Ümide Demir Özkay

Anti-depressant-like effect of vitexin in BALB/c mice and evidence for the involvement of monoaminergic mechanisms.

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 α-methyl-para-tyrosine methyl ester (AMPT, an inhibitor of catecholamine synthesis, 100mg/kg, i.p.), yohimbine (an α(2)-adrenoceptor antagonist, 1mg/kg, i.p.), NAN 190 (a 5-HT(1A) antagonist, 0.5mg/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, 50mg/kg, i.p.). The same effect was not reversed, however, by p-chlorophenylalanine methyl ester (PCPA; an inhibitor of serotonin synthesis 100mg/kg, i.p., administered for 4 consecutive days), ketanserin (a 5-HT(2A/2C) antagonist, 1-4 mg/kg, i.p.), ondansetron (a 5-HT(3) antagonist, 0.1-0.4 mg/kg, i.p.), prazosin (an α(1)-adrenoceptor antagonist, 1-4 mg/kg, i.p.), or propranolol (a non-selective β-adrenoceptor antagonist, 5-20mg/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-HT(1A), noradrenergic α(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.

Design, synthesis, and AChE inhibitory activity of new benzothiazole-piperazines.

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, 1H NMR, 13C 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.

The effect of simvastatin treatment on behavioral parameters, cognitive performance, and hippocampal morphology in rats fed a standard or a high-fat diet.

The aim of this study was to examine the effect of simvastatin (SMV), a 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor, in rats fed with a standard or a high-fat diet (HFD) throughout the prenatal and the postnatal periods. The emotional status of the animals was evaluated by elevated plus-maze and modified forced swimming tests, whereas cognitive performance was assessed by a Morris water maze task. Morphological changes in the hippocampus were examined by design-based stereology. HFD exposure significantly increased blood serum triglycerides without altering cholesterol levels relative to the controls. After four weeks of oral SMV (5 mg/kg) administration, serum triglycerides reverted to the control level. SMV caused significant anxiolytic, antidepressant-like, and nootropic effects in animals fed the standard diet. In the HFD group, enhanced anxiety and depression, and reduced cognitive performances of animals were reversed by SMV treatment. Although a total volume estimation of the hippocampal subfields indicated no significant change among the groups, the total number of pyramidal neurons decreased significantly in animals fed the HFD; following SMV treatment, this detrimental effect was reversed. In conclusion, chronic SMV administration has significant therapeutic potential for the treatment of affective and cognitive disorders with or without altering the serum lipid profiles.

Anti-nociceptive effect of vitexin mediated by the opioid system in mice

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.

Effects of some 1,3,5-trisubstitued-2-pyrazoline derivatives on depression and anxiety parameters of mice

The aim of the present study was examining the effects of some 1,3,5-trisubstituted-2-pyrazoline derivatives on depression, anxiety and spontaneous locomotor activity parameters of mice. None of the compounds was effective at 50 mg/kg dose whereas at 100 and 200 mg/kg, pyrazoline-benzoxazole derivative test compound 4a and pyrazoline-benzimidazole derivative test compound 4d in the series were exhibited significant antidepressant effects in modified forced swimming tests. These two pyrazolines decreased the immobility and increased the swimming times of mice without any change in climbing durations suggesting the antidepressant-like effects of the test compounds. In spite of significant antidepressant effect, none of the compounds changed the exploratory parameters in hole-board tests or total numbers of spontaneous locomotor activities in activity cage measurements at any of the applied doses. In other words, neither anxiolytic nor sedative effects induced by the test compounds. The results obtained from this study supported the previous findings reporting the antidepressant activities of pyrazoline derivative compounds. Exact mechanism of the antidepressant action exhibited in the present study need to be clarified with further detailed investigations.

Synthesis of Thiadiazole Derivatives Bearing Hydrazone Moieties and Evaluation of Their Pharmacological Effects on Anxiety, Depression, and Nociception Parameters in Mice

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 1H-NMR, 13C-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.

Effects of hawthorn seed and pulp extracts on the central nervous system

Context: Investigating potential central nervous system (CNS) activities of Crataegus monogyna Jacq. (Rosaceae), hawthorn, fruit extracts. Objective: Evaluating CNS effects and analgesic activities of hawthorn fruit extracts based on the traditional uses of the plant for neurosedative and pain killer actions. Materials and methods: Effects of hawthorn pulp (HPE) and seed extracts (HSE) at the dose range of 1-1000 mg/kg were examined on anxiety level, spontaneous locomotor activity, motor coordination, and nociceptive perception of mice. Morphine was used as a reference drug. Results: HPE (100-1000 mg/kg) and HSE (10-1000 mg/kg) significantly decreased not only the exploratory behaviors in hole-board experiments, but also the spontaneous locomotor activities in activity cage tests. The same doses of extracts were found to be ineffective in Rota-Rod tests of mice. In tail-clip, hot-plate, and acetic acid-induced writhing tests, quite potent and dose-dependent analgesic activities were seen at 100-1000 mg/kg doses of HPE and 10-1000 mg/kg doses of HSE. Analgesic effects observed in all analgesia tests were antagonized by naloxone. Discussion: Significant and dose-dependent decreases in spontaneous locomotor activities and exploratory behaviors of animals suggested CNS depressant activities of both extracts. Complete naloxone antagonism in all applied analgesia tests indicated opioid-related analgesic activities of both extracts. Conclusion: These findings seem to support the traditional use of this plant to treat stress, nervousness, sleep disorders, and pain control.

Synthesis and Evaluation of New 1,5-Diaryl-3-(4-(methyl- sulfonyl)phenyl)-4,5-dihydro-1H-pyrazole Derivatives as Potential Antidepressant Agents

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.

Psychopharmacological profile of Chamomile (Matricaria recutita L.) essential oil in mice.

In this study, the effect of Matricaria recutita L. essential oil (MEO) on the central nervous system (CNS) of mice was investigated using some behavioral methods. Chemical profiling both by GC and GC-MS analyses of the hydrodistilled essential oil of M. recutita revealed α-bisabolol oxide A (28%), α-bisabolol oxide B (17.1%), (Z)-β-Farnesene (15.9%) and α-bisabolol (6.8%) as the main components. Changes induced by MEO (25, 50 and 100 mg/kg) and reference drug caffeine (25 mg/kg) in spontaneous locomotor activities and motor coordinations of mice were investigated by activity cage measurements and Rota-Rod tests, respectively. Open field, social interaction and elevated plus-maze tests were applied to assess the emotional state of the animals. Further, tail-suspension test was performed for evaluating the effect of MEO on depression levels of mice. As a result, at 50 and 100 mg/kg, MEO significantly increased the numbers of spontaneous locomotor activities, exhibited anxiogenic effect in the open field, elevated plus-maze and social interaction tests and decreased the immobility times of animals in tail suspension tests. The falling latencies in Rota-Rod tests did not change. This activity profile of MEO was similar to the typical psychostimulant caffeine. The exact mechanism of action underlying this stimulant-like effect should be clarified with further detailed studies.

Synthesis and analgesic effects of 2-(2-carboxyphenylsulfanyl)-N-(4-substitutedphenyl)acetamide derivatives

This present study was undertaken to synthesize and investigate possible analgesic activities of some 2-(2-carboxyphenylsulfanyl)-N-(4-substitutedphenyl)acetamide derivatives that were designed by combining an analgesic drug thiosalicylic acid and the main pharmacophore group of paracetamol, N-(4-substitutedphenylacetamide). Chemical structures of synthesized compounds were elucidated by IR, 1H-NMR, and Mass spectral data. Paracetamol, thiosalicylic acid and some of the synthesized compounds in the series exhibited significant analgesic activities in hot-plate, tail-clip, and acetic acid-induced writhing tests. Compound 2d showed more potent analgesic activity than both paracetamol and thiosalicylic acid. None of the compounds changed the responses of animals recorded in Rota-Rod or activity cage tests with respect to control values. Therefore, analgesic activities of the synthesized compounds evaluated in this study were not caused by motor impairments or neurosedative effects.