Dose-dependent protective effects of Lactobacillus rhamnosus GG against stress-induced ulcer.

BACKGROUND: Stress-related diseases are on the rise and stress is one of the common factors that lead to ulcer. Stress-induced mucosal bleeding is a serious complication observed in many critically ill patients. Due to the harmful side effects of proton pump inhibitors, natural and active alternative treatment methods for peptic ulcer treatment that are safe in terms of side effects are an urgent need for human health. We aimed to investigate the dose-dependent protective effects of Lactobacillus rhamnosus GG (LGG) against stress ulcer induced by cold restraint stress in rats. This study was performed in a total of 42 rats, in control group (C), stress group (S), pantoprazole (20 mg kg-1 day-1) group (P), LGG (3 × 108 cfu mL-1 day-1) + stress group (M1), LGG (15 × 108 mL-1 day-1) + stress group (M5) and LGG (30 × 108 mL-1 day-1) + stress group (M10) (each n = 7). Ulceration areas (mm2) were determined quantitatively with ImageJ software. Glucocorticoid, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels were determined by ELISA and malondialdehyde levels were determined by spectrophotometric measurement. Histopathological examinations were performed in gastric tissue. RESULTS: Therapeutic dose of LGG increased CAT, SOD and GPx levels; prevented excessive activation of the hypothalamic-pituitary-adrenal axis; reduced ulceration and bleeding in the gastric mucosal layer; and provided stabilization of mast cells. CONCLUSIONS: We can suggest that LGG may be beneficial for reducing the negative effects of stress on the body, for protecting against ulcer disease and for reducing or preventing the risk of stress-induced gastrointestinal bleeding in patients staying in intensive care units. © 2024 The Author(s). Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

The effects of galangin in prepulse inhibition test and experimental schizophrenia models.

OBJECTIVE: Acetylcholinesterase inhibitors are the focus of interest in the management of schizophrenia. We aimed to investigate the effects of acute galangin administration, a flavonoid compound with acetylcholinesterase inhibiting activity, on schizophrenia-associated cognitive deficits in rats and schizophrenia models in mice. METHODS: Apomorphine-induced prepulse inhibition (PPI) disruption for cognitive functions, nicotinic, muscarinic, and serotonergic mechanism involvement, and brain acetylcholine levels were investigated in Wistar rats. Apomorphine-induced climbing, MK-801-induced hyperlocomotion, and catalepsy tests were used as schizophrenia models in Swiss albino mice. The effects of galangin were compared with acetylcholinesterase inhibitor donepezil, and typical and atypical antipsychotics haloperidol and olanzapine, respectively. RESULTS: Galangin (50,100 mg/kg) enhanced apomorphine-induced PPI disruption similar to donepezil, haloperidol, and olanzapine (p < 0.05). This effect was not altered in the combination of galangin with the nicotinic receptor antagonist mecamylamine (1 mg/kg), the muscarinic receptor antagonist scopolamine (0.05 mg/kg), or the serotonin-1A receptor antagonist WAY-100635 (1 mg/kg) (p > 0.05). Galangin (50,100 mg/kg) alone increased brain acetylcholine concentrations (p < 0.05), but not in apomorphine-injected rats (p > 0.05). Galangin (50 mg/kg) decreased apomorphine-induced climbing and MK-801-induced hyperlocomotion similar to haloperidol and olanzapine (p < 0.05), but did not induce catalepsy, unlike them. CONCLUSION: We suggest that galangin may help enhance schizophrenia-associated cognitive deficits, and nicotinic, muscarinic cholinergic, and serotonin-1A receptors are not involved in this effect. Galangin also exerted an antipsychotic-like effect without inducing catalepsy and may be considered as an advantageous antipsychotic agent.

Protective effects of anandamide against cisplatin-induced peripheral neuropathy in rats

Background/aim: Cisplatin (CIS) is an effective antineoplastic agent used in the treatment of several cancer types. Peripheral neuropathy is a major dose-limiting side-effect in CIS therapy. Cannabinoids may alleviate this painful side effect. This study investigated the analgesic effects of anandamide (AN) on CIS-induced peripheral neuropathy, in vitro effects of AN in CIS neurotoxicity, and the contribution of nitric oxide (NO) in this effect. Materials and methods: This is an experimental animal study. Primary dorsal root ganglion (DRG) cultures were prepared from one-day-old rats for in vitro investigations. DRG cells were incubated with CIS (100­300 M), and AN (10, 50, 100, and 500 µM) was administered with the submaximal concentration of CIS. Female Sprague Dawley rats were divided into control, CIS, CIS+AN, CIS+AN+L-NG-nitro arginine methyl ester (LNAME). CIS was administered 3 mg/kg i.p once weekly for 5 weeks. AN (1 mg/kg i.p) or in combination with 10 mg/kg i.p LNAME was administrated 30 min before CIS injection. Mechanical allodynia, thermal hyperalgesia, and tail clip tests were performed. After intracardiac perfusion, sciatic nerves (SN), and DRGs were isolated and semi-thin sections were stained with toluidine blue and investigated histologically. SPSS v. 21.0 and Sigma STAT 3.5 were used for statistical analysis. One/two way ANOVA, Kruskal­Wallis, and Wilcoxon signed ranks tests were used. A p-value of 0.05 was accepted as significant. Results: CIS caused significant mechanical allodynia. AN and AN+LNAME significantly increased hind paw withdrawal latency in mechanical allodynia test. The degenerated axons significantly increased in CIS group, while decreased in AN group. The frequency of larger neurons seemed to be higher in CIS+AN group. Conclusion: AN may be a therapeutic alternative for the treatment of CIS-induced peripheral neuropathy. However, its central adverse effects must be considered.

In vitro/in vivo evaluation of gamma-aminobutyric acid-loadedN,N-dimethylacrylamide-based pegylated polymeric nanoparticles for brain delivery to treat epilepsy.

Objectives of this study were the delivery of gamma aminobutyric acid (GABA) into the brain by means of developing brain targeted, nanosized, non-toxic and biocompatible polymeric nanoparticles, and investigating their effectiveness in epilepsy. For this purpose, GABA conjugated N,N-dimethylacrylamide-based pegylated nanoparticles were designed and characterised for particle size, zeta potential, pH, morphology, DSC, XRD, FTIR, GABA quantification and in vitro release. Formulations showed smaller particle size, cationic zeta potential characteristic, possible GABA polymeric matrix interaction and prolonged release pattern. Brain responses were examined using epileptic rats. Both formulations prepared were found to increase latency of seizure, decrease ending time of convulsion, duration of severe convulsion and mortality rate significantly compared with GABA solution. When GABA concentration was measured in Stratum corsatum, there was no statistical difference between GABA solution and formulations. All findings suggested enhancement in all phases of seizures indicating efficient delivery of GABA into the brain via formulations.

Effects of tadalafil on hemorrhagic cystitis and testicular dysfunction induced by cyclophosphamide in rats.

INTRODUCTION: The protective and/or therapeutic potential of tadalafil (TDL) on cyclophosphamide (CP)-induced hemorrhagic cystitis (HC) and testicular dysfunction in rats was evaluated. MATERIALS AND METHODS: The animals except from the control group were divided into four groups and treated with saline, or 1, 5 or 10 mg/kg TDL orally (CP, TDL1, TDL5 and TDL10 groups, respectively) before and after CP injection. Body and organ weights, sperm count, cGMP, nitric oxide (NO), IL-6 and IL-10 levels in serum and bladder tissue, and serum testosterone (T), LH and FSH levels were determined. The histological analysis of bladder and testis was performed and the number of apoptotic cells was determined. RESULTS AND CONCLUSION: The CP group had decreased cGMP and NO levels in the bladder, serum T level (p < 0.05) and sperm count (p < 0.001) and higher IL-6 levels in serum and bladder (p < 0.01). Treatment with TDL resulted in increased cGMP (p < 0.001), NO (p < 0.05) and serum T (p < 0.05) levels. Histological analysis of the CP group showed severe HC in bladder and testicular damage. TDL-treated animals showed a dose-dependent improvement in all of these histological impairments. In conclusion, a selective inhibitor of phosphodiesterase-5 enzyme, TDL, showed a protective and/or therapeutic effect on CP-induced HC and testicular dysfunction in rats.

Chlorogenic acid co-administration alleviates cisplatin-induced peripheral neuropathy in rats.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is still an unresolved problem in cisplatin (CIS) use. OBJECTIVES: This study investigates possible anti-neuropathic effect of chlorogenic acid (CGA) against CIS-induced CIPN in rats while also investigating the contribution of nitric oxide (NO) to this phenomenon. METHODS: Initially, CGA (250-1000 µM) was tested by MTT assay on primary DRG neurons. Subsequently, CIPN was induced in Sprague-Dawley rats by 3 mg/kg intraperitoneal injections of CIS once/week for 5 weeks. CGA (100 mg/kg) was co-administered with CIS, both alone and in combination with l-arginine (LARG) or l-nitro-arginine-methyl-ester (LNAME), to elucidate the contribution of nitrergic system to anti-neuropathic effects. Mechanical allodynia, thermal hyperalgesia, and cold plate tests were performed to test CIPN. Rotarod, footprint analysis, and activitymeter were used to evaluate motor coordination and performance. Tumor necrosis factor alpha (TNF-α) was measured as a marker of inflammation. Histological evaluations of DRG and sciatic nerves (SNs) were performed utilizing toluidine blue staining. Two-way analysis of variance and Kruskal-Wallis following Tukey's test were used as statistical analysis. RESULTS: Higher concentration of CGA (1000 µM) exhibited protective effect against in vitro neurotoxicity. Neither LARG nor LNAME exerted significant change in this effect. Co-administration of CGA alleviated histological abnormalities and neuropathic effects induced by CIS. Ameliorative effect of CGA was not changed in mechanical allodynia but attenuated in cold allodynia, and motor activity/coordination tests by LARG and LNAME. Neuropathic effects of CIS remained unchanged with LARG and LNAME in behavioral experiments. CONCLUSION: The study identified CGA as candidate agent in mitigating CIPN. NO seems to play a modulatory role in this effect.

Antinociceptive effects of gabapentin & its mechanism of action in experimental animal studies.

BACKGROUND & OBJECTIVES: Several studies have shown the possible analgesic effects of gabapentin, widely used as an antiepileptic. Thus, clinical studies have been carried out especially for neuropathic syndroms. This study was undertaken to investigate experimentally whether gabapentin has analgesic effects in mice and rats. METHODS: The mice were divided into 10 groups (n=7) with various treatments to assess central and peripheral antinociceptive activity of gabapentin. Hot plate, tail clip and tail flick tests were applied for the investigation of central antinociceptive activity and the writhing test was applied for the investigation of peripheral antinociceptive activity. In addition, we also evaluated the levels of PGE 2 and nNOS on perfused hippocampus slices of rats. RESULTS: Gabapentin showed a peripheral antinociceptive effect at all doses and a central antinociceptive effect at 30mg/kg dose. While the L-NAME and cyproheptadine changed the central and peripheral effects of gabapentin, naloxone did not change these effects. In vitro studies showed that gabapentin significantly increased nNOS level. PGE 2 and nNOS were found to have an important role in the antinociceptive effects of gabapentin at all doses and its combinations with L-NAME, cyproheptadine, indomethacine, and naloxone. As expected, PGE 2 levels decreased in all groups, while nNOS levels increased, which is believed to be an adaptation mechanism. INTERPRETATION & CONCLUSIONS: Our findings indicate that arachidonate, nitrergic and serotonergic systems play an important role in the antinociceptive activity of gabapentin except for the opioidergic system. Additionally, this effect occured centrally and peripherally. These effects were also mediated by nNOS and PGE2.

Effects of sertraline on experimental mouse models of psychosis.

OBJECTIVE: To study the effects of sertraline on neuroleptic-induced catalepsy, apomorphine-induced climbing behavior, and amphetamine or MK-801-induced locomotor activities in female Swiss albino mice weighing 30-35 g. METHODS: This study was performed in the Department of Pharmacology, Eskisehir Osmangazi University, Eskisehir, Turkey between April 2008 and January 2010. Catalepsy was induced by haloperidol (1 mg/kg intraperitoneally [ip]). Apomorphine (1.5 mg/kg subcutaneously [sc]) was used for studying climbing behavior, and d-amphetamine (30 mg/kg ip) or MK-801 (0.3 mg/kg ip) was used for testing locomotor activities. Eight animals were used in each group. Sertraline (10 mg/kg ip) was injected either acutely, or over 5 days of repeated treatment. RESULTS: Sertraline inhibited catalepsy and climbing behavior when it was used for 5 days in repeated doses, while it augmented amphetamine-induced locomotor activity. It reduced MK-801-induced stereotypic movements, but did not significantly affect amphetamine-induced stereotypic movements when used in a single dose or repeated doses. CONCLUSION: These results suggest that sertraline, a selective serotonin reuptake inhibitor may be a beneficial adjuvant drug during psychosis therapy.

Acute antidepressant and anxiolytic effects of simvastatin and its mechanisms in rats.

OBJECTIVE: The aim of this study is to investigate the antidepressant and anxiolytic effects of simvastatin in rats. METHODS: Sixty-four male adult (8-9 weeks old) Sprague-Dawley rats (200-250 g) were used. The forced swimming test and the elevated plus maze test were used for testing the antidepressant and anxiolytic effects. Eight groups were formed: control (saline), simvastatin 10, 30, and 50 mg/kg, amitriptyline 10 mg/kg, sertraline 5 mg/kg, simvastatin 30 mg/kg+amitriptyline 10 mg/kg, and simvastatin 30 mg/kg+sertraline 5mg/kg combinations. The study was conducted at the Animal Experiment Laboratories, Department of Pharmacology, Eskisehir Osmangazi University Medical School, Eskisehir, Turkey from March to May 2010. RESULTS: The immobility periods were significantly reduced by all doses of simvastatin. Simvastatin 10 and 30 mg/kg but not 50 mg/kg increased time spent in the open arm. A single dose of amitriptyline 10 mg/kg showed significant antidepressant and anxiolytic effects. Sertraline 5 mg/kg showed significant antidepressant, but not anxiolytic effects. There was no change in the antidepressant and anxiolytic effects of simvastatin when combined with amitriptyline. A potentialization in antidepressant effect, and a decrease in anxiolytic effect of simvastatin were observed in combinations of simvastatin and sertraline. CONCLUSION: Simvastatin presents significant antidepressant and anxiolytic effects in rats similar to selective serotonin reuptake inhibitors, and interactions between the effects of simvastatin on indoleamine 2,3-dioxygenase enzymes, N-methyl-D-aspartic acid receptor blockade, and dopaminergic functions possibly mediate its antidepressant and anxiolytic effects.

Antinociceptive, anxiolytic, and depression-like effects of hydrogen sulfide, nitric oxide, and carbon monoxide in rats and the role of opioidergic and serotonergic systems in antinociceptive activity.

l-Arginine, a nitric oxide (NO) donor; sodium hydrosulfide (NaHS), a hydrogen sulfide (H2 S) donor; and tricarbonyldichlororuthenium(II) dimer (CORM-2), carbon monoxide (CO) donor, are characterized as bioactive gas mediators that have been researched for their roles in human physiology. This study aimed to compare the effects of these mediators on pain, anxiety, and depression. Ninety-one adult male Sprague-Dawley rats were used for the experiments. Locomotor activity, elevated plus maze, forced swimming, tail clip, hot plate, and writhing tests were used for the assessments after the administration of l-arginine (30-100 mg/kg), a NO donor; NaHS (5-10 mg/kg), a H2 S donor; and CORM-2 (5-10 mg/kg), CO donor. Intraperitoneal H2 S, NO, malondialdehyde (MDA), glutathione (GSH), and tumor necrosis factor-α (TNF-α) levels were determined by enzyme-linked immunosorbent assay (ELISA). No statistical significance was found in the locomotor activity. NO and CO significantly extended latency at high doses in tail clip test. No significant activity was observed at any dose of all three substances on a hot plate. Both doses of CO and high doses of NO and H2 S showed an antinociceptive effect in the writhing test. While the opioidergic system plays a role in the spinal antinociceptive effect of l-arginine, both serotonergic and opioidergic systems play a role in its peripheral antinociceptive effect. The serotonergic system plays a role in the peripheral antinociceptive effect of CORM-2. The time spent in open arm increased significantly in all groups an elevated plus maze. High doses of all three substances significantly increased the duration of immobility in the forced swimming test. No statistical significance was observed in MDA, GSH, and TNF-α levels. High doses of NO and CO showed a spinal antinociceptive effect. Both doses of CO and high doses of NO and H2 S showed a peripheral antinociceptive effect. All three agents showed anxiolytic and depression-like effects.

2-Aminoethoxydiphenyl borate ameliorates functional and structural abnormalities in cisplatin-induced peripheral neuropathy.

AIM OF THE STUDY: Cisplatin is a platinum-derived chemotherapeutic agent commonly used in the treatment of various tumors. Ototoxicity, nephrotoxicity, and peripheral neuropathy are the most common side effects of this drug. 2-Aminoethoxydiphenyl borate (2-APB), boron- containing compound, has some protective effects against various tissue damage. The present study aimed to investigate the potential protective effects of 2-APB on in vitro and in vivo cisplatin-induced neurotoxicity. MATERIALS AND METHODS: MTT assay was used to determine cell viability in DRG cells. Peripheral neuropathy was induced in forty male Sprague-Dawley rats (200-250g) by administering cisplatin (3 mg/kg/week) intraperitoneally (i.p) for five weeks. 2-APB (2, 4, and 8 mg/kg, i.p) was administered. Mechanical allodynia, thermal hyperalgesia, cold allodynia, mechanical stimuli, motor coordination, and locomotor activity tests were performed. DRG cells and sciatic nerves were analyzed histologically. NGF, BDNF, TNF-α, GSH, MDA, and LDH levels were investigated in rat DRG tissue homogenates. RESULTS: Our results revealed that 2-APB ameliorated cisplatin-induced neurotoxicity by improving mechanical and cold allodynia and motor coordination impairment. It also reduced cisplatin-induced structural toxicity in peripheral tissues. CONCLUSION: These findings demonstrated that 2-APB could be considered as a potential therapeutic strategy for the treatment of cisplatin-induced peripheral neuropathy.

Effects of the probiotic, Lactobacillus rhamnosus GG, on ulcer pathogenesis, HSP70 stress protein and nitric oxide levels in stress induced ulcer.

Peptic ulcer is a gastric or duodenal mucosal injury; psychological stress may participate in development of the lesions. Heat shock protein-70 (HSP70) is a molecular chaperone that is responsible for cellular healing; it is an early biomarker of cellular damage. Nitric oxide (NO) is an intra- and intercellular messenger in the gastrointestinal system that protects mucosal integrity. Lactobacillus rhamnosus is among the microflora of the intestinal tract; it is resistant to gastric acidity. We investigated the efficacy of L. rhamnosus administration on ulcer pathogenesis, stress protein HSP70 and NO levels in experimental stress induced ulcer. The proton pump inhibitor, pantoprazole, was used for comparison with the gastroprotective effect of the probiotic. We administered 10 mg/kg pantoprazole and L. rhamnosus at doses of 3 × 108 cfu/ml (M1), 15 × 108 cfu/ml (M5), 30 × 108 cfu/ml (M10) to rats according to McFarland-1, McFarland-5, McFarland-10 standards, respectively. Rats were stressed by immobilization at 4 °C, then sacrificed. The pH, amounts of gastric mucus, NO and HSP70 levels were measured and the histological structure of stomach was assessed. We found increased NO levels in the M5 group and increased HSP70 expression in the pantoprazole group. Significant epithelial damage was observed in the stressed groups and minimal epithelial damage was observed in M5 group compared to controls. The probiotic, L. rhamnosus, may be useful for preventing stress induced ulcers.

The acute effects of mirtazapine on pain related behavior in healthy animals.

OBJECTIVE: To investigate whether the tetracyclic antidepressant mirtazapine has a pain-suppressing effect in healthy animals. METHODS: In the first step, Swiss albino female mice weighing 25-35 g were used. Eight groups each containing 8 mice were established as follows:- Control (saline), mirtazapine 5 mg/kg, 10 mg/kg, and 20 mg/kg, mirtazapine 10mg/kg and its combinations L-Nitro-L-Arginine Methyl Ester (L-NAME) 100 mg/kg, L-Arginine 100 mg/kg, naloxone 1 mg/kg, and cyproheptadine 50 ug/kg. This study was performed in the Department of Pharmacology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey during March, April, and May 2009. One hour after the drugs were given intraperitoneally, hot plate, tail clip, tail flick, and writhing tests were used for evaluating antinociceptive effects. In the second step, the brain hippocampus of Sprague Dawley type male rats weighing 250±20 g were isolated and 0.6 um hippocampus slices were obtained. In vitro groups were established as control, mirtazapine 3x10(-3)M, 4x10(-3)M, 5x10(-3)M, mirtazapine 4x10(-3)M and its combinations L-NAME, L-Arginine, naloxone, and cyproheptadine 4x10(-3)M. RESULTS: Mirtazapine did not show central spinal analgesic activity, but had significant peripheral and biphasic central analgesic effects at the supraspinal level. In addition, there were no significant differences between the different groups in nitric oxide synthase levels on the brain slices. CONCLUSION: The nitrergic pathway does not have an effect on the central antinociceptive activity of mirtazapine, while opiatergic and serotonergic pathways have a significant role.

Do Resveratrol and Dehydroepiandrosterone Increase Diminished Ovarian Reserve?

OBJECTIVE: In this study, the aim is to observe changes induced by dehydroepiandrosterone (DHEA) and resveratrol (RES) in diminished ovarian follicles that was induced by 4-vinylcyclohexenediepoxide (VCD). MATERIALS AND METHODS: Twenty four Wistar albino female rats were divided into 3 groups: control, DHEA and RES. Unilateral oophorectomy was performed in control group to remove the right ovary of 4 rats and the left ovary of 4 rats. After administration of 160 mg/kg VCD, remaining ovaries were removed. Following the same VCD treatment, in DHEA and RES groups, 60 mg/kg DHEA and 20 mg/kg RES were given for 45 days respectively and residual ovaries were removed. Hematoxylin-eosin and TUNEL staining were performed. Follicle stimulating hormone (FSH), estradiol (E2) and anti-mullerian hormone (AMH) values were measured. RESULTS: In control group, VCD-induced apoptosis in follicles increased the TUNEL-positive cell counts (p<0.001) with decreased number of follicles. On the other hand, DHEA significantly increased all three follicle types in the ovaries and decreased apoptosis (p<0.001). The decreased follicle number in all three follicle types after VCD treatment were found to be significantly increased after RES treatment (p<0.001). Apoptosis in the follicles was significantly decreased by RES administration (p<0.001). FSH values were found to be increased with VCD and to reach control values with DHEA and RES. E2 values significantly decreased with VCD, but significantly increased with RES and DHEA. CONCLUSION: Both DHEA and RES may improve VCD-induced diminished ovarian reserve. DHEA and RES increased the number of primary, primordial and growing follicles, with no significant difference between them.

Protective effects of melatonin on lung damage associated with one-lung ventilation: An experimental study.

BACKGROUND: This study aims to investigate the protective effect of melatonin on lung damage induced by one-lung ventilation in a rat model. METHODS: A total of 20 healthy, Sprague-Dawley male rats were randomized into two equal groups as control (n=10) and melatonin groups (n=10). The control group underwent 60 min of one-lung ventilation, followed by 30 min of two-lung ventilation. In the melatonin group, the rats were administered 10 mg/kg melatonin intraperitoneally 10 min before the start of the experiment. At the end of both ventilation periods, tissue samples were obtained from the lungs of the control and melatonin groups for biochemical analysis and histopathological examinations. Tissue superoxide dismutase, malondialdehyde, and tumor necrosis factor-alpha levels were measured. Lung tissue samples were examined based on the presence and amount of alveolar congestion, intra-alveolar bleeding, and leukocyte and lymphocyte infiltration. RESULTS: At the end of the study, lung tissue malondialdehyde (3.8±0.9 vs. 1.8±0.8 µM; p<0.001) and tumor necrosis factor-alpha levels (47.2±15.0 vs. 21.8±7.2 pg/mL; p<0.001) of the melatonin group were found to significantly decrease, compared to the control group. Superoxide dismutase levels of the melatonin group increased at the end of both ventilation periods, and the increase at the end of one-lung ventilation was found to be statistically significant (0.6±0.2 vs. 1.3±0.7 U/mL; p<0.05). Histopathological examination demonstrated that the tissue damage was less in the melatonin group. There was a significant decrease in the alveolar congestion in this group (p=0.0401). Although other histopathological parameters decreased in the melatonin group, no significant difference was found. CONCLUSION: Our study results demonstrate that melatonin has protective effects on the lung damage induced by one-lung ventilation both at biochemical and histopathological levels in rats.

Physicochemical characterization and pharmacokinetic evaluation of rosuvastatin calcium incorporated solid lipid nanoparticles.

Rosuvastatin calcium (RCa) is a very efficient antihyperlipidemic agent, however, being a BCS class II drug, results in poor oral bioavailability. The present study focused on the enhancement of oral bioavailability of RCa with solid lipid nanoparticles (SLNs). Physicochemical properties of the particles were evaluated by particle size (PS), polidispersity index (PDI), zeta potential (ZP), DSC, FT-IR, XRD, 1H NMR analyses. Entrapment efficiency (EE), drug loading capacity (DL), in vitro release and release kinetics were also analyzed. Safety and efficacy of the formulations were analyzed by cytotoxicity, permeability and pharmacokinetic studies. PS values were ranged between ∼134 and 351 nm with homogenous size distribution (PDI ∼ 0.130-0.33) and ZP data were valued within the range of ∼-17 mV to -41 mV. The SLN2 formulation showed the best cytotoxicity test results and had medium permeability (Papp 5.72 × 10-6 cm sec-1) while pure RCa resulted in low permeability (Papp 3.08 × 10-7 cm sec-1). According to the stability analyses (3 months) 5 ±â€¯3 °C and 25 ±â€¯2 °C were found suitable storage temperatures for SLNs. Pharmacokinetic studies confirmed significant improvement in Cmax (1.4 fold) and AUClast (8.5 fold) by SLNs in comparison with the pure drug indicating the enhanced biopharmaceutical performance of the RCa loaded SLNs.

New pyrazoline bearing 4(3H)-quinazolinone inhibitors of monoamine oxidase: synthesis, biological evaluation, and structural determinants of MAO-A and MAO-B selectivity.

A new series of pyrazoline derivatives were prepared starting from a quinazolinone ring and evaluated for antidepressant, anxiogenic and MAO-A and -B inhibitory activities by in vivo and in vitro tests, respectively. Most of the synthesized compounds showed high activity against both the MAO-A (compounds 4a-4h, 4j-4n, and 5g-5l) and the MAO-B (compounds 4i and 5a-5f) isoforms. However, none of the novel compounds showed antidepressant activity except for 4b. The reason for such biological properties was investigated by computational methods using recently published crystallographic models of MAO-A and MAO-B. The differences in the intermolecular hydrophobic and H-bonding of ligands to the active site of each MAO isoform were correlated to their biological data. Compounds 4i, 4k, 5e, 5i, and 5l were chosen for their ability to reversibly inhibit MAO-B and MAO-A and the availability of experimental inhibition data. Observation of the docked positions of these ligands revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Among the pyrazoline derivatives, it appears that the binding interactions for this class of compounds are mostly hydrophobic. All have potential edge-to-face hydrophobic interactions with F343, as well as pi-pi stacking with Y398 and other hydrophobic interactions with L171. Strong hydrophobic and H-bonding interactions in the MAO recognition of 4i could be the reason why this compound shows selectivity toward the MAO-B isoform. The very high MAO-B selectivity for 4i can be also explained in terms of the distance between the FAD and the compound, which was greater in the complex of MAO-A-4i as compared to the corresponding MAO-B complex.

The Role of Ionic Homeostasis in Cisplatin-Induced Neurotoxicity: A Preliminary Study.

OBJECTIVE: The aim of the present study was to investigate the role of ionic homeostasis in cisplatin (cisdiamminedichloroplatinum (II), CDDP)-induced neurotoxicity. CDDP is a severely neurotoxic antineoplastic agent that causes neuronal excitotoxicity. According to some studies, calcium influx increases, whereas potassium efflux decreases neuronal death. Nimodipine and glibenclamide were used to analyze the role of ionic flows in CDDP-induced neurotoxicity in rat primary cerebellar granule cell (CGC) culture. MATERIALS AND METHODS: CGC culture was prepared from the cerebella of Sprague Dawley 5-day-old pups. The submaximal concentration of CDDP was determined and then given with 1, 10, or 50 µM of drugs into culture. Neurotoxicity was investigated using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole) assay. One-way analysis of variance, Kruskal-Wallis H test, and Tukey test were applied for statistical analysis. RESULTS: CDDP induced neurotoxicity in a concentration-dependent manner. Neither nimodipine nor glibenclamide was able to protect CGCs against CDDP neurotoxicity. CONCLUSION: By blocking L-type voltage-gated calcium channels, nimodipine did not prevent CDDP neurotoxicity in CGCs. Ca2+ influx via these channels seemed to be insufficient to cause a change in CDDP-induced neurotoxicity. Similarly, glibenclamide failed to prevent CDDP neurotoxicity. Further studies are needed to elucidate the mechanisms of these preliminary results.

Cannabinoids and agmatine as potential therapeutic alternatives for cisplatin-induced peripheral neuropathy.

Cisplatin is a widely used antineoplastic agent in the treatment of various cancers. Peripheral neuropathy is a well-known side effect of cisplatin and has the potential to result in limiting and/or reducing the dose, decreasing the quality of life. Unfortunately, the mechanism for cisplatin-induced neuropathy has not been completely elucidated. Currently, available treatments for neuropathic pain (NP) are mostly symptomatic, insufficient and are often linked with several detrimental side effects; thus, effective treatments are needed. Cannabinoids and agmatine are endogenous modulators that are implicated in painful states. This review explains the cisplatin-induced neuropathy and antinociceptive effects of cannabinoids and agmatine in animal models of NP and their putative therapeutic potential in cisplatin-induced neuropathy.

Agmatine co-treatment attenuates allodynia and structural abnormalities in cisplatin-induced neuropathy in rats.

Cisplatin is a widely used antineoplastic agent in the treatment of various cancers. Peripheral neuropathy is a well-known side effect of cisplatin and has potential to result in limiting and/or reducing the dose, decreasing the quality of life. Thus, effective treatments are needed. Agmatine is an endogenous neuromodulator that has been shown to exert antiallodynic effects in various animal studies. The first aim of this study was to investigate the in vitro effects of agmatine on cisplatin-induced neurotoxicity. Primary cultures of dorsal root ganglia (DRG) which are the primary target of drug injury were prepared. DRG cells were incubated with cisplatin (100, 200, 500 µm). Then, agmatine (10, 100, 500 µm) was administered with the submaximal concentration of cisplatin. Cisplatin caused concentration-dependent neurotoxicity, and agmatine did not alter this effect. The second aim was to investigate the effects of agmatine on cisplatin-induced peripheral neuropathy in rats and the influence of nitric oxide synthase (NOS) inhibitor, L-NAME, in this effect. Female Sprague Dawley rats received intraperitoneal saline (control), cisplatin (3 mg/kg), cisplatin+agmatine (100 mg/kg), or cisplatin+agmatine+L-NAME (10 mg/kg) once a week for 5 weeks. The mechanical allodynia, thermal hyperalgesia [corrected], and tail clip tests were performed, and DRG cells and sciatic nerves were analyzed. Agmatine and agmatine+L-NAME combination attenuated CIS-induced mechanical allodynia and degeneration in DRG cells and sciatic nerves. However, L-NAME did not potentiate the antiallodynic or neuroprotective effect of agmatine. These findings indicate that agmatine co-administration ameliorates cisplatin-induced neuropathy and may be a therapeutic alternative.