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Background: Depression is a disease that affects millions of people worldwide, and the discovery and development of effective and safe antidepressant drugs is one of the important topics of psychopharmacology. Objectives: In this study, it was aimed to investigate the antidepressant-like activity potential of tofisopam, an anxiolytic drug with 2,3-benzodiazepine structure, and to elucidate the pharmacological mechanisms mediating this effect. Methods: The antidepressant-like activity of tofisopam was investigated using tail suspension and modified forced swimming tests. Possible interactions of tofisopam with µ- and δ-opioid receptor subtypes were clarified by pharmacological antagonism, molecular docking and molecular dynamics simulation studies. Results: Tofisopam (50 and 100 mg/kg) significantly shortened the immobility time of mice in both the tail suspension and the modified forced swimming tests. The drug, at the same doses, prolonged the duration of swimming and climbing behaviours measured in modified forced swimming tests. A dosage of 25 mg/kg was ineffective. Mechanistic studies showed that the pretreatment with p-chlorophenylalanine methyl ester (serotonin synthesis inhibitor; 4 consecutive days, 100 mg/kg), α-methyl-para-tyrosine methyl ester (catecholamine synthesis inhibitor; 100 mg/kg), naloxonazine (selective µ-opioid receptor blocker, 7 mg/kg) and naltrindole (a selective δ-opioid receptor blocker, 0.99 mg/kg) abolished the anti-immobility effect induced by the 50 mg/kg dose of tofisopam in the tail suspension tests. Our in silico studies supported the behavioural findings that the antidepressant-like effect of tofisopam is mediated by μ- and δ-opioid receptors. Conclusion: This study is the first to show that tofisopam has antidepressant-like activity mediated by the serotonergic, catecholaminergic and opioidergic systems.

WOS: 000522840800017, PubMed: 31912189, Rationale Current data indicate that the noradrenergic system plays a critical role in neuropathic pain treatment. Notably, drugs that directly affect this system may have curative potential in neuropathy-associated pain. Objectives the aim of this study was to evaluate the potential therapeutic efficacy of reboxetine, a potent and selective noradrenaline reuptake inhibitor, on hyperalgesia and allodynia responses in rats with experimental diabetes. Furthermore, mechanistic studies were performed to elucidate the possible mode of actions. Methods Experimental diabetes was induced by a single dose of streptozotocin. Mechanical hyperalgesia, mechanical allodynia, thermal hyperalgesia, and thermal allodynia responses in diabetic rats were evaluated by Randall-Selitto, dynamic plantar, Hargreaves, and warm plate tests, respectively. Results Reboxetine treatment (8 and 16 mg/kg for 2 weeks) demonstrated an effect comparable to that of the reference drug, pregabalin, improving the hyperalgesic and allodynic responses secondary to diabetes mellitus. Pretreatment with phentolamine, metoprolol, SR 59230A, and atropine did not alter the abovementioned effects of reboxetine; however, the administration of alpha-methyl-para-tyrosine methyl ester, propranolol, ICI-118,551, SCH-23390, sulpiride, and naltrindole significantly inhibited these effects. Moreover, reboxetine did not induce a significant difference in the rat plasma glucose levels. Conclusions Our findings indicate that the antihyperalgesic and antiallodynic effects of reboxetine are mediated by the catecholaminergic system; beta(2)-adrenoceptors; D-1-, D-2/D-3-dopaminergic receptors; and delta-opioid receptors. the results suggest that this analgesic effect of reboxetine, besides its neutral profile on glycemic control, may be advantageous in the pharmacotherapy of diabetic neuropathy-induced pain.

Amaç: Diyabetik hastalarda duygu-durum hastalıklarının ve kognitif bozukluk insidansının genel popülasyona oranla daha yüksek olduğu bilinmektedir. Bu çalışmada, klinikte antidepresan etkinliği için reçete edilen reboksetin’in sıçanlarda diyabet ile indüklenen davranışsal ve bilişsel değişiklikler üzerine etkinliğinin araştırılması amaçlanmıştır.Gereç ve Yöntem: Sıçanlarda deneysel diyabet modeli 50 mg/kg tek doz streptozotosin enjeksiyonu (i.v.) ile oluşturulnuştur. Reboksetin tedavisine diyabetik komplikasyonların oluşması için 4 hafta beklendikten sonra başlanmıştır. Deney hayvanlarının depresyon ve anksiyete düzeyleri sırasıyla modifiye zorlu yüzme ve yükseltilmiş artı şekilli labirent testleri ile araştırılmış; kognitif performansları ise Morris su tankı ve pasif sakınma testleri ie değerlendirilmiştir. Hayvanlarının motor aktiviteleri de aktivite kafesi ve Rota-rod testleri ile incelenmiştir.Sonuç ve Tartışma: Deneyler sonucunda, diyabetik sıçanların depresyon ve anksiyete düzeylerinin yükseldiği ve bilişsel performanslarının zayıfladığı belirlenmiştir. İki hafta süre ile uygulanan reboksetin tedavisi (8 ve 16 mg/kg) diyabetik sıçanların yüksek depresyon ve anksiyete düzeylerini azaltırken, zayıflamış olan bilişsel performanslarını kayda değer ölçüde güçlendirmiştir. Elde edilen bulgular reboksetin’in diyabete bağlı olarak ortaya çıkan davranışsal ve bilişsel bozuklukların tedavisinde terapötik bir potansiyele sahip olabileceğine işaret etmiştir., Objective: The incidence of emotional and cognitive disorders are higher in diabetic patients with respect to the general population. In this study, it was aimed to investigate the efficacy of reboxetine, a clinically prescribed drug for its antidepressant effect, on behavioral and cognitive alterations caused by diabetes in rats.Material and Method: An experimental diabetes model in rats was induced with a single 50 mg/kg injection of streptozotocin (i.v.). Reboxetine treatment was started 4 weeks after induction of diabetes in order to observe diabetic complications. Depression and anxiety levels of experimental animals were investigated by modified forced swimming and elevated plus-maze tests, respectively; cognitive performances were evaluated by Morris water-maze and passive avoidance experiments. The motor activities of the animals were also examined with the activity cage and Rota-rod tests.Result and Discussion: Obtained results indicated that the depression and anxiety levels of diabetic rats were increased and their cognitive performances were weakened. Reboxetine treatment (8 and 16 mg/kg) for two weeks reduced the elevated depression and anxiety levels in diabetic rats, while significantly improving their weakened cognitive performance. The findings indicated that reboxetine might possess a therapeutic potential for the cure of behavioral and cognitive impairements concomitant with diabetes.

In this study, we aimed to design and synthesize novel molecules carrying both the thiazole and piperazine rings in their structures and to investigate their antinociceptive activity. Targeted compounds were obtained by reacting thiosemicarbazide derivative and appropriate 2-bromoacetophenone in ethanol. The structures of the obtained compounds were determined using data from various spectroscopic methods (IR, 1H-NMR, 13C-NMR, and LCMSMS). Experimental data from in vivo tests showed that test compounds 3a–3c, 3f, and 3g (50 mg/kg) significantly prolonged reaction times of animals in tail-clip and hot-plate tests compared to the controls, indicating that these compounds possess centrally mediated antinociceptive activities. Furthermore, these compounds reduced the number of writhing behaviors in the acetic acid-induced writhing tests, showing that the compounds also possess peripheral antinociceptive activity. In the mechanistic studies, naloxone pre-treatments abolished the antinociceptive activities of compounds 3a–3c, 3f, and 3g, indicating that opioidergic mechanisms were involved in their antinociceptive effects. Molecular docking studies demonstrating significant interactions between the active compounds and µ- and δ-opioid receptor proteins supported the pharmacological findings. This study is the first showing that molecules designed to bear thiazole and piperazine moieties together on their structure exert centrally and peripherally mediated antinociceptive effects by activating the opioid system.

WOS: 000467942800006, PubMed ID: 30822229, Objectives: Neuropathic pain reduces the life qualities of patients with Diabetes mellitus. Clinical guidelines recommend relief in diabetic neuropathic pain through the use of some antidepressants, anticonvulsants, opioids as well as capsaicin cream or lidocaine patches. However, since the majority of patients do not or partially respond to current treatments, there is a growing necessity for new drugs increasing the pain relief in patients with diabetes. Therefore, based on the therapeutic potential of antidepressants on neuropathic pain, we investigated the promising antihyperalgesic effect of mirtazapine (MRT) in painful diabetic neuropathy. Methods: Experimental diabetes was induced in rats by single intraperitoneal injection of 55 mg/kg dose of streptozocin (STZ). After 4 weeks of injection of STZ, MRT was administrated for 14 days at 40 mg/kg dose. Randall-Selitto and Hargreaves tests were applied for paw-withdrawal threshold and paw-withdrawal latency measurement. TRPV1 and ASIC1 expressions measured by Western blot in dorsal root ganglion and spinal cord. Results: Administration of MRT significantly improved both of the decreased paw-withdrawal threshold and shortened the paw-withdrawal latency of diabetic rats, respectively. Besides, increased levels of TRPV1 and ASIC1 channels in dorsal root ganglion and spinal cord of diabetic rats, evaluated by Western blot method, were decreased following the MRT treatment. Discussion: These data show, for the first time, that MRT has beneficial effects against diabetes-induced hyperalgesia, and that suppressive effect of this drug on TRPV1 and ASIC1 levels, which are increased in diabetic rats, may be some of the pharmacological mechanisms underlying the exhibited antihyperalgesic effect of MRT., Eskisehir Osmangazi University (ESOGU) Science Foundation [2014-515], This work was funded by the Eskisehir Osmangazi University (ESOGU) Science Foundation Grant No. 2014-515.

Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30–180 min) showed that vortioxetine (10 and 20 mg/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), α-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective α-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, α-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.

WOS: 000521117200001, PubMed: 31981560, In this study, we investigated the potential therapeutic effects of tofisopam, a 2,3-benzodiazepine derivative anxiolytic, on cognitive deficits in rats with scopolamine-induced amnesia. Cognitive performance of the rats was investigated by using the Morris water maze and passive avoidance tests. Changes in motor activity were assessed by using the activity cage and Rota-rod tests and then morphological changes in the hippocampus were assessed via immunohistochemical stainings. the results indicated that scopolamine impaired learning and memory parameters in rats. Worsened cognitive performance, neuronal loss, and decreased hippocampal synaptophysin, Ki-67, and glial fibrillary acidic protein density were observed. Tofisopam administration at a dose of 50 mg/kg for seven days improved the impaired cognitive performance, enhanced the attenuated synaptic transmission in the hippocampus, increased proliferation in subgranular zones, and improved the decrease in astrocytes in amnesic rats. These findings point out the anti-amnesic effects of tofisopam with concomitant improvements in the hippocampal synaptogenesis, neurogenesis, and glial plasticity, for the first time. Presented beneficial effects of tofisopam on cognitive dysfunctions may have a notable clinical value considering the fact that one of the most important side effects of 1,4-benzodiazepines, which are classical anxiolytic drugs, is amnesia. However, these preclinical results need to be confirmed with further clinical studies, first.

WOS: 000418498400031, PubMed ID: 29132093, Background: Acetylcholinesterase (AChE) inhibitors are frequently prescribed to mitigate the cognitive decline in Alzheimer's disease. Thus, we investigated the possible efficacy of the AChE inhibitor 2-[(6-Nitro-2-benzothiazolyl) amino]-2-oxoethyl4-[2-(N, N-dimethylamino) ethyl] piperazine-1 carbodithioate (BPCT) in a streptozotocin (STZ)-induced Alzheimer's disease model (SADM). Methods: First, we analyzed the molecular interaction of BPCT with AChE via a docking study. Then, the cognitive effects of BPCT (10 and 20 mg/kg) were evaluated in intracerebroventricular STZ- and vehicle-administered rats with the elevated plus maze (EPM), Morris water maze (MWM), and active avoidance (AA) tests. Locomotor activity was also assessed. Results: Docking analysis indicated significant binding of BPCT to the AChE active site. In behavioral tests, STZ administration impaired cognitive performance in SADM rats versus control rats. Treatment with donepezil or BPCT significantly decreased the prolonged 2nd retention transfer latency and 2nd retention latency time values of the SADM group in the EPM and MWM tests, respectively. Further, prolonged latency times were decreased and reduced frequency of avoidance events were increased in the AA test. Locomotor activity between groups was not different. Conclusion: BPCT appears to function as a central AChE inhibitor, and its improvement of deficits in SADM rats suggests that it has therapeutic potential in Alzheimer's disease., Anadolu University Research Foundation (Eskisehir, Turkey) [1105S084], The authors with to thank Assoc. Prof. Dr. Yusuf Ozkay for the synthesis of the test compounds. This work was financially supported by the Anadolu University Research Foundation (Eskisehir, Turkey), Project No. 1105S084.

Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30–180 min) showed that vortioxetine (10 and 20 mg/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), α-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective α-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, α-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.

WOS: 000459738800012, Background: Benzimidazole and piperidine rings are important pharmacophore groups for drug design studies. Objective: In this study, we aimed to investigate the antidepressant-like activity of some 2-(4- substituted-phenyl)-1-[2-(piperidin-1-yl)ethyl]-1H-benzimidazole derivatives. Methods: Tail-suspension Test (TST) and Modified Forced Swimming Tests (MFST) were used to assess antidepressant-like activities of the test compounds. Moreover, locomotor activity performances of the animals were evaluated by an activity cage device. Results: In the TST and MFST, compounds 2c-2h (10 mg/kg) and the reference drug fluoxetine (20 mg/kg) significantly reduced the immobility time of mice indicating the antidepressant-like activities of these compounds. Further, in MFST, the same compounds induced significant enhancement in the duration of active swimming behaviors without affecting the climbing performance of the animals. This prolongation in the swimming time, similar to fluoxetine, pointed out that antidepressant-like activity of the compounds 2c-2h might be related to the serotonergic rather than noradrenergic mechanisms. Besides, results of the activity cage tests demonstrated that none of the tested compounds caused an alteration in the locomotor activities of mice, signifying that antidepressant-like effects presented in this study were specific. Conclusion: In conclusion, results of this present study supported the previous papers reporting the therapeutic potential of compounds carrying benzimidazole and/or piperidine rings in their structure and emphasized, once again, the importance of these pharmacophore groups in drug design studies., Anadolu University Scientific Research Projects Commission [1606S567], This research was supported from the Anadolu University Scientific Research Projects Commission (Project No: 1606S567). Moreover, the authors thank to the Prof. Dr. Yusuf Ozkay for the synthesis of the test compounds.

AMAÇ: Leptin hormonu, iştah ve vücut metabolizması- nın düzenlenmesinde önemli görevler üstlenmekte ve başlıca yağ dokusunda sentezlenmektedir. Leptinin yağ dokuda sentezlendikten sonra koroid pleksus aracılığı ile beyne taşındığı bilinmektedir. Bu çalışmanın amacı Tip 1 diyabetes mellitus oluşturulan sıçanların beyninde leptin ifadesinin ve miktarının araştırılmasıdır. GEREÇ VE YÖNTEM: Çalışmamızda toplam 14 adet yetiş- kin, erkek Wistar Albino sıçan 2 eşit gruba ayrıldı (n=7). Kontrol grubuna hiçbir uygulama yapılmadı. Diyabetes mellitus grubundaki hayvanlara ise tek doz (55 mg/kg) streptozotosin intraperitoneal olarak verildi ve kan glukoz seviyesi >280 mg/dL ölçüldüğünde Tip 1diyabetes mellitus geliştiği kabul edildi. Deney sonunda alınan beyin örnekleri %10’luk formaldehit ile fikse edildikten sonra rutin doku takip işleminin ardından alınan kesitlere leptin immünohistokimyasal boyaması uygulandı. Beyin dokularında western blot yöntemi ile leptin miktarına bakıldı. BULGULAR: Tüm gruplara ait beyin kesitlerinde sadece koroid pleksusta leptin boyanması saptandı. Buna göre, leptin boyanmasının Tip 1 diyabetes mellitus geliştirilen sıçanlarda azaldığı saptandı. Western blot ile Tip 1 diyabetes mellitus grubunda leptin miktarının belirgin olarak azaldığı saptandı. SONUÇ: Bu çalışmayla tokluk hissini oluşturmak üzere koroid pleksus üzerinden beyne geçen leptin hormonu ile diyabet arasında yakın bir ilişki olduğu ve bu hormonun diyabetle azaldığı gösterilmiştir. Bu çalışmadan yola çıkarak Tip 1 diyabet ve leptin hormonu ilişkisi derinlemesine irdelenmelidir. OBJECTIVE: Leptin hormone plays an important role in regulation of appetite and body metabolism and is mainly synthesized in fat tissue. It is known that leptin is transported to the brain via choroid plexus after synthesized in the fat tissue. The aim of this study is to investigate the amount and expression of leptin in the brain of rats with type 1 diabetes mellitus. MATERIAL AND METHODS: A total of 14 adult male Wistar Albino rats were divided into 2 equal groups (n = 7). No application was made to the control group. A single dose (55 mg/kg) of streptozotocin was administered intraperitoneally to the animals of the diabetes mellitus group and it was considered that type 1 diabetes mellitus developed when blood glucose level > 280 mg/dL. Brain samples taken at the end of the experiment were fixed with %10 formaldehyde and then subjected to routine tissue monitoring followed by leptin immunohistochemical staining. The amount of leptin was determined by western blotting in brain tissues. RESULTS: In all groups leptin staining was detected only in the choroid plexus of rat brains. According to this knowlodge, it was determined that leptin staining decreased in type 1 diabetes mellitus developed rats. The decreased leptin in the type 1 diabetes mellitus group was showed by western blot too. CONCLUSIONS: Type 1 diabetes reduces the expression and amount of leptin in the choroid plexus.

WOS: 000451641900153, PubMed ID: 30400609, Novel benzazole derivative compounds 4a-4h were obtained by the reaction of corresponding 2-(benzazol-2-ylthio)acetohydrazide and appropriate 4-substituted benzaldehydes. The chemical structures of the synthesized compounds were elucidated by FT-IR, H-1-NMR, C-13-NMR and LCMS spectroscopic methods. Antidepressant-like effects of the compounds were evaluated by tail suspension test (TST) and modified forced swimming tests (MFST). Moreover, locomotor activities of the animals were assessed by an activity cage apparatus. In the series, compounds 4a, 4b, 4e and 4f (at 50 mg/kg) significantly decreased the immobility time of mice in both of the TST and MFST. The same compounds prolonged the swimming time of animals in MFST without any change in the climbing duration. These data indicated that compounds 4a, 4b, 4e and 4f possess significant antidepressant-like activities. Moreover, pre-treatments with p-chloro-phenylalanine methyl ester (an inhibitor of serotonin synthesis), NAN-190 (a 5-HT1A antagonist), ketanserin (a 5-HT2A/2C antagonist), and ondansetron (a 5-HT3 antagonist) reversed the exhibited pharmacological effects. Results of the mechanistic studies suggested the involvement of serotonergic system and contributions of 5-HT1A, 5-HT2A/2C and 5-HT3 receptors to the antidepressant-like effects of compounds 4a, 4b, 4e and 4f. Furthermore, unchanged locomotor activity of mice following the administrations of these four derivatives confirmed that the presented antidepressant-like effects are specific., Anadolu University Scientific Research Projects Commission [1805S189], This research was supported from the Anadolu University Scientific Research Projects Commission (Project No: 1805S189).

WOS: 000387597900007, PubMed ID: 27421789, In this study, we investigated the effects of subacute agomelatine (40 and 80 mg/kg) administration on chronic hyperglycemia, metabolic parameters, and pain perception in streptozotocin-induced diabetic rats. Fasting blood glucose measurements and oral glucose tolerance tests were performed to evaluate the effect of agomelatine on glycemia, while metabolic parameters were monitored using metabolic cages. Potential effect of agomelatine on diabetes-induced mechanical and thermal allodynia was evaluated using dynamic plantar aesthesiometer and warm plate (38 degrees C) tests, respectively. Additionally, influence of agomelatine on hyperalgesia occurring in connection with diabetic neuropathy was examined using the Randall-Selitto (mechanical nociceptive stimulus), Hargreaves (thermal nociceptive stimulus), and cold plate (4 degrees C, thermal nociceptive stimulus) tests. Obtained data indicated that, in diabetic rats, agomelatine significantly improved hyperalgesia and allodynia responses, without no effect on hyperglycemia or the associated polydipsia, polyuria, and hyperphagia. Therapeutic potential of agomelatine on neuropathic pain was suppressed with -methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis), phentolamine (a nonselective -adrenoceptor antagonist), and propranolol (a nonselective -adrenoceptor antagonist) administrations. However, p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis) pretreatment could not be achieved to reverse these antihyperalgesic and antiallodynic effects. These results suggest that the curative effect of agomelatine on neuropathic pain is mediated through rising synaptic catecholamine levels as well as through interactions with both - and -adrenoceptors. To our knowledge, this is the first study to show findings that indicate catecholaminergic system mediated antihyperalgesic and antiallodynic effects of agomelatine., Anadolu University Research Foundation (Eskisehir, Turkey) [1105S084], This work was financially supported by the Anadolu University Research Foundation (Eskisehir, Turkey), Project No. 1105S084.

WOS: 000385057400006, PubMed ID: 27590609, Aims: This study was planned to examine the antinociceptive efficacy of agomelatine against acute mechanical, thermal, and chemical nociceptive stimuli, as well as to determine the opioid receptor subtypes mediating these effects. Main methods: Tail-clip, hot-plate, and acetic acid-induced writhing tests were performed to evaluate antinociceptive effect. Besides, possible effect of agomelatine on the motor coordination of animals was assessed with a Rota-rod test. Keyfindings: Agomelatine (40 mg/kg and 60 mg/kg) significantly prolonged the reaction time of mice in both the tail-clip and hot-plate tests, suggesting the antinociceptive activity is related to both spinal and supraspinal mechanisms. This drug also reduced the number of writhing behaviors indicating the presence of a peripherally mediated antinociceptive effect Rota-rod testing displayed no notable effect on the motor activity of the animal supporting the conclusion that the observed antinociceptive effect is specific. The agomelatine-induced antinociceptive activity abrogated following pretreatment with naloxone (a non-selective opioid receptor antagonist, 5.48 mg/kg, i.p.), which suggested the participation of opioid mechanisms to the antinociception. The possible contribution of mu, delta and kappa subtypes of opioid receptors to the anti-nociceptive effect were evaluated using naloxonazine (7 mg/kg, s.c.), naltrindole (0.99 mg/kg, i.p.), and nor-binaltorphimine (1.03 mg/kg, i.p.), respectively. Pretreatments using these antagonists abolished the antinociceptive activity of agomelatine in all of the nociceptive test paradigms used, which pointed out that mu, delta, and kappa opioid receptors participated to the action of agomelatine on pain. Significance: These results demonstrated the therapeutic potential of agomelatine in the treatment of pain disorders, Anadolu University Research Foundation (Eskisehir, Turkey) [1404S127], This work was financially supported by the Anadolu University Research Foundation (Eskisehir, Turkey), project no. 1404S127.

WOS: 000374883700008, This study was planned to investigate possible antinociceptive activity of 1,5-diaryl-3-[4-(methylsulfonyl) phenyl]-4,5-dihydro-1H-pyrazole derivatives (2a-s), based on the analgesia-inducing potential of 4,5-dihydro-1H-pyrazole moiety carrying compounds. Tail-clip and hot-plate tests, measuring centrally organized responses to a noxious stimulus, were performed in order to examine antinociceptive potential of the test compounds (100 mg/kg, i.p). In addition, peripherally mediated antinociceptive effect was evaluated by acetic acid-induced writhing tests. Motor coordination of the animals was tested in a Rota-rod apparatus. Among the tested compounds 2c, 2e, 2g, 2h, 2j, 2l, 2m, 2o and 2r prolonged the reaction time, measured in the tail-clip and hot-plate tests, with respect to the control values. The same compounds also decreased the quantity of acetic acid-induced writhing behaviours. In the Rota-rod tests, compound 2r was the only derivative decreasing the falling latency of mice. The obtained results indicated that some of the tested 4,5-dihydro-1H-pyrazole derivatives induce notable antinociceptive activity by effecting both of the central and peripheral nociceptive pathways. In addition, this study provided some information about structure-activity relationship for the compounds carrying similar chemical scaffold. Nevertheless, it should be noted that mechanism of action for these agents should be clarified with further detailed investigations.

WOS: 000540959600007, PubMed: 32388433, …, Hacettepe University Scientific Research Projects Coordination Unit, Ankara, TurkeyHacettepe University [THD-2018-16721], This study was supported by Hacettepe University Scientific Research Projects Coordination Unit, Ankara, Turkey (Project number: THD-2018-16721). We thank Hacettepe University Technology Transfer Center for providing English language editing service.

WOS: 000442869800313, PubMed ID: 30127276, Researches that are related to the central nervous system complications of diabetes have indicated higher incidence of cognitive disorders in patients. Since the variety of nootropic drugs used in clinics is limited and none of them consistently improves the outcomes, new and effective drug alternatives are needed for the treatment of diabetes-induced cognitive disorders. Based on the nootropic potential of agomelatine, the promising efficacy of this drug on cognitive impairments of diabetic rats was investigated in the current study. Experimental diabetes model was induced by streptozotocin. After development of diabetes-related cognitive impairments in rats, agomelatine (40 and 80 mg/kg) was administrated orally for two weeks. Cognitive performance was assessed by Morris water-maze and passive avoidance tests. Then, the total numbers of neurons in both dentate gyrus and Cornu Ammonis (CA) 1-3 subfields of the hippocampus were estimated by the optical fractionator method. Agomelatine treatment induced notable enhancement in the learning and memory performance of diabetic rats. Moreover, it reversed the neuronal loss in the hippocampal subregions of diabetic animals. Obtained results suggest that agomelatine has a significant potential for the treatment of diabetes-induced cognitive impairments. However, therapeutic efficacy of this drug in diabetic patients suffering from cognitive dysfunctions needs to be confirmed by further clinical trials., Anadolu University Scientific Research Projects Commission [1501S005], This research was supported from the Anadolu University Scientific Research Projects Commission (Project no: 1501S005).

WOS: 000466261400005, PubMed ID: 30711241, Aim The aim of this study was to investigate the effects of mirtazapine, which is anti-oxidative and antidepressant agent, on the kidney damage caused by diabetes mellitus. Materials and methods: The rats were randomly divided into three groups (n = 7 animals in each group). The group I rats served as control and they received 0.1 mol/L of citric acid buffer (pH = 4.5) as vehicle. The rats in the group II (DM group) and III (DM + Mirtazapine-treated group) were treated intraperitoneally with a single dose of 55 mg/kg streptozotocin dissolved in 0.1 mol/L of citric acid buffer. Group DI rats were also received 20 mg/kg/day of mirtazapine for 2 weeks. At the end of the experiment, the rats were sacrificed. Then, the kidneys were excised and prepared for microscopical examination, caspase-1 and NLRP3 proteins were examined using immunohistochemistry and western blotting. The TUNEL assay for apoptosis and ELLSA assay for IL-1 beta were performed. Results: Histological examination showed that mirtazapine administration has an ameliorative effect on DM-induced kidney damage. Immunohistochemical and western blot analyses showed that NLRP3 and caspase-1 expressions were increased in the DM group according to the control group and the mirtazapine administration decreased these expressions. The intraglomerular and tubular TUNEL-positive cells were numerous in the DM group compared to the mirtazapine-treated group. The level of IL-1 beta was highest in the DM group, and decreased significantly in the mirtazapine-treated group. Conclusion: In this study, 20 mg/kg/day mirtazapine administration for 2 weeks reduced NLRP3 and caspase-1 expressions and IL-1 beta level in the diabetic rat kidneys. These results suggesting that mirtazapine may be useful in the treatment of DM and other metabolic diseases. Advanced molecular studies are needed to elucidate the exact effects of mirtazapine on NLRP3 inflammasome.

WOS: 000355933000011, In the present study, new 4-[4-[2-(2-(4-substituted benzylidene)hydrazinyl)-2-oxoethoxy]phenyl]-4-oxobutanoic acid derivatives were synthesized, and their anti-nociceptive and anti-inflammatory activities were investigated. In the synthesis of the compounds, 4-[4-(2-ethoxy-2-oxoethoxy)phenyl]-4-oxobutanoic acid molecule was used as starting material. The intermediate hydrazide compound (1) was reacted with appropriate aromatic aldehydes to obtain final hydrazone compounds (2a-i). All final compounds are well characterized by IR, H-1 NMR, C-13 NMR, and MS spectroscopic data. Hot-plate and tail-clip tests, measuring centrally organized responses to a nociceptive stimulus, were performed in order to examine anti-nociceptive potentials of the compounds (50 mg/kg). In addition, peripherally mediated anti-nociceptive effect was assessed by acetic acid-induced writhing tests. Further, carrageenan-induced paw edema method was used in order to evaluate the anti-inflammatory activity potential of the compounds. Motor coordination of the animals was examined in a Rota-rod apparatus. The obtained data indicated that compounds 2a, 2b, 2c, 2d, 2e, 2f decreased the number of acetic acid-induced writhing behaviors comparable with diclofenac sodium (10 mg/kg). The same compounds significantly decreased the paw swelling rate (%) of the mice with respect to the control values. These results indicated that compounds 2a, 2b, 2c, 2d, 2e, and 2f have peripherally mediated anti-nociceptive and anti-inflammatory activities. On the other hand, none of the tested compounds changed the reaction time of mice in hot-plate or tail-clip tests indicating that neither supraspinal nor spinal pathways were affected. The observed effect seems to be specific, since Rota-rod tests did not point out any motor impairment induced by the test compounds.

WOS: 000398360500015, The present study was undertaken to synthesize some novel lipophilic piperazine and piperidinedithiocarbamates and investigate their inhibitory potencies against cholinesterase enzymes. In the synthetic studies, 44 new compounds were isolated. The structures of the synthesized compounds were confirmed by spectroscopic analyses. Enzymatic studies were carried out using modified Ellman's assay against Acetyl cholinesterase (AChE) and Butrylcholinesterase (BChE) enzymes, and it was observed that some of the compounds selectively inhibit AChE. Theoretical ADME predictions were calculated for selected compounds in the series. Enzyme kinetics and molecular docking studies were performed for the most active compound C41 and nature of inhibition and interactions between enzyme and ligand were explained., Anadolu University [1305S83], This study was financially supported by Anadolu University Scientific Research Projects Funds. Project No: 1305S83.

WOS: 000413397800016, PubMed ID: 28942286, Aims: This study was planned to examine the antidepressant potency of gallic acid (30 and 60 mg/kg), a phenolic acid widely distributed in nature, together with its possible underlying monoaminergic mechanisms. Main methods: Antidepressant-like activity was assessed using the tail suspension (TST) and the modified forced swimming tests (MFST). Locomotor activity was evaluated in an activity cage. Key findings: Administration of gallic acid at 60 mg/kg reduced the immobility duration of mice in both the TST and MFST without any changes in the locomotor activity. The anti-immobility effect observed in the TST was abolished with pre-treatment of p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis; 100 mg/kg i. p. administered for 4-consecutive days), ketanserin (a 5-HT2A/2C antagonist; 1 mg/kg i. p.), ondansetron (a 5-HT3 antagonist; 0.3 mg/kg i. p.), alpha-methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis; 100 mg/kg i. p.), phentolamine (non-selective alpha-adrenoceptor antagonist; 5 mg/kg i. p.), SCH 23390 (a dopamine D1 antagonist; 0.05 mg/kg s. c.), and sulpiride (a dopamine D2/D3 antagonist; 50 mg/ kg i. p.). However, NAN 190 (a 5-HT1A antagonist; 0.5 mg/kg i. p.) and propranolol (a non-selective beta-adrenoceptor antagonist; 5 mg/kg i. p.) pre-treatments were ineffective at reversing the antidepressant-like effects of gallic acid. Significance: The results of the present study indicate that gallic acid seems to have a dual mechanism of action by increasing not only serotonin but also catecholamine levels in synaptic clefts of the central nervous system. Further alpha adrenergic, 5-HT2A/2C and 5-HT3 serotonergic, and D1, D2, and D3 dopaminergic receptors also seem to be involved in this antidepressant-like activity.

Amaç: Bu çalışmada, atipik bir antidepresan olan mianserin’in normoglisemik ve diyabetik sıçanlarda glisemi düzeyi ve metabolik parametreler üzerine olası etkilerinin araştırılması amaçlanmıştır. Gereç ve Yöntem: Mianserin’in subakut uygulamasının, streptozotosin (STZ) ile diyabet oluşturulmuş sıçanların kan glukoz seviyeleri üzerine etkileri, “açlık kan glukozu ölçümleri”, “glikozile hemoglobin ölçümleri” ve “oral glukoz tolerans testi” ile değerlendirilmiştir. Yem ve su tüketimi, idrar ve dışkı atılımı gibi metabolik parametrelerin değişimi ise metabolik kafes düzenekleri ile izlenmiştir. Bulgular: Mianserin’in 30 ve 45 mg/kg dozlarda 7 ve 14 gün süre uygulamasının diyabetik sıçanlardaki hiperglisemiyi ve artmış HbA1c düzeylerini azalttığı; söz konusu hiperglisemiye bağlı olarak gelişen polidipsiyi, poliüriyi, polifajiyi ve dışkı atılımındaki artışı anlamlı biçimde düzelttiği belirlenmiştir. Mianserin uygulandığı iki dozda da diyabetik hayvanların vücut ağırlıklarındaki kaybı azaltmıştır. Antihiperglisemik etki açısından mianserin’in 30 mg/kg dozu referans ilaç metformin (1 g/kg) kadar etkili bulunmuştur. Sonuç: Bu çalışma ile atipik bir antidepresan olan mianserin’in metformin ile kıyaslanabilir ölçüde antihiperglisemik etkinlik gösterdiği ortaya konulmuştur. Bununla birlikte, mianserin’in antihiperglisemik etkinliğinin altında yatan farmakolojik mekanizmalar aydınlatılmayı beklemektedir., Purpose: The aim of this study was to investigate possible effects of atypical antidepressant mianserin on glycemia levels and metabolic parameters of normoglycemic and diabetic rats. Material and Methods: Effects of mianserin administration on blood glucose levels in rats were assessed by measuring “fasting blood glucose”, “glycosylated haemoglobin” levels and conducting the “oral glucose tolerance test”. Changes in metabolic parameters such as food and water consumption and urine and faeces excretion were observed using metabolic cages. Results: Administration of mianserin for 7 and 14 days at doses of 30 and 45 mg/kg significantly reduced the hyperglycemia and elevated HbA1c levels; also improved hyperglycemia induced polydipsia, polyuria, polyphagia, and increased faeces amounts. Mianserin, at both of the administrated doses, reduced the weight loss observed in diabetic animals. With regard to the anti-hyperglycaemic effect, mianserin administered at a dose of 30 mg/kg was found to be as effective as the reference drug metformin (dose, 1 g/kg). Conclusion: This study showed that the anti-hyperglycemic effect of mianserin, an atypical antidepressant, was comparable to those of the reference drug metformin. However, the pharmacological mechanisms underlying this anti-hyperglycemic effect of mianserin remain to be elucidated.

Bu calismanin amaci benzotiyazol halkasi tasiyan bazi bilesiklerin antinosiseptif ve anksiyolitik-benzeri etkilerinin incelenmesidir. 40 mg/kg dozda uygulanan test bilesiklerinin antinosiseptif etkileri kuyruk sikistirma, sicak plaka ve asetik asid ile induklenen kivranma testleri ile arastirilmistir. Bilesiklerin anksiyolitik-benzeri etkilerini incelemek icin delikli tahta ve yukseltilmis arti labirent testleri gerceklestirilmistir. Farelerin motor koordinasyonlarini degerlendirmek uzere Rota-rod cihazi kullanilmistir. Deneyler sonucunda 3f, 3g ve 3h kodlu bilesiklerin kuyruk sikistirma ve sicak plaka testlerinde hayvanlarin reaksiyon surelerini artirdigi ve 3e kodlu bilesigin ise asetik asid ile induklenen kivranma testinde farelerin kivranma sayilarini azalttigi belirlenmistir. Diger yandan, 3f, 3g ve 3h kodlu bilesikler delikli tahta testinde farelerin ilk bas daldirma surelerini kisaltirken toplam bas daldirma sayilarini artirmistir. Yukseltilmis arti labirent testinde ise ayni turevlerin farelerin ac i k kola giris say i lar i n i n ve ac i k kolda kalma surelerinin y u zdelerini art i rd igi ortaya konulmustur. Rota-rod testlerinde test bilesikleri farelerin donen milden dusme surelerini degistirmemistir. Tum bu bulgular, 3f, 3g ve 3h kodlu bilesiklerin santral antinosiseptif ve anksiyolitik-benzeri etki gosterdiklerine; 3e kodlu bilesigin ise periferal antinosiseptif etki gosterdigine isaret etmektedir.

WOS: 000321605200004, PubMed ID: 23639588, In the present study, we determined the potential anti-nociceptive activity of vitexin, a C-glycosylated flavone, by conducting some acute nociceptive tests in mice. Centrally mediated anti-nociceptive effect was evaluated by hot-plate and tail-clip tests, whereas peripherally mediated anti-nociception was assessed by acetic acid-induced writhing tests. Rota-rod test was performed to evaluate the probable effect of vitexin on the motor coordination of mice. Vitexin administered orally at doses of 10, 20, and 30 mg/kg significantly increased the reaction times of animals in the hot-plate and tail-clip tests and reduced the number of acetic acid-induced writhes and stretches in writhing tests, which clearly indicated the presence of the anti-nociceptive effect. This effect disappeared by pretreatment with naloxone (a non-selective opioid receptor antagonist, 5.48 mg/kg, i.p.), which indicated the involvement of opioid mechanisms in anti-nociception. We evaluated the contribution of mu, delta, and kappa subtypes of opioid receptors to the anti-nociceptive activity by using naloxonazine (7 mg/kg, s.c.), naltrindole (0.99 mg/kg, i.p.), and nor-binaltorphimine (1.03 mg/kg, i.p.), respectively. Pretreatment using these antagonists reversed the anti-nociceptive effect of vitexin in all the nociceptive tests, which indicated that mu, delta, and kappa opioid receptors contributed to the anti-nociceptive effect of this flavonoid. Falling latencies of mice in the Rota-rod test did not change upon the administration of vitexin, which indicated that vitexin showed specific anti-nociceptive effect. To the best of our knowledge, this is the first study on centrally and peripherally mediated anti-nociceptive effect of vitexin via opioid-related mechanisms

WOS: 000321387500003, PubMed ID: 23595553, In this study, we synthesized eight novel 1-phenyl-2-(4-substituted-piperazin-1-yl)-propanol derivatives and evaluated their antidepressant-like activities. The chemical structures of the synthesised compounds were elucidated by spectroscopy and elemental analyses. Potential antidepressant-like effects of the test compounds (20 mg kg(-1)) were investigated using the tail-suspension test and modified forced swimming test (MFST) in mice. Additionally, the spontaneous locomotor activity of the mice was assessed using the activity cage apparatus. Both the reference drug fluoxetine (20 mg kg(-1)) and the test compounds 3a-3e and 3g significantly shortened the immobility time of the mice in both the behavioural tests. These test compounds also increased the swimming time in MFST without any change in the climbing duration. Compounds 3c-3e and 3g were significantly more potent in inducing these effects than 3a and 3b. None of the compounds changed the locomotor activities of the animals, thus antidepressant-like effects of test compounds were specific. The findings support those of previous studies that reported antidepressant-like activities of aryl alkanol piperazine derivatives.

WOS: 000388251400004, PubMed ID: 27789142, In the current study, 14 new benzothiazole-piperazine compounds were designed to meet the structural requirements of acetylcholine esterase (AChE) inhibitors. The target compounds were synthesised in three steps. Structures of the newly synthesised compounds (7-20) were confirmed using IR, H-1 NMR, C-13 NMR, and HRMS methods. The inhibitory potential of the compounds on AChE (E.C.3.1.1.7, from electric eel) was then investigated. Among the compounds, 19 and 20 showed very good activity on AChE enzyme. Kinetics studies were performed to observe the effects of the most active compounds on the substrate-enzyme relationship. Cytotoxicity studies, genotoxicity studies, and theoretical calculation of pharmacokinetics properties were also carried out. The compounds 19 and 20 were found to be nontoxic in both of the toxicity assays. A good pharmacokinetics profile was predicted for the synthesised compounds. Molecular docking studies were performed for the most active compounds, 19 and 20, and interaction modes with enzyme active sites were determined. Docking studies indicated a strong interaction between the active sites of AChE enzyme and the analysed compounds, Anadolu University Scientific Projects Fund [1605S314], This study was financially supported by Anadolu University Scientific Projects Fund, Project No: 1605S314.

WOS: 000382334600043, PubMed ID: 27490523, In the current work, new 1,3,4-thiadiazole derivatives were synthesized and investigated for their antinociceptive effects on nociceptive pathways of nervous system. The effects of these compounds against mechanical, thermal and chemical stimuli were evaluated by tail-clip, hot-plate and acetic acid-induced writhing tests, respectively. In addition, activity cage was performed to assess the locomotor activity of animals. The obtained data indicated that compounds 3b, 3c, 3d, 3e, 3g and 3h increased the reaction times of mice both in the hot-plate and tail-clip tests, indicating the centrally mediated antinociceptive activity of these compounds. Additionally, the number of writhing behavior was significantly decreased by the administration of compounds 3a, 3c, 3e and 3f, which pointed out the peripherally mediated antinociceptive activity induced by these four compounds. According to the activity cage tests, compounds 3a, 3c and 3f significantly decreased both horizontal and vertical locomotor activity of mice. Antinociceptive behavior of these three compounds may be non-specific and caused by possible sedative effect or motor impairments., Anadolu University Scientific Research Projects Commission [1605S299], This study was supported by Anadolu University Scientific Research Projects Commission under grant No: 1605S299.

Pharmacological effects of hydroalcoholic extract prepared from Hypericum origanifolium Willd. (Guttiferae) on behavioral parameters and pain perceptions of mice were investigated in this study. Depression, anxiety, spontaneous locomotor activity, and motor coordination parameters of mice were assessed by modified forced swimming, hole board, activity cage, and rota-rod tests, respectively. In addition, antinociceptive effect was evaluated by performing hot-plate, tail-clip, and formalin tests. Reboxetine (20 mg/kg), diazepam (1 mg/kg), and morphine (10 mg/kg) were used as reference antidepressant, anxiolytic, and analgesic drugs, respectively. Phytochemical analyses exhibited that chlorogenic acid (2317.12 ppm) and rutin (2108.79 ppm) were the main phenolic compounds in the H. origanifolium extract. The extract (50, 100, and 250 mg/kg) induced significant antidepressant, anxiolytic, and antinociceptive activities following the acute administrations. Anxiolytic effect was antagonized by flumazenil (a benzodiazepine receptor antagonist, 2.5 mg/kg, i.p.) pre-treatment, which indicated the participation of GABA(A)-benzodiazepine receptor complex in the activity. Moreover, centrally and peripherally mediated antinociception reversed by naloxone (a non-selective opioid receptor antagonist, 5 mg/kg, i.p.) pre-treatment, indicating the involvement of opioid system in the pharmacological action. These findings are the first to indicate the pharmacological effects of the H. origanifolium extract on the emotional state and pain perceptions of mice. Copyright © 2012 John Wiley & Sons, Ltd.

WOS: 000310420500006, PubMed ID: 23087135, Background: In this study, benzothiazolc-piperazine compounds were synthesized by condensing the functional groups of donepezil (DNP), FK-960, and sabeluzole, which are known to have therapeutic potential against Alzheimer's disease, with the aim of obtaining new and potent anti-Alzheimer agents. Methods: Initially, acetylcholinesterase/butyrylcholinesterase enzyme inhibition activities of the synthesized test compounds were investigated by Ellman's method. Effects of the compounds on a streptozotocin (STZ) model of Alzheimer's disease (SMAD) were investigated in rats. SMAD was established by intracerebroventricular (icy) injection of STZ (3 mg/kg), bilaterally. The elevated plus maze, Morris water maze, and active avoidance tests were used to examine the effects of test compounds (I, 5, and 10 mg/kg) on learning and memory parameters of icy STZ-injected rats. Effects of the test compounds on spontaneous locomotor activities of rats were examined with the activity cage test. Results: The compounds B2-B5 and DNP exhibited significant selective inhibitory potencies against acetylcholinesterase. Compounds B2 and B3 at 10 mg/kg doses and compounds B4 and B5 at 5 and 10 mg/kg doses, as well as the reference drug DNP (1 and 3 mg/kg), significantly improved the learning and memory parameters of animals in all cognition tests. None of the test compounds changed spontaneous locomotor activities. Conclusion: Results of the present study revealed that compounds B2-B5 repaired the parameters related to the learning and memory deficits of icy STZ-injected rats. Potencies of these test compounds were comparable to the activity of DNP., Anadolu University Research Foundation (Eskisehir, Turkey) [070321], This work was financially supported by Anadolu University Research Foundation (Eskisehir, Turkey). Project No. 070321. The authors would like to thank Dr. Erols ener from Anadolu University, Faculty of Pharmacy, Department of Analytical Chemistry, for his help in stereotaxic applications.

The present study was undertaken to investigate the putative activity of a methanol extract of Hypericum montbretti (Guttiferae) on the central nervous system. Rutin (1519 ppm) and quercitrin (784 ppm) were identified as the major phenolic compounds in the extract. When administered at 25, 50 and 100 mg/kg doses, the extract decreased the total number of head-dipping behaviours performed by mice during a hole-board test. Administration of both the extract and diazepam (2 mg/kg) reduced spontaneous locomotory activity, potentiated hexobarbital (60 mg/kg)-induced sleeping parameters and prevented pentylenetetrazole (80 mg/kg)-induced seizures relative to the controls. These findings are the first to indicate the sedative and anticonvulsant activities of H. montbretti extract. Atropine (2 mg/kg) and naloxone (5 mg/kg) pre-treatment did not reverse the sedative effect, indicating that muscarinic and opioidergic mechanisms did not contribute to the pharmacological action. However, pre-treatment with flumazenil (a benzodiazepine receptor antagonist) reversed both the sedative and anticonvulsant effects induced by a 100 mg/kg dose of the extract, indicating the involvement of the GABA(A)-benzodiazepine receptor complex. In conclusion, H. montbretti extract is a novel candidate as a sedative and anticonvulsant drug for the treatment of sleep disorders and for the prevention of epileptic seizures. Copyright © 2012 John Wiley & Sons, Ltd.

WOS: 000445295500237, PubMed ID: 30126223, Atomoxetine is a selective noradrenaline reuptake inhibitor drug. Based on the knowledge that agents increasing monoamine levels in the central nervous system have therapeutic potential for neuropathic pain, it is planned to investigate the possible efficacy of atomoxetine on diabetes-induced hyperalgesia, in this study. Randall-Selitto (mechanical noxious stimuli) and Hargreaves (thermal noxious stimuli) tests were used to evaluate nociceptive perception of rats. Obtained data indicated that streptozotocin-induced diabetes causes significant decreases in the paw withdrawal threshold and paw withdrawal latency values of the animals, respectively. However, atomoxetine administered at 3 mg/kg/day for 7 and 14 days improved these diabetes-induced hyperalgesia responses. Furthermore, antihyperalgesic activity was antagonized with -methyl-para-tyrosine methyl ester, phentolamine, propranolol, and sulpiride pre-treatments. The same effect was not reversed, however, by SCH 23390. These findings demonstrated, for the first time, that atomoxetine possesses significant antihyperalgesic activity on diabetes-induced neuropathic pain and this effect seems to be mediated by - and -adrenergic and D-2/D-3 dopaminergic receptors. Results of this present study seem to offer a new indication for an old drug; atomoxetine, but these preclinical data should first be confirmed with further well-designed clinical trials., Anadolu University Scientific Research Projects Commission [1705S549, 1805S200], This research was supported from the Anadolu University Scientific Research Projects Commission (Project No: 1705S549 and Project No: 1805S200).

WOS: 000434717300008, PubMed ID: 29561803, Novel thiadiazole derivatives were synthesized through the reaction of acetylated 2-aminothiadiazole and piperazine derivatives. The chemical structures of the compounds were clarified by Infrared Spectroscopy (IR), H-1 Nuclear Magnetic Resonance Spectroscopy (H-1-NMR), C-13 Nuclear Magnetic Resonance Spectroscopy (C-13-NMR) and Electronspray Ionisation Mass Spectroscopy (ESI-MS) spectroscopic methods. Antidepressant-like activities were evaluated by the tail-suspension (TST) and modified forced swimming (MFST) methods. Besides, possible influence of the test compounds on motor activities of the animals were examined by activity cage tests. In the TST, administration of the compounds 2c, 2d, 2e, 2f, 2g and 2h significantly decreased the immobility time of mice regarding the control values. Further, in the MFST, the same compounds reduced the total number of immobility behaviors while increasing swimming performance. However, no change was observed in the total number of climbing behaviors. These data suggested that compounds 2c, 2d, 2e, 2f, 2g and 2h possess notable antidepressant-like activities. Reference drug fluoxetine (10 mg/ kg) was also exhibited its antidepressant activity, as expected. No significant difference was seen between the locomotor activity values of the test groups signifying that observed antidepressant-like activities are specific. Theoretical calculation of absorption, distribution, metabolism, excretion (ADME) properties for the obtained compounds were performed and obtained data supported the antidepressant-like potential of these novel thiadiazole derivatives., Anadolu University [1606S567], This study was financially supported by Anadolu University Scientific Research Projects. Commission, Project no. 1606S567.

WOS: 000359600300007, PubMed ID: 26110225, Agomelatine is an antidepressant with a distinct pharmacological mechanism of action as an MT1 and MT2 receptor agonist and as a 5-HT2C receptor antagonist. We evaluated the chronic effects of agomelatine administration (40mg/kg, 20 weeks) on the cognitive performance of rats in the Morris water maze task. We applied unbiased stereological quantification methods to estimate the total numbers of granular and pyramidal neurons located in the dorsal hippocampus. We also analyzed the dendritic spines of pyramidal neurons in the CA1 region using the Golgi-Cox impregnation method. The agomelatine-treated group found the hidden platform more quickly than did the control group and spent significantly more time in the target quadrant. Agomelatine administration caused significant volumetric and numerical enhancements in granular and pyramidal neurons in the dentate gyrus and CA1-3 subregions, respectively. Increased densities of the mushroom and stubby types of spines, with no alteration in the thin-shaped spines, were observed in the agomelatine-treated group. These results showed that long-term agomelatine administration induced a nootropic effect supported by structural changes. Enhancement of the more stable types of dendritic spines might indicate improved adaptive capacity in hippocampal neurons. Future studies will provide a better understanding of the effect of this drug on synaptic plasticity., Anadolu University Research Foundation (Eskisehir, Turkey) [1209S139], This work was financially supported by Anadolu University Research Foundation (Eskisehir, Turkey) under project no. 1209S139.

WOS: 000350748200049, PubMed ID: 25658142, In an effort to develop potent antidepressant agents, new pyrazoline derivatives 2a-s were synthesized and evaluated for their antidepressant-like activity by tail suspension test (TST) and modified forced swimming test (MFST). The effects of the compounds on spontaneous locomotor activity were also investigated using an activity cage apparatus. Among these derivatives, compounds 2b, 2d, 2f, 2o, and 2r decreased both horizontal and vertical activity number of the mice. On the other hand, compounds 2a, 2h, 2j, 2k, 2l, 2m, and 2n, which did not induce any significant change in the locomotor activity, significantly shortened the immobility time of mice in TST and MFST, representing the presence of the antidepressant-like effect. Additionally, the same compounds increased the swimming time of mice in MFST without any change in climbing duration, similar to the reference drug fluoxetine (10 mg/kg). In the light of previous papers examining the effects of pyrazolines on central nervous system, this study, once more, pointed out remarkable antidepressant activity potential of pyrazoline derivatives., Anadolu University Scientific Research Projects Commission [1406S315, 1206S105], This study was supported by Anadolu University Scientific Research Projects Commission under the grant no: 1406S315 and 1206S105.

WOS: 000353195600013, PubMed ID: 25771454, This study used various experimental pain methods to investigate the effects of subacute mianserin administration on diabetes-induced neuropathic pain in rats. The effect of mianserin on hyperalgesia occurring in connection with peripheral diabetic neuropathy was examined using the Randall-Selitto (mechanical nociceptive stimulus), Hargreaves (thermal nociceptive stimulus), and cold-plate (4 degrees C, thermal nociceptive stimulus) tests. The dynamic plantar aesthesiometer, which measures the threshold values for mechanical stimuli, was used for allodynia studies. Thermal allodynia was evaluated with the warm-plate (38 degrees C) test. At 30 and 45 mg/kg, mianserin effectively improved mechanical and thermal hyperalgesia occurring in connection with diabetic neuropathy. Subacute administration of mianserin also reduced diabetes-associated mechanical and thermal allodynia. The ability of mianserin to reduce diabetic neuropathic pain was comparable to that of pregabalin (10 mg/kg). The antihyperalgesic and antiallodynic effects of mianserin were reversed with alpha-methyl-para-tyrosine methyl ester (AMPT, an inhibitor of catecholamine synthesis), phentolamine (a non-selective alpha-adrenoceptor antagonist), propranolol (a non-selective beta-adrenoceptor antagonist), and naloxone (a non-selective opioid receptor antagonist) administrations. The same effects were not reversed, however, by para-chlorophenylalanine methyl ester (PCPA; an inhibitor of serotonin synthesis). These results suggest that the beneficial effect of mianserin on diabetic neuropathic pain is mediated through an increase in catecholamine levels in the synaptic cleft as well as through interactions with both subtypes of adrenoceptors and opioid receptors. Considering that mianserin exhibits simultaneous antidepressant and antinociceptive effects, this drug could provide a good alternative for treating the pain associated with diabetic neuropathy and the mood disorders caused directly by diabetes, Anadolu University Research Foundation (Eskisehir, Turkey) [1105S084], This work was financially supported by the Anadolu University Research Foundation (Eskisehir, Turkey), Project no. 1105S084.

WOS: 000411499400085, PubMed ID: 28880242, Within the scope of our new antidepressant drug development efforts, in this study, we synthesized eight novel benzothiazole derivatives 3a-3h. The chemical structures of the synthesized compounds were elucidated by spectroscopic methods. Test compounds were administered orally at a dose of 40 mg/kg to mice 24, 5 and 1 h before performing tail suspension, modified forced swimming, and activity cage tests. The obtained results showed that compounds 3c, 3d, 3f-3h reduced the immobility time of mice as assessed in the tail suspension test. Moreover, in the modified forced swimming tests, the same compounds significantly decreased the immobility, but increased the swimming frequencies of mice, without any alteration in the climbing frequencies. These results, similar to the results induced by the reference drug fluoxetine (20 mg/kg, po), indicated the antidepressant-like activities of the compounds 3c, 3d, 3f-3h. Owing to the fact that test compounds did not induce any significant alteration in the total number of spontaneous locomotor activities, the antidepressant-like effects of these derivatives seemed to be specific. In order to predict ADME parameters of the synthesized compounds 3a-3h, some physicochemical parameters were calculated. The ADME prediction study revealed that all synthesized compounds may possess good pharmacokinetic profiles., Anadolu University Scientific Projects Fund [1705S312], This study was financially supported by Anadolu University Scientific Projects Fund, Project No: 1705S312.

WOS: 000408602900137, PubMed ID: 28825626, The aim of this study was to investigate acetylcholinesterase (AChE), monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme inhibitory, and antimicrobial activities of a new series of 2-(4-substituted phenyl)-1-[2-(morpholin-4-yl)ethyl]-1H-benzimidazole derivatives, for their possible use as multi-action therapeutic agents. Target compounds (n = 15) were synthesized under microwave irradiation conditions in two steps, and their structures were elucidated by FT-IR, H-1-NMR, C-13-NMR and high resolution mass spectroscopic analyses. Pharmacological screening studies revealed that two of the compounds (2b and 2j) have inhibitory potential on both COX-1 and COX-2 enzymes. In addition, cytotoxic and genotoxic properties of the compounds 2b, 2j and 2m were investigated via the well-known MTT and Ames tests, which revealed that the mentioned compounds are non-cytotoxic and non-genotoxic. As a concise conclusion, two novel compounds were characterized as potential candidates for treatment of frequently encountered inflammatory diseases., Anadolu University Scientific Research Projects Commission [1105S101, 1606S567], This study was financially supported by Anadolu University Scientific Research Projects Commission, Project no. 1105S101 and 1606S567.