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Abuse of alcohol triggers neurodegeneration in human brain. Minocycline has characteristics conferring neuroprotection. Current study evaluates the role of the CREB-BDNF signaling pathway in mediating minocycline's neuroprotective effects against alcohol-induced neurodegeneration. Seventy adult male rats were randomly split into groups 1 and 2 that received saline and alcohol (2 g/kg/day by gavage, once daily), respectively, and groups 3, 4, 5, and 6 were treated simultaneously with alcohol and minocycline (10, 20, 30 and 40 mg/kg I.P, respectively) for 21 days. Group 7 received minocycline alone (40 mg/kg, i.p) for 21 days. Morris water maze (MWM) has been used to assess cognitive activity. Hippocampal neurodegenerative and histological parameters as well as cyclic AMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) levels were assessed. Alcohol impaired cognition, and concurrent therapy with various minocycline doses attenuated alcohol-induced cognition disturbances. Additionally, alcohol administration boosted lipid peroxidation and levels of glutathione in oxidized form (GSSG), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and Bax protein, while decreased reducing type of glutathione (GSH), Bcl-2 protein, phosphorylated CREB, and BDNF levels in rat hippocampus. Alcohol also decreased the activity in the hippocampus of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR). In comparison, minocycline attenuated alcohol-induced neurodegeneration; elevating expression levels of P-CREB and BDNF and inhibited alcohol induced histopathological changes in both dentate gyrus (DG) and CA1 of hippocampus. Thus, minocycline is likely to provide neuroprotection against alcohol-induced neurodegeneration through mediation of the P-CREB/BDNF signaling pathway.

Proton pump inhibitors (PPIs) are one of the highly prescribed or over-the-counter available medications among Iranians, mainly to treat conditions such as helicobacter pylori infection, gastroesophageal reflux disease or frequent heartburn. In recent years, several reports have shown potential adverse effects of PPI administration among which cardiovascular adverse events, myocardial infarction and chronic kidney disease are considered as the greatest risks. Recent addition of proton pump inhibitors to the list of medications on Beers Criteria of Potentially Inappropriate Drugs has arisen significant concerns about their safety. This review aims at providing an up-to date overview of PPIs indications and their pharmacogenomics and pharmacokinetics in Iranian population. The focus of this review is on PPIs regimens in Iranian population and then it is compared with the reported studies performed on other ethnic groups around the world. An extensive review of the literature was carried out and data under various sections were identified using a computerized literature search via Pubmed, Web of Science, Google Scholar and some local search engines. All abstracts and full text articles were examined and most relevant papers were selected for inclusion in this review. Also several expert internalists were interviewed for their clinical experiences in this field.

Methylphenidate (MPH) abuse causes adverse neurobehavioral and neurochemical effects. Some herbal components such as crocin have shown neuroprotective properties. The current study evaluates the potential role of the cyclic AMP response element binding protein (CREB)‑brain‑derived neurotrophic factor (BDNF) signaling pathway in mediating the neuroprotective effects of crocin against MPH‑induced neurotoxicity in rats. Seventy adult male rats were randomly divided into seven groups. Group 1 and 2 received 0.7 ml/rat of normal saline and 10 mg/kg of MPH, respectively. Groups 3, 4, 5, and 6 were treated simultaneously with MPH (10 mg/kg) and crocin (10, 20, 40, and 80 mg/kg, respectively) for 21 days. Group 7 was treated with crocin (80 mg/kg) alone for 21 days. The Morris water maze (MWM) and open field test were used to assess cognitive and locomotor activities. Hippocampal neurotoxicity parameters and levels of BDNF and CREB were evaluated. Simultaneous treatment with various doses of crocin reduced the MPH‑induced cognition disturbances and hyperlocomotion. In addition, lipid peroxidation increased with MPH treatment and levels of the oxidized forms of glutathione (GSSG), interleukin 1 beta (IL‑1β), tumor necrosis factor alpha (TNF‑α), and Bax increased. MPH treatment decreased levels of the reduced form of glutathione (GSH), P‑CREB, Bcl‑2, and BDNF in the hippocampus. MPH also reduced activity of superoxide dismutase, glutathione peroxidase, and glutathione reductase in the hippocampus. In contrast, crocin attenuated MPH‑induced oxidative stress, inflammation, and apoptosis, and increased levels of P‑CREB and BDNF. Thus, crocin - likely via stimulation of the P‑CREB/BDNF signaling pathway - displayed neuroprotection against MPH‑induced neurotoxicity.

Background Methamphetamine is a neuro-stimulant with neurodegenerative effects, and ambiguous mechanism of action. Metformin is an antidiabetic agent with neuroprotective properties but not fully understood mechanisms. The present study investigated the molecular basis of metformin neuroprotection against methamphetamine-induced neurodegeneration. Brief method Sixty adult male rats were randomly divided into six groups: group 1 (received normal saline), group 2 (received 10 mg/kg of methamphetamine) and groups 3, 4, 5 and 6 [received methamphetamine (10 mg/kg) plus metformin (50, 75, 100 and 150 mg/kg) respectively]. Elevated Plus Maze (EPM), Open Field Test (OFT), Forced Swim Test (FST), Tail Suspension Test (TST) and Morris Water Maze (MWM) were used to assess the level of anxiety, depression and cognition in experimental animals. Also animals’ hippocampus were isolated and oxidative stress and inflammatory parameters and expression of total and phosphorylated forms of cAMP response element binding (CREB), brain-derived neurotrophic factor (BDNF), protein kinase B (Akt) and glycogen synthase kinase 3 (GSK3) proteins were evaluated by ELISA method. Results According to the data obtained, methamphetamine caused significant depression, anxiety, motor activity disturbances and cognition impairment in experimental animals. Metformin, in all used doses, decreased methamphetamine induced behavioral disturbances. Also chronic administration of methamphetamine could increase malondialdehyde (MDA), tumor necrosis factor-Alpha (TNF-α) and interleukine-1 beta (IL-1β) in rats, while caused reduction of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities. Metformin, especially in high doses, could prevent these malicious effects of methamphetamine. Also Metformin could activate CREB (both forms), BDNF and Akt (both forms) proteins’ expression and inhibited GSK3 (both forms) protein expression in methamphetamine treated rats. Significance According to obtained data, metformin could protect the brain against methamphetamine-induced neurodegeneration probably by mediation of CREB/BDNF or Akt/GSK3 signaling pathways. These data suggested that CREB/BDNF or Akt/GSK3 signaling pathways may have a critical role in methamphetamine induced neurotoxicity and/or neuroprotective effects of metformin.

Objectives Given the cardiac pathological remodeling following to anabolic androgenic steroids (AASs) consumption, we examined the effect of chronic administration of nandrolone decanoate with high-intensity endurance exercise on the left ventricular hypertrophy index, levels of hydroxyproline, tumor necrosis factor-alpha (TNF-α), adiponectin (APN) and its receptors (AdipoR1 and AdipoR2) expression in rats’ hearts. Methods The male Wistar rats randomly divided to six groups included the control (CTL), exercise (Ex), nandrolone (Nan), vehicle (Arach), trained vehicle (Ex + Arach), and trained nandrolone (Ex + Nan) groups that were treated for eight weeks. Results Nandrolone consumption significantly enhanced the hypertrophy index (p Conclusions Despite an additive effect of high-intensity endurance exercise plus nandrolone on TNF-α level, their effects on hydroxyproline and APN receptors expression is incompatible in heart of rat. It is suggests a part of beneficial regulatory role of endurance exercise against nandrolone induced heart remodeling may apply through modulation of APN system.

The drastic decrease in estrogen levels in menopausal women can elevate bone resorption and osteoporosis. Cornus mas extract (C. mas extract) is a potential candidate for treating menopausal-related bone complications because of its phytoestrogen and anti-inflammatory contents. It was an interventional double-blind placebo-controlled randomized study. Eighty-four women aged 45-60 years old were randomly allocated to either the extract group receiving 3 capsules of 300 mg C. mas extract or the placebo group receiving 3 capsules of 300 mg of starch powder per day for 8 weeks. Then, venous blood was used to measure bone-specific alkaline phosphatase (BAP), osteocalcin (OC), C-terminal telopeptide (TC) as well as serum levels of PTH and hsCRP. Our results indicated the decrease in alkaline phosphatase, PTH, and as an inflammation biomarker, hsCRP, between two groups at the end of the study. No statistically significant difference was observed in telopeptide C, osteocalcin, and calcium between the placebo and extract groups after 8 weeks of intervention. In conclusion, the results indicate that the C. mas extract supplement of 900 mg/day may decrease levels of BAP, PTH, and hsCRP. However, this intervention had no beneficial effect on OC and TC in healthy postmenopausal women.

Propose/aim of study: Forced exercise can act as a neuroprotective factor and cognitive enhancer. The aim of the current study was to evaluate the effects of forced exercise on topiramate (TPM) induced cognitive impairment and also on TPM anti-seizure activity and neurodegeneration status after seizure.Material and method: Forty adult male rats were divided into four groups receiving normal saline, TPM (100 mg/kg), TPM in combination with forced exercise and forced exercise only respectively for 21 days. MWM test, and PTZ induced seizure were used and some oxidative, inflammatory and apoptotic biomarkers were measured for assessment of experimental animals.Results: Forced exercise in combination with TPM could abolish the TPM induced cognitive impairment and potentiates its anti-seizure activity. Also forced exercise in combination with TPM decreased malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) and Bax protein, while caused increase in superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities after PTZ administration.Conclusion: It seems that forced exercise could act as an adjunct therapy with TPM for management of induced cognitive impairment and can also potentiate TPM antiepileptic and neuroprotective effects.

Aim To evaluate the effects of Barberry (Berberis integerrima) on clinical signs and inflammatory factors in patients with Rheumatoid arthritis (RA). Method A total of 70 patients with active RA in a double-blind, placebo-controlled clinical trial (IRCT 201409249472N7) were randomly allocated to intervention and control groups. All the patients consumed 1500 mg of barberry extract and 1500 mg Hydroxypropyl methylcellulose (HPMC) each day respectively for three months. Clinical signs and serum levels of high-sensitivity C-reactive protein (hs-CRP), Tumor necrosis factor alpha (TNFα), and erythrocyte sedimentation rate (ESR) were measured before and after the intervention. Results The results showed that consumption of the extract of Berberis integerrima resulted in a significant decrease in Visual Analog Scale (VAS), morning stiffness, number of tender joints, Disease Activity Score 28 (DAS28), Global Physician Assessment (GPA), serum levels of ESR, TNFα (p Conclusion Barberry can improve clinical signs and inflammatory factors in RA patients and may be useful in their treatment approaches.

BACKGROUND AND PURPOSE Epilepsy is one of the most common serious neurological conditions. The current therapeutic treatment of epilepsy with modern antiepileptic drugs is associated with side effects, dose-related and chronic toxicity, and teratogenic effects and in approximately 30% of the patients is ineffective. Alpinia officinarum is used in Iranian traditional medicine for treatment of different diseases like back pain and seizure. METHODS In this study, anticonvulsant effects of hydroalcoholic extract of Alpinia officinarum rhizomes were examined by using pentylentetrazole (PTZ) model in mice. Alpinia officinarum rhizomes extract (200, 400 and 600 mg/kg), diazepam (1 mg/kg) and normal saline (10 mL/kg) were injected (ip) 30 minutes before PTZ (90 mg/kg, ip). The time taken before the onset of clonic convulsions, the duration of colonic convulsions, and the percentage of seizure and mortality protection were recorded. For further clarification of the mechanism of action for Alpinia officinarum, flumazenil (2 mg/kg, ip) and naloxone (5 mg/kg, ip) were also injected 5 minutes before Alpinia officinarum extract. RESULTS Alpinia officinarum extract at the doses of 200 and 400 mg/kg prolonged the time of onset of seizure and decreased the duration of seizures compared to control (saline) group (p < 0.05). At the dose of 600 mg/kg, percentage of seizure protection was 16.66%. Naloxone and flumazenil could suppress anticonvulsant effects of Alpinia officinarum. CONCLUSIONS It seems that Alpinia officinarum could be a good candidate and be useful for seizure control and treatment, and in these effects, opioid and benzodiazepine receptors might probably be involved.

Background: Duloxetine is used for treating depression and anxiety. The current study evaluated the effects of duloxetine against methamphetamine withdrawal-induced anxiety, depression, and motor disturbances and methamphetamine use-induced cognitive impairments. Materials and Methods: Ninety-six adult male rats were used for two independent experiments. Each experiment consisted of Groups 1 and 2 which received normal saline (0.2 ml/rat) and methamphetamine (10 mg/kg) respectively, Groups 3, 4, and 5 received both methamphetamine and duloxetine at doses of 5, 10, and 15 mg/kg, respectively. Groups 6, 7, and 8 received 5, 10, and 15 mg/kg of duloxetine, respectively. All administrations were performed for 21 days. In experiment 1, elevated plus maze (EPM), open-field test (OFT), forced swim test (FST), and tail suspension test (TST) were used to examine anxiety and depression in animals during withdrawal period. In experiment 2, Morris water maze (MWM) test was used to assess the effect of methamphetamine use followed by duloxetine treatment, on learning and memory. In the experiments, the expression of cyclic AMP response element binding (CREB) and brain-derived neurotrophic factor (BDNF) proteins were evaluated using enzyme-linked immunosorbent assay. Results: In the first experiment, duloxetine at all doses attenuated methamphetamine withdrawal induced-depression, anxiety, and motor disturbances in FST, OFT, EPM, and TST. In the second experiment, duloxetine at all doses attenuated methamphetamine use-induced cognitive impairment in MWM. In both experiments, duloxetine activated cAMP, CREB, and BDNF proteins' expression in methamphetamine-treated rats. Conclusions: Duloxetine can protect the brain against methamphetamine withdrawal-induced mood and motor disturbances and can also inhibit methamphetamine-induced cognitive impairment, possibly via cAMP/CREB/BDNF signaling pathway.

Neurodegeneration induced by methylphenidate (MPH), as a central stimulant with unknown long-term consequences, in adult rats’ brain and the possible mechanisms involved were studied. Rats were acutely treated with MPH in presence and absence of some receptor antagonists such as ketamine, topiramate, yohimibine and haloperidol. Motor activity and anxiety level in rats were monitored. Anti-oxidant and inflammatory parameters were also measured in isolated hippocampus and cerebral cortex. MPH treated groups (10 and 20 mg/kg) demonstrated anxiety-like behavior and increased motor activity. MPH significantly increased lipid peroxidation, GSSG content, IL-1β and TNF-α levels in isolated tissues, and also significantly reduced GSH content, superoxide dismutase, glutathione peroxidase and glutathione reductase activities in hippocampus and cerebral cortex. Pretreatment of animals by receptor antagonists caused inhibition of MPH-induced motor activity disturbances and anxiety-like behavior. Pretreatment of animals by ketamine, topiramate and yohimibine inhibited the MPH-induced oxidative stress and inflammation; it significantly decreased lipid peroxidation, GSSG level, IL-1β and TNF-α levels and increased GSH content, superoxide dismutase, glutathione peroxidase and glutathione reductase activities in hippocampus and cerebral cortex of acutely MPH treated rats. Pretreatment with haloperidole did not cause any change in MPH-induced oxidative stress and inflammation. In conclusion, acute administration of high doses of MPH can cause oxidative and inflammatory changes in brain cells and induce neurodegeneration in hippocampus and cerebral cortex of adult rats and these changes might probably be mediated by glutamate (NMDA or AMPA) and/or α2 adrenergic receptors. This article is protected by copyright. All rights reserved.

The risk of serious side-effects such as nephrotoxicity is the principal limitation of gentamicin (GEN) therapeutic efficacy. Oxidative stress is considered to be an important mediator of GEN-induced nephrotoxicity. The present study was designed to evaluate the efficacy of the combination of melatonin (MT) plus atorvastatin (ATO) against GEN-induced nephrotoxicity in rats. We utilized 30 male Wistar albino rats allocated in 5 groups, each containing 6 rats: control, GEN (100 mg/kg/day), ATO (10 mg/kg/day) + GEN, MT (20 mg/kg/day) + GEN, and ATO (10 mg/kg/day) plus MT (20 mg/kg/day) + GEN. Kidney weight, serum creatinine and urea concentration, renal ROS, MDA, GSH levels, SOD, and CAT activity were determined. GEN-induced nephrotoxicity was evidenced by marked elevations in serum urea and creatinine, kidney weight, renal ROS, and MDA levels and reduction in renal GSH level, SOD and CAT activity. MT pretreatment significantly lowered the elevated serum creatinine concentration, kidney weight, renal ROS and MDA levels. However ATO could not reduce these parameters, but similarly to MT, it was able to enhance the renal GSH level, CAT and SOD activity. In addition, a combination therapy of MT plus ATO enhanced the beneficial effects of ATO, while not changing the effects of MT effects or even improving them. The present study indicates that a combination therapy of MT plus ATO can attenuate renal injury in rats treated with GEN, possibly by reducing oxidative stress, and it seems that MT can enhance the beneficial effects of ATO.

Methylphenidate (MPH) abuse causes neurodegeneration. The neuroprotective effects of topiramate (TPM) have been reported but its putative mechanism remains unclear. The current study evaluates the role of various doses of TPM on protection of rat hippocampal cells from MPH-induced oxidative stress and inflammation in vivo. Seventy adult male rats were divided into six groups. Group 1 received normal saline (0.7 mL/rat) and group 2 was injected with MPH (10 mg/kg) for 21 days. Groups 3, 4, 5, 6 and 7 concurrently were treated by MPH (10 mg/kg) and TPM (10, 30, 50, 70 and 100 mg/kg, intraperitoneally (i.p.)), respectively for 21 days. After drug administration, the open field test (OFT) was used to investigate motor activity. Oxidative, antioxidant and inflammatory factors were measured in isolated hippocampus. Also, the brain-derived neurotrophic factor (BDNF) level was measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. Cresyl violet staining of Dentate Gyrus (DG) and CA1 cell layers of the hippocampus were also performed. MPH significantly disturbs motor activity in OFT and TPM (70 and 100 mg/kg) decreased this disturbance. Also MPH significantly increased lipid peroxidation, mitochondrial reduced state of glutathione (GSH) level, interleukin (IL)-1β and tumour necrosis factor (TNF)-α and BDNF level in isolated hippocampal cells. Also superoxide dismutase, glutathione peroxidase and glutathione reductase activity significantly decreased. Various doses of TPM attenuated these effects and significantly decreased MPH-induced oxidative damage, inflammation and hippocampal cell loss and increased BDNF level. This study suggests that TPM has the potential to be used as a neuroprotective agent against oxidative stress and neuroinflammation induced by frequent use of MPH.

The aim of this study was to evaluate the effects of orexin-A (OX-A) on behavioral and pathological parameters and on gene expression of some multiple sclerosis-related peptides in a model of experimental autoimmune encephalomyelitis (EAE). EAE was induced by subcutaneous administration of MOG 35-55. Following immunization, the treatment was initiated by using SB.334867 (orexin-1 receptor antagonist) and/or OX-A. Locomotor activity and exploratory behaviors were monitored using open field and T-maze continuous alternation task (T-CAT) respectively. Pain sensitivity was assessed by hot-plate test. Histopathological assessments were performed by H&E staining. The expression of TGF-β, MBP, MMP-9, IL-12, iNOS and MCP-1 were measured using real-time PCR method in lumbar spinal cord. OX-A administration in EAE mice remarkably attenuated the clinical symptoms, increased latency response in hot plate test, inhibited infiltration of inflammatory cells, up-regulated mRNA expression of TGF-β as well as MBP and down-regulated mRNA expression of iNOS, MMP-9 and IL-12. In contrast SB.334867 administration in EAE mice deteriorated the clinical symptoms, decreased the alternation in T-CAT, increased infiltration of inflammatory cells, down-regulated mRNA expression of TGF-β and MBP and up-regulated mRNA expression of iNOS. Results of this study suggest that the orexinergic system might be involved in pathological development of EAE. These findings suggest orexinergic system as a potential target for treatment of multiple sclerosis.

Aim Neurodegeneration is one of the serious adverse effects of stimulant agents such as nicotine. Minocycline possess established neuroprotective properties. The role of CREB-BDNF signaling pathway in mediating the neuroprotective effects of minocycline against nicotine-induced neurodegeneration in rats was evaluated in current study. Methods Seventy adult male rats were divided randomly into seven groups. Group 1 and 2, received 0.7 ml/rat of normal saline (i.p) and nicotine (10 mg/kg, s.c) respectively. Groups 3, 4, 5 and 6, treated concurrently with nicotine (10 mg/kg) and minocycline (10, 20, 30 and 40 mg/kg, i.p, respectively) for 21 days. Group 7 received minocycline alone (40 mg/kg, i.p) for 21 days. From 17th to 21 st days of experiment, Morris water maze (MWM) was used to evaluate learning and spatial memory in rats treated in different groups. According to the critical role of hippocampus in cognitive behavior, hippocampal neurodegenerative parameters (oxidative stress and inflammatory biomarkers) and also cyclic AMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) levels were evaluated in isolated hippocampus in day 22 of experiment and after drug treatment. Also hippocampal cell density and tissue changes were evaluated by hematoxylin and eosin staining. Result Nicotine administration impaired the learning and spatial memory in rats and simultaneous treatment with various doses of minocycline attenuated the nicotine-induced cognition disturbances. In addition, nicotine treatment increased lipid peroxidation and the levels of oxidized form of glutathione (GSSG), interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and Bax protein, while decreasing reduced form of glutathione (GSH), Bcl-2 protein, P-CREB and BDNF levels in the hippocampus of experimental animals. Nicotine also reduced the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) in the hippocampus. Minocycline attenuated nicotine-induced neurodegeneration and elevating CREB (both forms) and BDNF levels. Also minocycline treatment alone increases the cognitive activity and increased CREB (both forms) and BDNF levels and decreased oxidative stress, inflammation and apoptotic biomarkers. Minocycline at high doses cause inhibition of nicotine induced cell density and changes in both area of dentate gyrus (DG) and CA1 in hippocampus. Conclusion It can be concluded that minocycline, probably through activation of P-CREB/BDNF signaling pathway, confers neuroprotection against nicotine-induced neurodegeneration in rat hippocampus.

BACKGROUND The Elaeagnus angustifolia fruit has been traditionally used in Iranian herbal medicine to treat diarrhea and rheumatoid arthritis. In the present study, the effects of E. angustifolia fruit extract on the acute and chronic phases of formalin-induced rat paw edema were examined. METHODS The acute and chronic anti-inflammatory effects of E. angustifolia fruit extract were investigated through the subcutaneous injection of 100 μL of formalin (2.5%) into a rat's hind paw. Thirty minutes before the procedure, the experimental groups were treated intraperitoneally with hydroalcoholic fruit extracts of E. angustifolia (concentrations of 100, 300, 700, and 1000 mg/kg); sodium salicylate (SS, 400 mg/kg) and distilled water were used as positive and negative control groups, respectively. Treatment with SS and the fruit extracts were performed daily for 8 days, and the degree of edema was measured by using mercury plethysmometer and digital caliper. RESULTS In the acute anti-inflammatory study, the extract showed a significant anti-inflammatory effect in a dose-dependent manner. The results of 1000 mg/kg of the extract was significantly different compared with the negative control group (p

Background : The neuroprotective effects of duloxetine and neurodegenerative effects of methamphetamine have been shown in previous studies, but their exact mechanism remain unclear. In the current study it involved molecular mechanisms of neuroprotective effects of duloxetine against methamphetamine induced neurodegeneration were clarified. Methods : About 40 adult male rats randomly were divided to 5 groups. Group 1 and 2, as control and methamphetamine treated, received normal saline and methamphetamine (10 mg/kg) respectively. Groups 3, 4 and 5 concurrently treated with methamphetamine and duloxetine at doses of 10, 20 and 30 mg/kg respectively. All treatments were undertaken for 21 days. On day 22 Open Field Test (OFT) were used to examine the level of motor activity disturbance and anxiety in animals. After that hippocampus was isolated from each rat and oxidative, antioxidant, inflammatory factors and also level or expression of total and phosphorylated forms of CREB and P‑CREB and BDNF proteins were measured. Results : Duloxetine in all mentioned doses could inhibit the effects of methamphetamine induced motor activity disturbance in MWM. Chronic abuse of methamphetamine could increase malondialdehyde (MDA), tumor necrosis factor‑Alpha (TNF‑ α ) and interleukine‑1beta (IL‑1 β ) while caused decreases in superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities and decreased CREB (both forms) and BDNF proteins, while duloxetine could prevent these malicious effects of methamphetamine. Conclusions : We conclude that P‑CREB/ BDNF signaling pathways might have critical role in duloxetine neuroprotective effects against methamphetamine induced neurodegeneration. Keyword : Duloxetine, methamphetamine, motor activity, neurodegeneration, P‑CREB/BDNF pathway

Omeprazole is metabolized in the liver mainly by the polymorphic CYP2C19 enzyme. Considerable ethnic differences have been reported in the pharmacokinetics of omeprazole. The present study was conducted to evaluate the pharmacokinetic parameters of omeprazole after a single oral administration to a random Iranian population. Thirty healthy male subjects, aged 24–31 years, weighing 60–98 kg completed the study. Plasma concentrations of omeprazole were measured over a 12 h period after administration of a single oral dose of 20 mg omeprazole. The pharmacokinetic parameters were calculated from the plasma concentration–time profiles. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to quantify 5-hydroxyomeprazole. The mean area under the concentration–time curve (AUC) from time zero to infinity (AUC∞) values of omeprazole and the corresponding coefficient of variation (CV%) was 987.3 ng h/ml (65%). In general, most subjects showed a normal distribution. Only one subject showed a very high AUC compared with the corresponding mean AUC level. This subject had the highest half-life and the lowest rate of elimination. The omeprazole metabolic ratio for this subject was 2.9, while for the others it was in the range 0.12–0.56. These results are consistent with previous literature that showed the existence of interindividual variability in omeprazole pharmacokinetics, even within a single ethnic group. Differences in the pharmacokinetics could be due to differences in the genetic make-up of subjects as found in their omeprazole metabolic ratios. Copyright © 2012 John Wiley & Sons, Ltd.

Background: Forced exercise can act as non-pharmacologic neuroprotective agent. In current study, we tried the involved molecular mechanisms of protective effects of forced exercise against methamphetamine induced neurodegeneration. Materials and Methods: Forty adult male rats were divided to Group 1 and 2 which received normal saline and methamphetamine (10 mg/kg) respectively for 30 days. Groups 3, 4 and 5 were treated with methamphetamine for first 15 days and then were treated by forced exercise, bupropion (20 mg/kg/day) or combination of them for the following 15 days. Between 26th and 30th days, Morris Water Maze (MWM) was used to evaluate the cognition. On day 31, hippocampus was isolated from each rat and oxidative, antioxidant and inflammatory factors also the level of total and phosphorylated forms of cAMP response element-binding protein (CREB) and brain derived neurotrophic factor (BDNF) proteins were also evaluated. Results: Chronic abuse of methamphetamine could decreases cognition and increase malondialdehyde (MDA), Tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), while caused decreases in superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities all these changes was significant (P < 0.001) in compared to control group while treatment with bupropion, forced exercise and bupropion in combination with forced exercise could prevent all these malicious effects of methamphetamine (P < 0.001). Bupropion, forced exercise and bupropion in combination with forced exercise could activate CREB (both forms) and activates BDNF proteins' expression with P < 0.001 in methamphetamine treated rats. Conclusions: P-CREB/BDNF signaling pathways might have critical role in forced exercise protective effects against methamphetamine induced neurodegeneration.

This study investigated the anticonvulsant activity of Citrullus colocynthis fruit extract used traditionally in the treatment of convulsion. Albino mice were pretreated with extract in different doses (10, 25, 50, and 100 mg/kg), prior to injection of pentylenetetrazole. Animals received pretreatments with naloxone and flumazenil to further clarify the mechanisms of anticonvulsant action. The total flavonoid content of Citrullus colocynthis extract was also determined. Citrullus colocynthis hydroalcoholic extract with doses 25 and 50 mg/kg prolonged the onset of seizures and decreased the duration compared with control group. Pretreatment by flumazenil could inhibit the effect of Citrullus colocynthis on latency of seizure to some extent and administration of naloxone significantly inhibited changes in latency and duration of seizure produced by Citrullus colocynthis. This study showed that Citrullus colocynthis has significant anticonvulsant effect in pentylenetetrazole-induced seizures in mice, and these effects may be related to its effect on γ-aminobutyric acid-ergic and opioid systems. These results confirmed the traditional use of Citrullus colocynthis in Iranian traditional medicine.

Methylphenidate (MPH) is a central stimulant, prescribed for the treatment of attention deficit/hyperactivity disorder. The long-term behavioral consequences of MPH treatment are unknown. In this study, the oxidative stress and neuroinflammation induced by various doses of MPH were investigated. Forty adult male rats were divided into 5 groups; and treated with different doses of MPH for 21 days. Twenty four hours after drug treatment, Open Field Test (OFT) was performed in all animals. At the end of the study, blood cortisol level (BCL) was measured and hippocampus was isolated and oxidative stress and inflammation parameters and histological changes were analyzed. Chronic MPH at all doses decreased central square entries, number of rearing, ambulation distance and time spent in central square in OFT. BCL increased in doses 10 and 20mg/kg of MPH. Furthermore, MPH in all doses markedly increased lipid peroxidation, mitochondrial oxidized glutathione (GSSG) level, Interleukin 1β (IL-1β) and Tumor Necrosis Factor α (TNF-α) in isolated hippocampus. MPH (10 and 20mg/kg) treated groups had decreased mitochondrial reduced glutathione (GSH) content, and reduced superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRx) activities. 10 and 20mg/kg of MPH change cell density and morphology of cells in Dentate Gyrus (DG) and CA1 areas of hippocampus. Chronic treatment with high doses of MPH can cause oxidative stress, neuroinflammation and neurodegeneration in hippocampus of adult rats.

Methylphenidate (MPH) is a stimulatory agent in brain with unknown long-term consequences. In this study, MPH-induced neurodegeneration in adult rat brain was assessed. Rats were acutely treated with different doses of MPH. Open Field Test was used to investigate anxiety and depression levels. Inflammatory factors and anti-oxidant activity were also evaluated in isolated hippocampus and cerebral cortex. MPH treated groups (10 and 20 mg/kg) demonstrated anxiety and depression like behavior in OFT. MPH significantly increased lipid peroxidation, GSSG level, IL-1β and TNF-α in isolated tissues. In addition, MPH at the same doses (10 and 20 mg/kg) reduced GSH, superoxide dismutase, glutathione peroxidase and glutathione reductase activity significantly in hippocampus and cerebral cortex. In conclusion, acute administration of high doses of MPH can cause oxidative and inflammatory changes in brain cells and induce neurodegeneration in hippocampus and cerebral cortex of adult rats.

Background: Methylphenidate (MPH) is a neural stimulant agent, which its neurochemical and behavioral effect remain unclear. Venlafaxine is a serotonin-norepinephrine reuptake inhibitor antidepressant, which was used for management of depression and anxiety. In this study, protective effects of venlafaxine on MPH induced anxiety, depression and cognition impairment were investigated. Methods: Forty-eight adult male rats were divided randomly to 5 groups. Group 1, received normal saline (0.2 ml/rat) for 21 days and served as control group. Group 2, received MPH (10 mg/kg) for 21 days. Groups, 3, 4, 5 and 6 concurrently were treated by MPH (10 mg/kg) and venlafaxine at doses of 25, 50, 75 and 100 mg/kg respectively for 21 days. On day 22, elevated plus maze (EPM), open field test (OFT), forced swim test (FST) and tail suspension test (TST) were used to investigate the level of anxiety and depression in animals. In addition, between days 17 and 21, Morris water maze (MWM) was used to evaluate the effect of MPH on spatial learning and memory. Results: MPH caused depression and anxiety in a dose-dependent manner in FST, OFT, EPM and TST, which were significantly different compared with control group. Furthermore, MPH can significantly attenuate the motor activity in OFT. Venlafaxine in all doses can attenuate MPH induced anxiety, depression and motor activity alterations. MPH also can disturb learning and memory in MWM, but venlafaxine did not alter this effect of MPH. Conclusions: We conclude that venlafaxine can be protective in the brain against MPH induced anxiety and depression.

Background The importance of inflammatory diseases and side effects of conventional drugs necessitate the finding of new anti-inflammatory agents from natural sources. In this study, for the first time, the anti-inflammatory and analgesic effects of the aqueous extract of Astragalus arbusculinus gum were evaluated in animal models. Methods Thirty-five male Wistar rats were divided into five groups and pretreated with different doses of A. arbusculinus gum extract before the injection of formalin. Paw edema was measured by a plethysmometer at time 0 and after 8 days and compared to controls. The analgesic effect of the extract was evaluated using the hot-plate test in 42 male albino mice. Results The extract of A. arbusculinus gum decreased the rat paw edema in a dose-dependent manner. The effect on inflammation of the highest dose of extract was comparable to sodium salicylate. Astragalus arbusculinus gum extract at doses of 300 and 1000 mg/kg showed analgesic effects comparable to sodium salicylate and morphine, respectively. A preliminary phytochemical study and the determination of the total phenolic content of the gum extract were performed for the first time. Conclusions The aqueous extract of A. arbusculinus gum reduced the inflammation and pain in a dose-dependent manner and is a good candidate for further studies of safety and efficacy. The clarification of active components of the plant is necessary.

Background: Many previous studies showed that maternal forced exercise can reduce some central disorders in offsprings, but its clear mechanism remains unclear. In this study, the role of 5-HT2 and D2 receptors in neuroprotective effects of maternal forced exercise in offspring neurodevelopment and effect on some behaviors were evaluated. Materials and Methods: Forty-eight pregnant rats were trained by forced exercise, and some behavioral assays in their offspring were performed in the presence and absence of 5-HT2 and D2 receptor antagonists in various experimental groups. Results: Our data showed that maternal forced exercise caused increase in latency of pain perception in offsprings in hot plate test, writhing test (WT), and tail flick test. Furthermore, a decrease in intensity was shown by WT. On the other hand, treatment of mothers by forced exercise in combination with 5-HT2 and D2 receptor antagonists could inhibit these effects of forced exercise and cause disturbances in pain perception and intensity. Conclusion: Our data suggested that maternal forced exercise causes protective effects on offspring pain perception and intensity, and in this effect, 5-HT2 and D2 receptors are probably involved.

Background: Methylphenidate (MPH), a neural stimulant, can cause damages to brain; the chronic neurochemical and behavioral effects of MPH remain unclear. Exercise lowers stress and anxiety and can act as non-pharmacologic neuroprotective agent. In this study protective effects of exercise in MPH-induced anxiety, depression and cognition impairment were investigated. Materials and Methods: Seventy adult male rats were divided randomly into five groups. Group 1 served as negative control, received normal saline (0.2 ml/rat) for 21 days, group 2 and 3 (as positive controls) received MPH (10 and 20 mg/kg) for 21 days. Groups 4 and 5 concurrently were treated with MPH (10 and 20 mg/kg) and forced exercise for 21 days. On day 21, Elevated Plus Maze (EPM), Open Field Test (OFT), Forced Swim Test (FST) and Tail Suspension Test (TST) were used to investigate the level of anxiety and depression in animals. In addition between 17 th and 21 th days, Morris Water Maze (MWM) was applied to evaluate the effect of MPH on spatial learning and memory. Results: MPH-treated animals indicated a reflective depression and anxiety in a dose-dependent manner in FST, EPM and TST which were significantly different from the control group and also can significantly attenuate the motor activity and anxiety in OFT. Forced exercise by treadmill can attenuate MPH-induced anxiety, depression and motor activity alteration in OFT. MPH also can disturb learning and memory in MWM and forced exercise can neutralize this effect of MPH. Conclusion : We conclude that forced exercise can be protective in brain against MPH-induced anxiety, depression and cognition alteration.

Background: Morphine withdrawal usually results in undesired outcomes , despite partial benefits of alternative medication such as methadone, because of the lack of mental sedation during the withdrawal period, may not lead to the desired result. In this study, forced exercise by treadmill is used to manage morphine dependence in animal model. Materials and Methods: Forty adult male mice were divided into 5 groups, from which 4 groups became dependent by increasing daily doses of morphine for 6 days (20-45 mg/kg, SC). Afterwards, the animals were treated for 21 days by either of the following protocol: Positive control (dependent) received once daily 45 mg/kg of morphine sulfate (SC) for 21 day, group under treatment by clonidine (0.4 mg/kg, SC) for 21 day group under treatment by forced exercise by treadmill for 21 day, group under treatment by combination of clonidine (0.4 mg/kg, SC) and forced exercise by treadmill for 21day and the negative control group(independent) received saline injection like other groups. Each of this administration was injected at 8 AM. Finally, in the test day (day 28), all animals received a single dose of naloxone (3 mg/kg, SC) at 8 AM and then were observed for withdrawal signs, and Total Withdrawal Score (TWS) was determined as described previously. After withdrawal sign evaluation for evaluation of stress level of dependent mice, blood cortisol and glucose level were measured in non-fasting situations well. Results: This study showed that TWS significantly decreased in all treatment groups in comparison with positive control group (P < 0.001). Moreover, blood cortisol and glucose level significantly decreased in group under treatment by clonidine (0.4 mg/kg) and group under treatment by combination of clonidine (0.4 mg/kg) and forced exercise by treadmill groups in comparison with control positive (dependent) (P < 0.05). Conclusion: This study suggested that forced exercise can be useful as adjunct therapy in dependent people and can ameliorate side effects and stress situation of withdrawal syndrome periods.

Sumatriptan is a selective agonist for a 5-HT1 -like receptor sub-type which mediates contraction of some cranial blood vessels in vitro. It has been shown to be a very effective novel agent for the acute treatment of migraine and this has stimulated much interest in its clinical mode of action. It has been suggested that the pain of migraine results from a sterile neurogenic inflammatory response of intracranial blood vessels innervated by the trigeminal nerve. Furthermore, sumatriptan has been shown to inhibit plasma protein extravasation from blood vessels of the dura mater, induced by antidromic stimulation of the trigeminal nerve in the anaesthetised rat and guinea-pig. This effect could be explained by a localised vasoconstriction of the meningeal vessels. We now provide evidence that sumatriptan will potently constrict the blood vessels within the human isolated perfused dura mater. Preliminary work on characterising the 5-HT receptor involved indicates that it is a 5-HT1- like receptor. These studies add weight to the view that the anti-migraine action of sumatriptan results from selective cranial vasoconstriction.