Hybridization of the effective pharmacophores for treatment of epilepsy: design, synthesis, in vivo anticonvulsant activity, and in silico studies of phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid hybrids.

BACKGROUND: Epilepsy is a common neurological disorder. The available drugs for this disease only control convulsions in nearly 70% of patients, while bearing many side effects. In this study, a new series of phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid hybrids 8a-m was designed, synthesized, and evaluated as potent anticonvulsant agents. METHODS: Phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid derivatives 8a-m were synthesized with well-known chemical reactions and anticonvulsant activity of them was determined by pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizures in mice. Phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid scaffold has the necessary pharmacophores to be a benzodiazepine (BZD) receptor agonist, thus, the most potent anticonvulsant compounds were assayed in vivo and in silico as BZD receptor agonist. Furthermore, in vivo neurotoxicity evaluation and in silico physicochemical, pharmacokinetic, and toxicity study on the most potent compounds were also performed. RESULTS: Obtained results demonstrated that two compounds among the title new compounds have anticonvulsant activity in PTZ test while all of the new compounds are active in the MES test. The best anticonvulsant activities were obtained with nitro derivatives 8k and 8L. In vivo evaluation of flumazenil effect (a BZD receptor antagonist) on anticonvulsant activity of compound 8k confirmed that this compound is a BZD receptor agonist. The most potent compounds 8k and 8L interacted with the important residues of BZD-binding site of GABAA receptor. Furthermore, neurotoxicity of the latter compounds was lower than positive control diazepam. CONCLUSION: According to these results, our designed scaffold can be a valuable lead structure for further structural developments and assessments to obtain a new potent anticonvulsant agent.

L-Carnitine Prevents Behavioural Alterations in Ketamine-Induced Schizophrenia in Mice: Possible Involvement of Oxidative Stress and Inflammation Pathways.

Schizophrenia is a chronic mental complaint known as cognitive impairment. There has been evidence that inflammation and oxidative stress play a main role in schizophrenia pathophysiology. This study aimed to investigate the effects of l-carnitine, as a potent antioxidant, on the treatment of behavioural and biochemical disturbances in mice with ketamine-induced schizophrenia. In this study, schizophrenia was induced in mice by ketamine (25 mg/kg/day, i.p). Before induction of schizophrenia, mice were treated with l-carnitine (100, 200, and 400 mg/kg/day, i.p). Then, behavioural impairments were evaluated by open field (OF) assessment and social interaction test (SIT). After brain tissue isolation, reactive oxygen species (ROS), glutathione concentration (GSH), lipid peroxidation (LPO), protein carbonyl oxidation, superoxide dismutase activity (SOD), and glutathione peroxidase activity (GPx) were assessed as oxidative stress markers. Furthermore, inflammatory biomarkers such as tumour necrosis factor alpha (TNF-α) and nitric oxide (NO) were evaluated in brain tissue. Our results showed ketamine increased inflammation and oxidative damage in brain tissue that was similar to behaviour disorders in mice. Interestingly, l-carnitine significantly decreased oxidative stress and inflammatory markers compared with ketamine-treated mice. In addition, l-carnitine prevented and reversed ketamine-induced alterations in the activities of SOD and GPx enzymes in mice's brains. Also, improved performance in OFT (locomotor activity test) and SIT was observed in l-carnitine-treated mice. These data provided evidence that, due to the antioxidant and anti-inflammatory effects of l-carnitine, it has a neuroprotective effect on mice model of schizophrenia.

Novel spiro[indene-1,2'-quinazolin]-4'(3'H)-one derivatives as potent anticonvulsant agents: One-pot synthesis, in vivo biological evaluation, and molecular docking studies.

A new series of spiro[indene-1,2'-quinazolin]-4'(3'H)-one derivatives 4a-m were synthesized via a one-pot method and evaluated for anticonvulsant activities using pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. Obtained results demonstrated that these compounds have not anticonvulsant activity in PTZ test while are active in the MES test. Among the synthesized compounds, the best anticonvulsant activity was obtained with compound 4h. This compound also was not neurotoxic. Given that the title new compounds have the pharmacophore requirement for benzodiazepine (BZD) receptor agonist, the most potent compound was assayed in vivo and in silico as BZD receptor agonist. After treatment with flumazenil as a standard BZD receptor antagonist, anticonvulsant activity of compound 4h decreased. Therefore, the involvement of BZD receptors in anticonvulsant activity of this compound confirmed. Furthermore, docking study of compound 4h in the BZD-binding site of GABAA receptor confirmed that this compound interacted with the important residues.

Zinc and selenium supplement mitigated valproic acid-induced testis toxicity by modulating the oxidative redox balance in male rats.

Valproic acid (VPA) is widely used antiepileptic agent which is associated with reproductive toxicity via impairment in oxidative redox. Zinc (Zn) and selenium (Se) are trace element with antioxidant effect that known to be essential for spermatogenesis. In the current study, the protective effect of co-administration of Zn and Se on VPA-induced reproductive toxicity in male rats was evaluated. Forty-eight male rats were divided into 8 groups of six (n=6): Control group (treated with normal saline); VPA only (250, 500, 1,000 mg/kg) group; VPA (500 mg/kg) plus Zn (2 mg/kg) group; VPA (500 mg/kg) plus Se (1.5 mg/kg) group; VPA (500 mg/kg) plus a combination of Zn and Se group; and VPA+vitamin E (20 mg/kg) group. The Animals were sacrificed after 28 days of treatment and sperm analysis was taken. Also, evaluation of oxidative stress markers including malondialdehyde (MDA), protein carbonyl (PC), glutathione (GSH) and histopathological changes were done on testis tissue. Morphological changes and a significant decrease in motility and sperm count in rats treated with VPA were observed. Also, an increase in oxidative stress marker, including MDA and PC and a decrease in GSH level was evident in VPA group. Zn and Se administration was able to protect against sperm abnormality, ameliorate the histological change in testis tissue, and suppressed the increase in oxidative stress markers induced by VPA. These results indicated that combination therapy with Zn and Se showed better an ameliorative effect than each one alone. Therefore, it can be suggested as an effective supplement for reproductive impairment in VPA-treated patient.

Taurine attenuates valproic acid-induced hepatotoxicity via modulation of RIPK1/RIPK3/MLKL-mediated necroptosis signaling in mice.

Valproic acid (VPA) is known as a common drug in seizure and bipolar disorders treatment. Hepatotoxicity is the most important complication of VPA. Taurine (Tau), an amino acid, has antioxidant effects. The present research was conducted to evaluate the protective mechanisms of Tau on VPA-induced liver injury, especially focusing on the necroptosis signaling pathway. The sixty-four male NMRI mice were divided into eight groups with eight animals per each. The experiment groups pretreated with Tau (250, 500, 1000 mg/kg) and necrostatine-1 (Nec-1, 1.8 mg/kg) and then VPA (500 mg/kg) was administered for 14 consecutive days. The extent of VPA-induced hepatotoxicity was confirmed by elevated ALP (alkaline phosphatase), AST (aspartate aminotransferase), ALT (alanine aminotransferase) levels, and histological changes as steatosis, accumulation of erythrocytes, and inflammation. Additionally, VPA significantly induced oxidative stress in the hepatic tissue by increasing ROS (reactive oxygen species) production and lipid peroxidation level along with decreasing GSH (glutathione). Hepatic TNF-α (tumor necrosis factor) level, mRNA and protein expression of RIPK1 (receptor-interacting protein kinase 1), RIPK3, and MLKL (mixed lineage kinase domain-like pseudokinase) were upregulated. Also, the phosphorylation of MLKL and RIPK3 increased in the VPA group. Tau could effectively reverse these events. Our data suggest which necroptosis has a key role in the toxicity of VPA through TNF-α-mediated RIPK1/RIPK3/MLKL signaling and oxidative stress. Our findings suggest that Tau protects the liver tissue against VPA toxicity via inhibiting necroptosis signaling pathway mediated by RIPK1/RIPK3/MLKL and suppressing oxidative stress, and apoptosis.

Synthesis, in silico, in vitro and in vivo evaluations of isatin aroylhydrazones as highly potent anticonvulsant agents.

In this study, a series of new isatin aroylhydrazones (5a-e and 6a-e) was synthesized and evaluated for their anticonvulsant activities. The (Z)-configuration of compounds was confirmed by 1H NMR. In vivo studies using maximal electroshock (MES) and pentylenetetrazole (PTZ) models of epilepsy in mice revealed that while most of compounds had no effect on chemically-induced seizures at the higher dose of 100 mg/kg but showed significant protection against electrically-induced seizures at the lower dose of 5 mg/kg. Certainly, N-methyl analogs 6a and 6e were found to be the most effective compounds, displaying 100% protection at the dose of 5 mg/kg. Protein binding and lipophilicity(logP) of the selected compounds (6a and 6e) were also determined experimentally. In silico evaluations of title compounds showed acceptable ADME parameters, and drug-likeness properties. Distance mapping and docking of the selected compounds with different targets proposed the possible action of them on VGSCs and GABAA receptors. The cytotoxicity evaluation of 6a and 6e against SH-SY5Y and Hep-G2 cell lines indicated safety profile of compounds on the neuronal and hepatic cells.

Synergistic enhancing-memory effect of D-serine and RU360, a mitochondrial calcium uniporter blocker in rat model of Alzheimer's disease.

BACKGROUND: Although Amyloid beta (Aß) and N - methyl d- aspartate receptors (NMDARs are involved in Ca2+ neurotoxicity, the function of mitochondrial calcium uniporter in cognition deficit remain uncertain. Here, we examined the effect of mitochondrial calcium uniporter (MCU) blocker, together with NMDA receptor agonist d-cycloserine (DCS) on memory impairment in a rat model of AD. METHODS: Forty adult male Wistar rats underwent stereotaxic cannulation for inducing AD by intracerebroventricular (ICV) injection of Aß1-42 (5 µg /8 µl/rat). Then animals were divided into 5 groups of: Saline + Saline, Aß + Saline, Aß + RU360, Aß + DCS, Aß + RU360 + DCS. Two weeks after the treatments, Morris Water Maze (MWM) and step through passive avoidance learning (SPL) were undertaken for evaluating of spatial and associative memories, respectively. Hippocampal level of cyclic-AMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were measured by western blot and ELISA. RESULTS: Co - administration of RU360 and DCS significantly improved both acquisition and retrieval of spatial memory as evident by decreased escape latency and increased time spent in the target quadrant (TTS) in MWM, together with increase in step-through latency, but reduced time spent in the dark compartment in SPL. Furthermore, there was a significant rise in the hippocampal level of CREB and BDNF in comparison with Aß + Saline. CONCLUSION: The present study supports the idea that co- administration of RU360 and DCS ameliorate memory impairment induced by Aß 1-42 probably via CREB / BDNF signaling.

Caffeine attenuates seizure and brain mitochondrial disruption induced by Tramadol: the role of adenosinergic pathway.

Tramadol (TR) is an analgesic drug used to treat moderate-to-severe pain but it induces seizure even at therapeutic doses. The exact mechanism of TR-inducing seizure is not clear but inhibition of the serotonin, GABA, and nitrous oxide (NOS) pathways are the commonly proposed mechanisms. Adenosinergic system has a crucial function in the modulation of seizure. Also, oxidative damage is an unavoidable effect of the seizure. This study was conducted to evaluate the role of the adenosinergic system on the seizure and oxidative stress biomarkers induced by TR using antagonist of the adenosinergic receptors in the Albino mice. For that purpose, generated clonic seizure, as seizure threshold, was evaluated by TR. Caffeine (CAF; 8 mg/kg, i.p.), a nonselective antagonist of adenosine receptors, was administered 1 hour before the seizure induction. The seizure threshold significantly increased by CAF-treated group when compared to TR group (p < 0.001). Oxidative stress biomarkers such as reactive oxygen species, protein carbonyl content, and lipid peroxidation significantly decreased and glutathione content significantly increased by CAF in brain mitochondria compared to the TR group, whereas oxidative biomarkers significantly increased in the TR group compared to the control group. The results of the present study suggested that the adenosinergic system is involved in seizure induced by TR and meanwhile, inhibition of adenosine receptors can decrease the TR seizure threshold and also decrease the induced oxidative damage in the brain mitochondria.

Ginkgo biloba attenuated hepatotoxicity induced by combined exposure to cadmium and fluoride via modulating the redox imbalance, Bax/Bcl-2 and NF-kB signaling pathways in male rats.

Aim of this study was to investigate the efficacy of Ginkgo Biloba (G.B) hydro-ethanolic extract against hepatotoxicity induced by combined exposure to cadmium (Cd) and fluoride (F) in Wistar rats. Animals were exposed to F (30 mg/L) + Cd (40 mg/L), F + Cd plus G.B (50,100 and 200 mg/kg), G.B (200 mg/kg), F + Cd plus Vit C(1000 mg/L) in drinking water for 42 days. Significant raise in liver enzymes and histopathological changes were observed in F + Cd treated rats. F + Cd exposure enhanced protein and glutathione oxidation, lipid peroxidation and decreased superoxide dismutase activity. F and Cd combination also caused mitochondrial dysfunction, swelling and mitochondrial membrane potential collapse in liver isolated mitochondria. Up-regulation of inflammatory genes (TNF-α, IL-1ß and NF-kB) and pro-apoptotic Bax as well as down-regulation of anti-apoptotic Bcl-2 were detected after co-exposure to F and Cd. Interestingly, G.B alleviated F + Cd induced liver oxidative stress, mitochondrial damage and prevented inflammation and apoptosis. Furthermore, decrease in serum liver enzymes and improvement of histopathologic lesions were observed in G.B treated rats. This study explored the potential beneficial role of G.B on F + Cd combined hepatotoxic effects via considering its possible antioxidant, anti-inflammatory, mitochondrial protection and anti-apoptotic effects.

Ameliorative Effect of Melatonin Against Reproductive Toxicity of Tramadol in Rats via the Regulation of Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis-related Gene Expression Signaling Pathway.

BACKGROUND: The aim of the present study was to investigate the protective properties of melatonin (MT) against oxidative stress, mitochondrial dysfunction, and apoptosis induced by tramadol-reproductive toxicity in male rats. METHODS: The rats were divided into the 7 groups of control, melatonin (1.5 mg/kg), tramadol (50 mg/kg), and melatonin (1, 1.5 and 2.5 mg/kg) administered 30 minutes before tramadol and vitamin C group (100 mg/kg). All injections were performed intraperitoneally. After administration for 3 consecutive weeks, the animals were killed and testis tissues were used for assessment of oxidative stress markers including lipid peroxidation (LPO), glutathione (GSH) content and protein carbonyl (PrC), and sperm analysis. Mitochondria were isolated from rat's testis using differential centrifugation technique and were studied in terms of mitochondrial viability, mitochondrial membrane potential (MMP), and mitochondrial swelling. The other part of the tissue sample was placed in RNA protector solution for assessment of Bax and Bcl-2 gene expression through real-time polymerase chain reaction (real-time PCR) assay. FINDINGS: Tramadol caused a significant decline in epidermal sperm count, motility, and morphology, as well as a significant decrease in GSH level and mitochondrial function, and a significant evaluation of LPO, PrC, MMP, and mitochondrial swelling. In addition, tramadol induced a significant decrease in Bcl-2 gene expression, and increase in Bax gene expression. However, pretreatment of rats with MT improved sperm analysis, and testicular antioxidative status, and mitochondrial function. Furthermore, MT pretreatment regulated testicular Bcl-2 and Bax expressions. CONCLUSION: Considering the protective effects of MT against reproductive toxicity induced by tramadol, this compound can be used as a possible agent for the prevention and treatment of tramadol-induced reproductive toxicity.

Co-exposure to non-toxic levels of cadmium and fluoride induces hepatotoxicity in rats via triggering mitochondrial oxidative damage, apoptosis, and NF-kB pathways.

Fluoride (F) and cadmium (Cd) are two common water pollutants. There is low information about their co-exposure in low doses. So, in this study, we evaluated the combination effects of non-toxic doses of F and Cd and the possible mechanism of their combined interaction. Male rats were exposed to non-toxic doses of sodium fluoride (30 mg/l) and/or cadmium chloride (40 mg/l) in drinking water for 6 weeks. Then, liver tissues were separated and several factors including oxidative stress, mitochondrial toxicity, inflammation, apoptosis, and biochemical and histopathological changes were evaluated. Cd and F alone did not induce any significant changes in evaluated factors compared to control group, while significant elevation in liver enzymes as well as histopathological changes were observed in rats treated with F+Cd. Also, a remarkable increase in oxidative stress markers including reactive oxygen species, lipid peroxidation, and protein carbonyl and also decreasing glutathione and superoxide dismutase levels were detected following co-exposure to F and Cd. Furthermore, a combination of F and Cd resulted in mitochondrial dysfunction, swelling, as well as a reduction in mitochondrial membrane potential in isolated liver mitochondria. On the other hand, TNF-α, IL-1ß, and NF-kB inflammatory genes were upregulated in the liver after combined exposure to F and Cd compared to individual treatments. Also, F+Cd treatment increased the Bax expression but decreased the expression of Bcl-2 significantly. These findings suggest that Cd and F can potentiate their individual toxic effects on the liver tissue through disruption of the cellular redox status, inflammation, and apoptosis pathway.

Polymorphisms in Phase I (CYP450) Genes CYP1A1 (rs4646421), CYP1B1 (rs1056836), CYP19A1 (rs749292) and CYP2C8 (rs1058930) and Their Relation to Risk of Breast Cancer: A Case-Control Study in Mazandaran Province in North of Iran.

BACKGROUND: The second leading cause of cancer-related death in women is breast cancer. Xenobiotic Metabolizing Enzymes (XMEs) contribute to the detoxification of numerous cancer therapy-induced products. In the metabolism of xenobiotic, cytochrome P450s or monooxygenases perform an important function by catalysing the hydroxylation reaction. In this study, the susceptibility and genetic polymorphisms of CYP450 isoenzymes was investigated that may have an etiological role in breast cancer. AIM: The main purpose of this study was to evaluate the association of CYP1A1 (rs4646421), CYP1B1 (rs1056836), CYP2C8 (rs1058930), and CYP19A1 (rs749292) polymorphisms with the risk of breast cancer in Mazandaran province. MATERIAL AND METHODS: This cross-sectional case-control study were recruited 72 patients and 51 healthy individuals and was performed between March 2018 to May 2018 in the Oncology Department at Imam Hospital in Sari city, Iran. Peripheral blood samples were collected in EDTA tube, and DNA extraction was performed using the salting-out method and WizPrep extraction kits. Breast cancer patients with known clinicopathological characters and healthy women as control group were genotyped for genes polymorphisms by PCR-RFLP technique, using restriction enzymes. Chi-square, Fisher exact test and Logistic regression model, were applied for statistical analysis. RESULTS: The results of the experiments showed that there was a significant relationship between two groups and the age of the patients is significantly higher than the control group (p = 0.044). According to the chi-square and Fisher exact test, education, pregnancy, menopause status and oppose were significant between the two groups. Based on using a logistic regression model in two normalized and age-adjusted models to finding relationship between the genotypes of each gene and breast cancer risk, it was determined that in the CYP2C8 genotype, those who have the CG allele have a 7.74 degree increased risk of breast cancer (CI = 95% 0.95-62.5) and in the CYP19A1 gene, individuals with GA genotype, increased risk of breast cancer (CI = %95 1.52-27.21), about the CYP1B1 gene, people with two genotypes of CG + GG had higher risk of breast cancer (CI = %95 1.19-5.71) and allele G has decreased risk of breast cancer in this gene (P = 0.0271), also allele G in CYP2C8 gene had the protective effect (P = 0.02). In the age-adjusted model, for the CYP2C8 gene, GG genotype increased risk of breast cancer (CI = %95 1.11-75.84) as well as, the CG + GG genotype in CYP1B1 gene (CI = %95 1.31-6.57). CONCLUSION: Our results confirm the association between CYP2C8 (rs1058930), CYP19A1 (rs749292) and CYP1B1 (rs1056836) gene polymorphisms and increased risk of breast cancer in women in Mazandaran province.

Design, synthesis, in vivo, and in silico evaluation of new coumarin-1,2,4-oxadiazole hybrids as anticonvulsant agents.

A novel series of coumarin-1,2,4-oxadiazole hybrids were designed, synthesized, and evaluated as anticonvulsant agents. The title compounds were easily synthesized from reaction of appropriate coumarins and 3-aryl-5-(chloromethyl)-1,2,4-oxadiazole derivatives. In vivo anticonvulsant activity of the synthesized compounds were determined using pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures confirming that they were more effective against MES test than PTZ test. It should be noted that compounds 3b, 3c, and 3e showed the best activity in MES model which possessed drug-like properties with no neurotoxicity. Anticonvulsant activity of the most potent compound 3b was remarkably reduced after treatment with flumazenil which confirmed the participation of a benzodiazepine mechanism in the anticonvulsant activity. Also, docking study of compound 3b in the BZD-binding site of GABAA receptor confirmed possible binding of 3b to the BZD receptors.

Evidence for the Involvement of the Dopaminergic System in Seizure and Oxidative Damage Induced by Tramadol.

Tramadol (TR) is a synthetic analgesic drug with central function that can induce seizures even at therapeutic doses. The exact mechanism of TR effect on seizure generation is not clear, but inhibition of the serotonin and nitric oxide pathways and inhibitory effects on GABA receptors are the most common hypotheses about the seizure-inducing mechanism of the TR. This study aimed to evaluate the role of dopaminergic system on the seizure and oxidative damage induced by TR using agonist and antagonist drugs of this system in the Albino mice. Clonic seizure induced by TR was evaluated as seizure threshold. Haloperidol (0.2 mg/kg, IP), a predominantly D2 receptor antagonist, and cabergolin (0.5 mg/kg, IP), a dopamine agonist specific for the D2 receptors, were injected 60 minutes before the seizure induction. The seizure threshold was significantly increased by dopaminergic antagonist, but it was decreased significantly by pretreatment with the selective agonist. Oxidative stress biomarkers (reactive oxygen species, lipid peroxidation, and protein carbonyl content) significantly increased and glutathione content significantly decreased in brain mitochondria by TR compared with the control group, whereas oxidative markers were decreased significantly after pretreatment with haloperidol compared with the TR group. This study revealed that the dopaminergic system is involved in TR-induced seizure, and meanwhile, inhibition of dopamine D2 receptors can increase the TR threshold seizure and decrease the oxidative damage in the brain mitochondria. Conversely, stimulation of dopamine D2 receptors by cabergolin can decrease the TR threshold seizure and glutathione content in the brain mitochondria.

Design, synthesis, in vivo and in silico evaluation of phenacyl triazole hydrazones as new anticonvulsant agents.

A series of phenacyl triazole hydrazones 3 have been designed based on the hybridization of (arylalkly)triazole and aroyl hydrazone scaffolds as new anticonvulsant agents. The target compounds 3 were easily synthesized from appropriate phenacyl triazoles and aryl acid hydrazides and characterized by IR, NMR and Mass spectroscopy. The in vivo anticonvulsant evaluation of synthesized compounds by using MES and PTZ tests revealed that they are more effective in MES model respect to PTZ test. All compounds showed 33-100% protection against MES-induced seizures at the dose of 100 mg/kg. However, the isonicotinic acid hydrazide derivative 3h showed the best profile of activity in both models. Molecular docking studies of compound 3h with different targets (NMDA, AMPA, GABAA and sodium channel), postulated that the compound acts mainly via GABAA receptors. In silico molecular properties predictions indicated that all compounds have favourable oral bioavailability and BBB permeability.

Zinc Deficiency and Oxidative Stress Involved in Valproic Acid Induced Hepatotoxicity: Protection by Zinc and Selenium Supplementation.

Valproic acid (VPA) is an antiepileptic drug, which its usage is limited due to its hepatotoxicity. The present study was conducted to investigate the efficacy of zinc (Zn) and selenium (Se), necessary trace elements, against VPA-induced hepatotoxicity in Wistar rats. The animals were divided into five groups: control, VPA 200 mg/kg, VPA + Zn (100 mg/kg), VPA + Se (100 mg/kg), and VPA + Zn + Se. The administration of VPA for four consecutive weeks resulted in decrease in serum level of Zn in rats. Also, an increase in liver marker enzymes (ALT and AST) and also histological changes in liver tissue were shown after VPA administration. Oxidative stress was evident in VPA group by increased lipid peroxidation (LPO), protein carbonyl (PCO), glutathione (GSH) oxidation, and reducing total antioxidant capacity. Zn and Se (100 mg/kg) administration was able to protect against deterioration in liver enzyme, abrogated the histological change in liver tissue, and suppressed the increase in oxidative stress markers. Zn and combination of Zn plus Se treatment showed more protective effects than Se alone. These results imply that Zn and Se should be suggested as effective supplement products for the prevention of VPA-induced hepatotoxicity.

Different Genotype of rs3130932 Single Nucleotide Polymorphism Between Gastric Cancer Patients and Normal Subjects.

PURPOSE: Octamer binding transcription factor B gene (OCT4) is responsible for development and self-renewal maintenance of embryonic stem cells. The rs3130932 single nucleotide polymorphism (SNP) may play a role in tumor genesis. Because of high prevalence of gastric cancer in north of Iran, this study was investigated role of rs3130932 polymorphism and stomach cancer. METHODS: Blood samples were collected from 100 informed gastric cancer patients and 100 age and sex-matched healthy individuals, and were genotyped for the presence of rs3130932G allele by ssp PCR. RESULTS: The mean age of participant (n = 200) was 67.83 ± 10.878 years. In genotyping and allelic analysis, TG genotype increased 66.147 times more likely to develop stomach cancer than the TT genotype, and disease risk increases 140.496 times more in GG genotype in comparison with TT genotype. CONCLUSION: This study clearly emphasis on different genetic profile in this population and show that the rs3130932G allele and odds of gastric cancer are related to each other in northern of Iran.

Melatonin can attenuate ciprofloxacin induced nephrotoxicity: Involvement of nitric oxide and TNF-α.

BACKGROUND: Ciprofloxacin is a synthetic broad-spectrum antimicrobial agent of fluoroquinolone family. The aim of our investigation was to evaluate the role of oxidative damage and inflammation in nephrotoxic potential of Ciprofloxacin and protective effects of melatonin against its nephrotoxicity in male Wistar rats. METHODS: The animals were divided into six groups: Control, ciprofloxacin (100mg/kg/day, i.p), ciprofloxacin with three doses (2.5, 5 and 10mg/kg/day) of melatonin and a group which received ciprofloxacin (100mg/kg/day) plus vitamin E (100mg/kg/day) for 8 consecutive days. 24h after last injection, the animals were euthanized and kidney tissues were separated. Finally reactive oxygen species, glutathione content, lipid peroxidation, protein carbonyl, nitric oxide and TNF-α were evaluated. Also, pathological examination and measuring of kidney biochemical markers (BUN and Cr) were done. RESULTS: The administration of ciprofloxacin for 8days resulted in significant increase (P<0.01) in kidney biomarkers (BUN and Cr) and pathological changes. Also, Oxidative stress was evident in ciprofloxacin group by significantly (p<0.001) increased reactive oxygen species, lipid peroxidation and protein carbonyl level and decreased glutathione content (p<0.001). Increased in inflammation process was shown by increase in NO and TNF-α (P<0.001). Administration of melatonin was able to protect against deterioration in nephrotoxic markers and suppressed the increase in oxidative stress and inflammatory markers. CONCLUSION: Our study showed the critical role of oxidative damage and inflammation in ciprofloxacin-induced nephrotoxicity that markedly inhibited by administration of melatonin. So, melatonin can be suggested for prevention of ciprofloxacin-induced nephrotoxicity.

Hypothermic activity of acetaminophen; involvement of GABAA receptor, theoretical and experimental studies.

OBJECTIVES: The mechanism of hypothermia action of acetaminophen (APAP) remains unclear even 125 years after its synthesis. Acetaminophen produces hypothermia. The mechanism of this reduction in core body temperature is not clear but evidence shows that it is not dependent on opioid and cannabinoid receptors. Because of strong documents about the roles of GABA and benzodiazepine receptors in hypothemic activity of some drugs such as diazepam, we determined if these receptors also contributes to the hypothermic effect of APAP. MATERIALS AND METHODS: Diazepam (5 mg/kg, IP) was used for induction of hypothermia. Flumazenil (10 mg/kg, IP) or picrotoxin (2 mg/kg, IP) used for reversal of this effect. Rats injected with APAP (100, 200 or 300 mg/kg, IP). Baseline temperature measurements were taken with a digital thermometer via rectum. To evaluate the structural correlation between APAP and benzodiazepine receptor ligands, numerous models are selected and studied at HF/6-31G* level of theory. Relative energies, enthalpies and Gibbs free energies were calculated for all selected drugs. RESULTS: Diazepam induced hypothermia was reversed by flumazenil or picrotoxin. Rats injected with APAP displayed dose- and time-related hypothermia. For combined administration, the hypothermic effect of APAP (200 mg/kg) was strongly reduced by pretreatment with picrotoxin or flumazenil P<0.0001and P<0.01, respectively. Selective structural data, bond length, dihedral angles, and related distance in pharmacophore of APAP and BZDR models were the same. Some significant structural analogues were obtained between these drugs. CONCLUSION: Results suggest hypothermic action of acetaminophen may be mediate by its effect at GABAA benzodiazepine receptor.

How aminoglycosides are used in critically ill patients in a teaching hospital in North of Iran.

BACKGROUND: Resistance to antimicrobial agents including aminoglycosides (AGs) is a great concern that is mainly related to inappropriate use. Since there were not adequate data regarding how rationally AGs are being prescribed in our critically ill patients, this study was conducted to determine the main issues in the area of appropriate use of this antibiotic class. METHODS: One hundred patients who were in the intensive care units (ICUs) of Imam Khomeini Teaching Hospital from February 2012 to August 2012 were included. A data gathering form was prepared based upon the recommendations provided by Up-to-date (20.1) 2012 and Medscape 2013. All demographic characteristics and other information about time of beginning and duration of dosage, interval of administration of AGs and creatinine (Cr) level were collected. In statistical analysis, SPSS Version 16 software was used. Independent samples t-test was used to compare the quantitative and chi-square for qualitative variables. RESULTS: Sixty six (66%) of patients received gentamicin and 38% received amikacin. In 27% of patients, serum creatinine (Cr) had been checked before and after AGs administration and 4 patients had no renal function monitoring. Monitoring of serum concentration and Cr clearance estimation was not carried out for any patients. Culture and laboratory sensitivity tests were done on 17 patients and E-coli (57%) was the most common isolated organism. CONCLUSION: The results of this study revealed that majority of the hospitalized patients in the ICU and the dosage of AGs had not been adjusted to renal function.