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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.

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: 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).

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: 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: 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: 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: 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: 000314659600034, PubMed ID: 23099258, The present study was designed to investigate the putative effect of vitexin, a flavone C-glucoside present in some drugs, medicinal plants and nutraceuticals, on the central nervous system. Vitexin (10-30 mg/kg) did not show significant alterations in the behaviour of mice tested in hole-board, plus-maze or activity cage tests. However, immobility time of the mice significantly reduced by vitexin administrations in both the tail-suspension and modified forced swimming tests. The anti-immobility effect of vitexin in the tail-suspension test was reversed with alpha-methyl-para-tyrosine methyl ester (AMPT, an inhibitor of catecholamine synthesis, 100 mg/kg, i.p.), yohimbine (an alpha(2)-adrenoceptor antagonist, 1 mg/kg, i.p.), NAN 190 (a 5-HT1A antagonist, 0.5 mg/kg, i.p.), SCH 23390 (a dopamine D-1 antagonist, 0.05 mg/kg, s.c.) and sulpiride (a dopamine D-2/D-3 antagonist, 50 mg/kg, i.p.). The same effect was not reversed, however, by p-chlorophenylalanine methyl ester (PCPA; an inhibitor of serotonin synthesis 100 mg/kg, i.p., administered for 4 consecutive days), ketanserin (a 5-HT2A/2C antagonist, 1-4 mg/kg, i.p.), ondansetron (a 5-HT3 antagonist, 0.1-0.4 mg/kg, i.p.), prazosin (an alpha(1)-adrenoceptor antagonist, 1-4 mg/kg, i.p.), or propranolol (a non-selective beta-adrenoceptor antagonist, 5-20 mg/kg, i.p.). These results suggest that the anti-depressant-like effect of vitexin is mediated through an increase in catecholamine levels in the synaptic cleft as well as through interactions with the serotonergic 5-HT1A, noradrenergic alpha(2), and dopaminergic D-1, D-2, and D-3 receptors. To our knowledge, this is the first study to show findings that indicate an anti-depressant-like effect of vitexin and its underlying mechanisms

WOS: 000303532800011, PubMed ID: 22553059, Novel thiadiazole derivatives bearing hydrazone moieties were synthesized through the reaction of 2-[(5-methyl-1,3,4-thiadiazol-2-yl)thio)]acetohydrazide with aldehydes/ketones. The chemical structures of the compounds were elucidated by H-1-NMR, C-13-NMR, MS-FAB spectral data, and elemental analyses. Behavioral effects of the test compounds in mice were examined by hole-board, activity cage, tail suspension and modified forced swimming tests (MFST). Antinociceptive activities were evaluated using the hot-plate and tail-clip methods. Results of the experiments indicated that the test compounds did not significantly change the exploratory behaviors or locomotor activities of animals in the hole-board and activity cage tests, respectively. Administration of the reference drug fluoxetine (10 mg/kg) and compounds 3a, 3b, 3c, 3j, 3k, and 3l significantly shortened the immobility times of animals in the tail suspension and MFST tests, indicating the antidepressant-like effects of these derivatives. Morphine (10 mg/kg) and compounds 3a, 3b, 3c, 3d, 3e, 3j, 3k, and 3l increased the reaction times of mice in both the hot-plate and tail-clip tests, indicating the antinociceptive effects of these compounds. To the best of our knowledge, this is the first study of central nervous system activities of chemical compounds carrying thiadiazole and hydrazone moieties together on their structures.