxic effects of titanium dioxide nanoparticles on a human embryonic lung cell line (HEL 299/An1) and the formation of oxidative DNA damage.Materials and methods: The cytotoxic effects of brookite-based titanium dioxide nanoparticles (<100 nm) were assessed using the 3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay for 24 and 48 h. Cell titanium levels were determined using inductively coupled plasma mass spectrometry. Oxidative DNA damage was assessed by measuring the levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) as a biomarker.Results: Titanium dioxide nanoparticles caused dose-dependent cytotoxicity in HEL 299/An1 cells. The IC50 values were 25.93 mu M and 0.054 mu M after 24 h and 48 h of exposure, respectively. Cell titanium levels were found to be 25,967 ppb after 24 h and 210,353 ppb after 48 h (p < 0.01). 8-OHdG was detected at 32.96 ng/mL after 24 h of exposure and 17.89 ng/mL after 48 h of exposure.Conclusion: In our study, it was shown that titanium nanoparticles caused dose-dependent cytotoxicity and oxidative DNA damage in human embryonic lung cells. The nanoparticles also accumulated in cells and were taken up in higher amounts after 48 h of exposure. These findings suggest that titanium dioxide nanoparticles may pose a health risk, especially for pregnant women who may not be aware of their pregnancy. Therefore, it is important to take preventive measures to reduce exposure to these nanoparticles.Öğe Galangin Protects AML-12 Cells Against Dactinomycin Induced Hepatotoxicity(Galenos Publ House, 2023) Akinci, Melek; Oltulu, Cagatay; Bakar, Elvan; Cevikelli Yakut, Zatiye AycaAim: The purpose of this study was to evaluate the effects of galangin (Gal) on dactinomycin induced hepatotoxicity in vitro. Materials and Methods: AML -12 cell line was divided into 4 groups as the control, Gal, dactinomycin, and Gal+dactinomycin groups. IC50 dose was determined by the thiazolyl blue tetrazolium bromide test. Gene expressions of glutathione (GSH), superoxide dismutase (SOD), catalase, caspase 3 (Cas-3), Cas-9, apoptotic protease activating factor -1 (Apaf-1), B cell CLL/lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), tumor protein p53 (p53), second mitochondria -derived activator of caspase/direct inhibitor of apoptosis-binding protein (smac/DIABLO), topoisomerase (Top) I, and Top II were determined with quantitative real-time polymerase chain reaction analysis. Results: Dactinomycin elevated the expression of SOD, catalase, and GSH in response to oxidative effects. In the Gal+dactinomycin group, Gal administration reduced Apaf-1 expression and increased Bcl-2 expression with antiapoptotic effects. In the dactinomycin group, p53 levels increased due to the defense mechanism against DNA damage. Gal increased smac/DIABLO expression to remove damaged structures. Bcl-2 and smac/DIABLO expression levels in the groups were inversely proportional. In the Gal+dactinomycin group, Top II expression level was lower than in the dactinomycin group. This result indicated that double strand of DNA damage was diminished by Gal. Conclusion: Gal protected against the hepatotoxicity due to dactinomycin with antioxidant and antiapoptotic effects. Further experimental studies are needed to establish the use of Gal in liver damage.Öğe Improving the Bioavailability and Efficacy of Coenzyme Q10 on Alzheimer's Disease Through the Arginine Based Proniosomes(Elsevier Science Inc, 2023) Ergin, Ahmet Dogan; Uner, Burcu; Balcib, Sencan; Demirbag, Caglar; Benetti, Camillo; Oltulu, CagatayCoenzyme Q10 (CoQ10) is a fat-soluble vitamin-with a benzoquinone-like structure. CoQ10 plays a role in membrane stability, energy conversion, and ATP production. It is also one of the important antioxidants in the body. The bioavailability of exogenous CoQ10 is extremely low due to its poor aqueous solubility and large molecular mass.In this study, mixed proniosomal drug delivery systems have been used to increase solubility and bioavailability of CoQ10. Arginine (semi-essential amino acid) was incorporated in the formulation composition to achieve higher efficacy by boosting nitric oxide presence, endothelial dysfunction, and cellular uptake.Proniosomes were investigated in terms of particle size, polydispersity index, zeta potential, encapsulation efficiency, and process yield, and optimization studies were carried on by utilizing STATISTICA 8.0 software considering dependent factors (carrier amount, drug amount, and surfactant ratio). Optimum proniosome formulation (particle size 187.5 +/- 16.35 nm, zeta potential: -44.7 +/- 12.8 mV, encapsulation efficiency 99.05 +/- 0.30%, and product yield: 90.55%) was evaluated for thermal analysis, in-vitro drug release using microcentrifuge method. In-vitro cytotoxicity studies of proniosomes were performed on intestinal Epithelial Cells (Cellartis (R), ChiPSC18) and no cytotoxic effects was seen during the 72 h. Besides, anti Alzheimer effect was investigated on APPSL-GFP lentivirus-infected human neural cells (APPSL-GFP-l-HNC) and Alzheimer biomarkers (p-tau181 and p-tau217).While CoQ10's relative bioavailability was statistically increased by proniosome compared to CoQ10 suspension (p<0.01, Grubb test). PK parameters of proniosome formulation, obtained with non-compartmental modeling, were fitting to the data (R-2=0.956 +/- 0.026).The study results proved that proniosomal formulation has a high potential drug delivery system for both increasing bioavailability and anti-Alzheimer effect of CoQ10.(c) 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.Öğe In vitro hepatotoxicity evaluation of methotrexate-loaded niosome formulation: fabrication, characterization and cell culture studies(Tubitak Scientific & Technological Research Council Turkey, 2023) Ergin, Ahmet Dogan; Oltulu, Cagatay; Turker, Nebiye Pelin; Demirbolat, Gulen MelikeBackground/aim: Methotrexate (MTX) is a folic acid antagonist that is widely used to treat osteosarcoma, leukemia, breast cancer, and autoimmune and inflammatory diseases. The most important concerns with MTX are its poor solubility and high toxicity, particularly in liver cells. To enhance its solubility and to minimize its toxicity, we encapsulated MTX in niosomes and investigated its hepatotoxicity mechanisms using genetic biomarkers. Materials and methods: Niosomes were successfully prepared using a modified thin film method, and the prepared monodisperse smallsized formulation was subsequently characterized. In vitro cytotoxicity studies were performed both in hepatocarcinoma (HEP3G) and healthy liver (AML12) cell lines. Specifically, immunofluorescence assay and evaluation of the expression levels of apoptotic, antioxidant, heat shock protein, and oxidative stress genes were performed. Results: The formulation had a particle size of 117.1 +/- 33 nm, a surface charge of -38.41 +/- 0.7 mV, and an encapsulation efficiency of 59.7% +/- 2.3%. The results showed that the niosomal formulation exhibited significantly higher cytotoxic effects in HEP3G than in AML12. The immunofluorescence and genetic analyses showed that the increased cytotoxicity of niosomes resulted mainly from oxidative stress and slight apoptosis. Conclusion: These results demonstrated that niosomal drug delivery systems could be a new potential formulation for minimizing MTX-related hepatotoxicity.Öğe Investigation of genotoxicity risk in healthcare workers that has occupational exposure to antineoplastic drugs(Elsevier Ireland Ltd, 2017) Oltulu, Cagatay; Akinci, Melek; Yesil, Tugce; Akgul, Vildan; Akgun, Sevcan; Motor, Deniz; Canbaz, Suat[Abstract Not Available]Öğe A New Tube Gastrostomy Model in Animal Experiments(Derman Medical Publ, 2013) Sezer, Atakan; Sagiroglu, Tamer; Copuroglu, Elif; Yagci, Mehmet Ali; Oltulu, Cagatay; Sut, NecdetAim: The orogastric route is the most preferred application method in the vast majority of the animal experiments in which application can be achieved by adding the material to the water of the experiment animal, through an orogastric tube or with a surgically managed ostomy. Material and Method: This experiment was constructed with twelve male Sprague-Dawley rats which were randomly assigned to one of two groups consist of control group (group C, n:6) and tube gastrostomy group (group TG, n:6). A novel and simple gastrostomy tube was derivated from a silicone foley catheter. Tube gastrostomy apparatus was constituted with a silicone foley catheter (6 French). In the group TG an incision was performed, and the stomach was visualized. A 1 cm incision was made in the midline and opening of the peritoneum. Anchoring sutures were placed and anterior gastric wall was lifted. The gastric wall is then opened. The apparatus was placed into the stomach and pulled through from a tunnel under the skin and fixed to the lateral abdominal wall with a 2/0 silk suture. Result: The procedure was ended in the 10th day of experiment. No mortality was observed in group C. The rats were monitored daily and no abnormal behavior consists of self harming incision site, resistance to oral intake or attending to displace. There was statistically significant difference in increasing alanine transaminase level (p<0.05) and decrease in the total protein and body weight (p<0.05) at the group TG at the end of experiment. There was significant increase in urea levels in Group C (p<0.05) at the end of experiment. The statistically significant decrease was observed in the same period in group C between aspartate transaminase, albumin, total protein, and body weight (p<0.05). Glucose (p=0.047) and aspartate transaminase (p=0.050) level decrease changes and weight loose (p=0.034) from preoperative period to the end of the experiment between gastrostomy and laparotomy groups were statistically significantly. Discussion: Here in we presented a novel and simple tube gastrostomy model in an experimental rat model in which rats had unrestrained movements. We believe that this new constructed tube gastrostomy model may be an alternative route for the experimental models in which orogastric route is unavailable to use.Öğe Pharmacological and behavioral characterization of the saphenous chronic constriction injury model of neuropathic pain in rats(Springer, 2011) Gunduz, Ozgur; Oltulu, Cagatay; Guven, Rabia; Buldum, Dilek; Ulugol, AhmetThe aim of the present study was to develop a new experimental pain model by adapting the chronic constriction injury (CCI) model of the sciatic nerve to the exclusively sensory saphenous nerve in rats. Animals were divided into na < ve, sham, and two experimental groups, in which two or four 4-0 chromic gut ligatures were loosely ligated around the saphenous nerve. Then, behavioral signs of neuropathic pain were observed for 8 weeks. In rats with four ligatures, prominent mechanical allodynia and thermal hyperalgesia developed; these behavioral signs were not prominent in rats with two ligatures. Pharmacological analysis was made in rats with four loose ligations; morphine and WIN 55,212-2, a cannabinoid agonist, reversed all of the modalities tested, whereas gabapentin only suppressed mechanical allodynia and amitriptyline only reduced mechanical hyperalgesia. Our data establish a rat model of saphenous CCI with significant allodynia and hyperalgesia, which is sensitive to a number of analgesic compounds.Öğe Puerarin Protects from Methotrexate Induced Hepatotoxicity in AML-12 Cells(Galenos Publ House, 2023) Akinci, Melek; Oltulu, Cagatay; Bakar, Elvan; Cevikelli Yakut, Zatiye AycaAim: The purpose of this study was to look into the effects of puerarin (PR) on methotrexate (MTX)-induced hepatotoxicity in vitro. Materials and Methods: We designed our research with four groups in the AML-12 cell line: control, PR, MTX, and PR+MTX groups. Administered concentration levels to the cell lines were determined with the MTT test. To investigate oxidative stress, the expression levels of glutathione, superoxide dismutase, and catalase were determined with quantitative real-time-polymerase chain reaction (qRT-PCR) analysis. To evaluate the role of apoptosis pathways in MTX induced hepatotoxicity and the hepatoprotective effects of PR, gene expressions of caspase 3 (Cas-3), Cas-9, apoptotic protease activating factor-1, Bcl-2, Bax, p53, second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein (smac/DIABLO), topoisomerase (Top) I, and Top II were investigated with qRT-PCR. Results: MTX impaired the antioxidant defense through SOD but elevated the expression of catalase and glutathione due to an increase in free radicals. In the PR+MTX group, SOD expression increased and catalase and glutathione expression decreased compared to the MTX group. Cas-9, Apaf-1, and Top I gene expression levels were reduced in group PR. In the group of PR+MTX, PR application increased the expression of Bax, p53, and smac/DIABLO while decreasing the expression of Bcl-2, which resulted in the elimination of damaged structures by apoptosis. Conclusion: PR alleviated the hepatotoxicity caused by MTX with its antioxidant effects and positive effects on apoptosis pathways. However, different dose studies are needed because PR could not prevent double-strand damage in DNA due to MTX and there is an increase in Top I expression in the PR group.Öğe Role of GLT-1 transporter activation in prevention of cannabinoid tolerance by the beta-lactam antibiotic, ceftriaxone, in mice(Pergamon-Elsevier Science Ltd, 2011) Gunduz, Ozgur; Oltulu, Cagatay; Ulugol, AhmetRecently, it has been indicated that beta lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Furthermore, these antibiotics have been shown to prevent the development of tolerance and dependence to opioids. Since cannabinoid tolerance is known to be similar to opioids, our purpose was to examine the effect of ceftriaxone on the development of tolerance to WIN 55,212-2, a cannabinoid agonist. The tail flick test, a rectal thermometer, and the ring test were used for evaluating the degree of tolerance to the analgesic, hypothermic, and cataleptic effects of WIN 55,212-2, respectively. Within one week, animals became completely tolerant to analgesic. hypothermic and cataleptic effects of WIN 55,212-2 (6 mg/kg). Ceftriaxone, with its higher doses (100-200 mg/kg), attenuated the development of tolerance to the analgesic and hypothermic effects of WIN 55,212-2, but had no effect on its cataleptic action. Dihydrokainic acid (10 mg/kg), a GLT-1 transporter inhibitor, prevented this effect of ceftriaxone. Our results suggest that repeated treatment with ceftriaxone prevents the development of tolerance to the analgesic and hypothermic effects of cannabinoids, and GLT-1 activation appears to play a key role in this preventive effect of beta-lactam antibiotics. (C) 2011 Elsevier Inc. All rights reserved.
