Engin Yildirim

Effects of sertraline on behavioral alterations caused by environmental enrichment and social isolation

Environmental conditions are known to play a critical role in the pathogenesis of affective disorders. In this study, the effects of sertraline, a selective serotonin (5-HT) reuptake inhibitor, on anxiety- and depression-like behaviors were investigated in rats reared in different housing conditions. Wistar rats of both sexes were divided into three groups according to their rearing conditions (Enriched = EC, Isolated = IC and Standard = SC), after weaning at postnatal day 21. While animals in control conditions were housed as a group of 4 rats in regular size plexiglass cages, social isolation groups were housed individually in metal cages. Animals in enriched conditions were housed as a group of 12 rats in specially designed cages equipped with different stimulating objects. Six weeks later, activitymeter, elevated plus maze, rotarod, grip, forced swimming and sucrose preference tests were applied to all animals and all of the tests were repeated after i.p. injection of sertraline (10 mg/kg/day) for 7 days. Environmental enrichment reduced the stereotypic behavior, improved the motor coordination and facilitated the learning skills in animals. However, housing conditions affected depression-like parameters, but not anxiety-like parameters. Sertraline treatment reduced the depression-like effect in EC and SC, but not in IC. It decreased anxiety-like behavior in IC while increased in EC. Socially isolated animals preferentially consumed more sucrose and water than the other groups, and interestingly, these differences became more significant following sertraline treatment. These results show that the responses of animals to anti-depressive drugs could be differentially affected by the behavioral consequences of the diverse housing conditions. Thus, to improve the treatment of depression; behavioral consequences of diverse housing conditions should be taken into consideration.

Synthesis and antinociceptive activity of (2-benzazolon-3-yl)propionamide derivatives.

The syntheses of (2‐benzothiazolinon‐3‐yl)propionamide and (2‐benzoxazolinon‐3‐yl)propionamide derivatives are reported. The structures of these compounds are elucidated by their IR and 1H‐NMR spectral data, as well as by elemental analysis. The compounds were tested for antinociceptive activity by hot plate, tail flick, tail clip, and modified Koster tests. Compounds 6b and 7d were found to be the most promising compounds among the substances investigated.

Effects of verapamil and nifedipine on different parameters in lipopolysaccharide-induced septic shock

Septic shock has a high mortality rate due to the hypotension and circulatory disorder that occurs during its pathogenesis. Recently, humoral factors such as cytokines and nitric oxide became important in the complex pathophysiology of septic shock because there is a close relationship between the determined levels of these humoral factors and the responses to the therapy and survival periods. Verapamil and nifedipine are calcium channel blockers commonly used in the pharmacotherapy of cardiovascular disorders. In the present study these drugs were investigated in the rat septic shock model. In vivo hemodynamic parameters were recorded using a data acquisition system in endotoxin-induced septic shock in rats. The animals were followed for 5 h and blood pressure, rectal temperature, and ECG were recorded. Blood samples were collected at 1 h and 5 h time points after the injection of endotoxin, and serological samples were stored at −25°C. Subsequently, tumor necrosis factor-α, interleukin-10 (enzyme-linked immunosorbent assay), and nitrite (Griess reagent) were determined in these serological samples. Significant correlations were observed between these humoral factors and the disordered hemodynamic factors. A reversal of changes was observed in the levels of serum cytokines, nitrite levels, and hemodynamic parameters with verapamil and nifedipine preadministration (P < 0.05). Additionally, superoxide dismutase (SOD), catalase, and malondialdehyde (MDA) were determined in livers obtained from these animals at the end of the experiments, and these results were compared to hemodynamic parameters and cytokines. Nifedipine and verapamil increased the levels of MDA and SOD but did not change catalase activity.

Synthesis and anticonvulsant activity of some (2/4-substituted)benzaldehyde (2-oxobenzothiazolin-3-yl)acetohydrazones

Fifteen new (2/4-substituted)benzaldehyde (2-oxobenzothiazolin-3-yl)acetohydrazones were synthesized and their structures were elucidated by NMR and elemental analysis. Their anticonvulsant activity was tested by a pentylenetetrazole induced seizure test. Compounds 4e and 4h were found to be the most promising among the others.

MORNING-EVENING ADMINISTRATION TIME DIFFERENCES IN DIGOXIN KINETICS IN HEALTHY YOUNG SUBJECTS

Digoxin, frequently used in the treatment of congestive heart failure, has a very narrow therapeutic index. We studied the differences in digoxin pharmacokinetics when ingested in the morning versus evening. A single digoxin (0.25 mg) dose was given orally to the same group of 10 diurnally active healthy (6 male and 4 female) volunteers in the morning at 08:00 and evening at 20:00 in separate experiments scheduled 2 weeks apart. Blood samples were collected at specific times for 48h after each timed dose; digoxin was determined by radioimmunoassay (RIA). Maximum plasma concentration Cmax; Tmax, the time to reach Cmax; area under plasma concentration curve AUC; and elimination half-time T1/2 of digoxin were determined. Tmax was statistically significantly shorter (54 min) following 08:00 dosing compared to 20:00 dosing (96 min). Although the Cmax was higher after morning than evening dosing, it was not significantly so. No other parameter of digoxin pharmacokinetics except Tmax exhibited administration time dependency. (Chronobiology International, 18(5), 841–849, 2001)

Effects of Nabumetone and Dipyrone on Experimentally Induced Gastric Ulcers in Rats

Nabumetone and dipyrone are non-acidic, nonsteroidal anti-inflammatory drugs. Both of them are known to have weak inhibitory effects of cyclooxygenases. Gastric side effects represent the most common adverse drug effects of the widely used nonsteroidal anti-inflammatory drugs. The gastric effects of these drugs may be comparable in experimental ulcer models. In the present study, the gastric ulcerogenic activity of nabumetone and dipyrone were investigated on stress- and diethyldithiocarbamate-induced experimental ulcer models by determining the ulcer index and gastric mucus secretion in rats. It was found that diethyldithiocarbamate increased both ulcer index and mucus secretion. Nabumetone inhibited dose-dependently the increase of diethyldithiocarbamate-induced mucus secretion. Dipyrone inhibited both stress- and diethyldithiocarbamate-induced ulcer index and mucus secretion. Nabumetone inhibited stress-induced ulcer index at 25-mg/kg dose but stimulated dose-dependently mucus secretion. These effects may be attributed to their non-acidic structures and weak inhibitory effects on gastric mucosal cyclooxygenases.

Association of angiotensin converting enzyme (ACE) gene I/D polymorphism and polycystic ovary syndrome (PCOS).

This study was conducted in Turkish patients with polycystic ovary syndrome to determine the frequency of I/D polymorphism genotypes of angiotensin converting enzyme gene, and to examine the role of this polymorphism in polycystic ovary syndrome development. Genomic DNA obtained from 200 persons (100 patients with polycystic ovary syndrome and 100 healthy controls) was used in the study. DNA was multiplied by polymerase chain reaction using I and D allele-specific primers. Polymerase chain reaction products were assessed with a charge coupled device (CCD) camera by being exposed to 2% agarose gel electrophoresis. There was statistically significant difference between the groups with respect to genotype distribution (p<0.001). The D allele frequency was indicated as 68% and I allele was as 32% in the patients, whereas it was 51.5-48.5% respectively in the control group. As a result of our study we may assert that angiotensin converting enzyme gene I/D polymorphism DD genotype should be considered as a genetic marker in polycystic ovary syndrome development in this Turkish study population.

Synthesis and antinociceptive activity of (5-chloro-2(3H)-benzoxazolon-3-yl) propanamide derivatives

In this study, (5-chloro-2(3H)-benzoxazolon-3-yl)propanamide derivatives were synthesized. The chemical structures of the compounds were elucidated by their IR and1H-NMR spectral data and microanalysis. The compounds were tested for antinociceptive activity by using the tail clip, tail flick, hot plate, and writhing methods. The varying levels of antinociceptive activity of the compounds were compared with those of dipyrone and aspirin. Among these compounds, compound5e, 5g, and5h have been found to be significantly more active than the others and the standards in all the tests.

The effects of testosterone on isolated sheep coronary artery.

OBJECTIVE Although estrogens have been shown to be vasoactive hormones, the vascular effects of testosterone are not well defined. Little is known about the in vitro effects of testosterone on isolated arteries. The purpose of this experimental prospective study was to assess the direct effect of testosterone on isolated sheep coronary artery in vitro. METHODS We evaluated whether the vascular effects of testosterone were altered in the presence of endothelium or it changed in accordance to gender or the concentration of testosterone. Coronary arterial rings were precontracted by KCl (30 mM). After plateau contraction levels were reached, testosterones (10(-7)-10(-4)M) were added in a cumulative manner. The effects of testosterone were also tested in the presence of NOS inhibitor Nω-nitro-L-arginine methyl ester (L-NAME, 10-4M), and L-arginine (10(-4)M). In statistical analysis, Students t-test was used for comparison between two groups and one-way ANOVA test for comparison among multiple groups. RESULTS Testosterone relaxed sheep coronary artery. Testosterone-induced relaxation was dependent of sex [male endothelium (ME(+)): 24.48±4.13; -29.36±6.41; female endothelium (FE(-)): -3.02±1.04: p<0.05); (ME(+): -24.61±4.14; -24.48±4.13; -29.36±6.41; FE(-): -3.64±0.67: p<0.01); (FE(-):-4.91±0.67: p<0.001)] and endothelium (ME(+): -9.23±2.4; FE(+): -6.33±1.5; -8.43±0.49; -8.83±0.9: p<0.05, p<0.01). L-NAME decreased relaxations in the male (ME(+): 0.77±0.72; 0.086±0.012; 0.0768±0.083; 0.51±0.44: p<0.01, p<0.001) and female (FE(+): 0.0318±0.052; 0.52±0.49; 0.029±70.05: p<0.05, p<0.001) with endothelium groups but only female without (0.01±0.011; -1.14±0.59; -1.23±1.21: p<0.01, p<0.001) endothelium group. L-arginine decreased relaxations especially in the male with endothelium (ME(+): -1.7±0.91; -3.02±1.42; -2.51±1.46; -6.68±2.15; p<0.01, p<0.001) group and in part in the female with (FE(+):-1.73±0.83; p<0.05) or without (FE(-): -1.14±0.59; p<0.01) endothelium groups. CONCLUSION Testosterone induces endothelium and sex-dependent relaxation on sheep coronary artery in vitro. Acute testosterone-induced coronary vasodilatation is mediated in part via endothelium-derived NO. Non-genomic mechanisms may be considered to play a role in the vasodilatory effect of testosterone especially in the female group.

Evaluation of Cisplatin Neurotoxicity in Cultured Rat Dorsal Root Ganglia via Cytosolic Calcium Accumulation

BACKGROUND Calcium homeostasis is considered to be important in antineoplastic as well as in neurotoxic adverse effects of cisplatin. AIMS This study aimed to investigate the role of Ca(2+) in cisplatin neurotoxicity in cultured rat dorsal root ganglia (DRG) cells. STUDY DESIGN Cell culture study. METHODS DRG cells prepared from 1-day old Sprague-Dawley rats were used to determine the role of Ca(2+) in the cisplatin (10-600 μM) neurotoxicity. The cells were incubated with cisplatin plus nimodipine (1-3 μM), dizocilpine (MK-801) (1-3 μM) or thapsigargin (100-300 nM). Toxicity of cisplatinon DRG cells was determined by the MTT assay. RESULTS The neurotoxicity of cisplatin was significant when used in high concentrations (100-600 μM). Nimodipine (1 μM) but not MK-801 or thapsigargin prevented the neurotoxic effects of 200 μM of cisplatin. CONCLUSION Voltage-dependent calcium channels may play a role in cisplatin neurotoxicity.