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Neurodegeneration is a side effect of methylphenidate (MPH), and minocycline possesses neuroprotective properties. This study aimed to investigate the neuroprotective effects of minocycline against methylphenidate-induced neurodegeneration mediated by signaling pathways of CREB/BDNF and Akt/GSK3. Seven groups of seventy male rats were randomly distributed in seven groups (n = 10). Group 1 received 0.7 ml/rat of normal saline (i.p.), and group 2 was treated with MPH (10 mg/kg, i.p.). Groups 3, 4, 5, and 6 were simultaneously administered MPH (10 mg/kg) and minocycline (10, 20, 30, and 40 mg/kg, i.p.) for 21 days. Minocycline alone (40 mg/kg, i.p.) was administrated to group 7. Open field test (OFT) (on day 22), forced swim test (FST) (on day 24), and elevated plus maze (on day 26) were conducted to analyze the mood-related behaviors; hippocampal oxidative stress, inflammatory, and apoptotic parameters, as well as the levels of protein kinase B (Akt-1), glycogen synthase kinase 3 (GSK3), cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF), were also assessed. Furthermore, localization of total CREB, Akt, and GSK3 in the DG and CA1 areas of the hippocampus were measured using immunohistochemistry (IHC). Histological changes in the mentioned areas were also evaluated. Minocycline treatment inhibited MPH-induced mood disorders and decreased lipid peroxidation, oxidized form of glutathione (GSSG), interleukin 1 beta (IL-1β), alpha tumor necrosis factor (TNF-α), Bax, and GSK3 levels. In the contrary, it increased the levels of reduced form of glutathione (GSH), Bcl-2, CREB, BDNF, and Akt-1 and superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) activities in the experimental animals' hippocampus. IHC data showed that minocycline also improved the localization and expression of CREB and Akt positive cells and decreased the GSK3 positive cells in the DG and CA1 regions of the hippocampus of MPH-treated rats. Minocycline also inhibited MPH-induced changes of hippocampal cells' density and shape in both DG and CA1 areas of the hippocampus. According to obtained data, it can be concluded that minocycline probably via activation of the P-CREB/BDNF or Akt/GSK3 signaling pathway can confer its neuroprotective effects against MPH-induced neurodegeneration.

The potential of minocycline to protect against methylphenidate‑induced neurodegeneration has been extensively reported in the literature but the mechanism of action is still unknown. This study aims to determine the role of mitochondrial chain enzymes and redox homeostasis on the neuroprotective effects of minocycline in methylphenidate‑induced neurodegeneration. Wistar adult male rats were randomly assigned to the seven experimental groups: Group 1 received saline solution; Group 2 received methylphenidate (10 mg/kg, i.p.); Groups 3, 4, 5, and 6 received methylphenidate and minocycline for 21 days; Group 7 received minocycline alone. Cognition was evaluated with the Morris water maze test. Activity of the hippocampal mitochondrial quadruple complexes I, II, III and IV, mitochondrial membrane potential, adenosine triphosphate (ATP) levels, total antioxidant capacity, and reactive oxygen species were determined. Treatment with minocycline inhibited methylphenidate‑induced cognitive dysfunction. Minocycline treatment increased mitochondrial quadruple complex activities, mitochondrial membrane potential, total antioxidant capacity, and ATP levels in the dentate gyrus and cornu ammonis‑1 (CA1) areas of the hippocampus. Minocycline is likely to confer neuroprotection against methylphenidate‑induced neurodegeneration and cognition impairment by regulating mitochondrial activity and oxidative stress.

Malaria is a parasitic lethal disease caused by Plasmodium protozoa. The resistance and drugs’ side effects have led to numerous researches for alternative suitable drugs with better efficiency and lower toxicity In the present study, we investigated in vivo antimalarial effects of G2 linear dendrimer-based nano-chloroquine. After the preparation of nano dendrimer G2, chloroquine loading was done. Determine the characterization of particles were specified by DLS, SLS and SEM. The LC–MS and FTIR were used for verifying the nano dendrimer G2 and the loading of chloroquine into the compound. The Solubility N-chloroquine and measurement of drug release rate were done. Antiplasmodial activity of N-chloroquine on BALB/c mice was performed by the microscope and enzymatic methods. At the end, In vivo toxicity of N-chloroquine on tissues was assayed. The RBC morphology and enzyme levels were identified. The results showed the synthesized N-chloroquine had suitable size and solubility. Highest inhibitory effect on Plasmodium parasitic growth was observed at 16 mg/kg dose of N-chloroquine, which eliminated 95% of the parasites (p > 0.05). ED50 is observed at 7.7 mg/kg of N-chloroquine dose. Biochemical findings showed the synthesized N-chloroquine was safer than chloroquine. The N-chloroquine no adverse effects were observed in examined tissues. Due to the better effect of the synthesized N-chloroquine on Plasmodium berghei in mice compared to chloroquine, this nanoparticle can be considered as an effective anti-plasmodium compound while more comprehensive research is recommended.

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.

Background:The reactive gliosis contributes to patterns of hydrocephalus injury and recovery. The study aimed at evaluating Origanum vulgare essential oil (OEO) effects on reactive astrogliosis and reduced lateral ventricle thickness in kaolin-induced hydrocephalic rats. Methods and Results:Thirty male Wistar rats received kaolin via a direct injection into the cisterna magna and compared to control animals. After 21 day post-injection of kaolin, the hydrocephalic rats were randomly divided to four groups and experimental groups underwent magnetic resonance imaging to determine the lateral ventricle volume. Rats received different doses of OEO for 10 days. The lateral ventricular dilatation was evaluated by MRI. Also to assess the Iba-1 and GFAP proteins’ expression level, immunohistochemistry test and western blot analysis were performed 10 days after the injection. The results showed lateral ventricular size in the OEO-treated hydrocephalic rats was smaller than that of those receiving kaolin without OEO. The hydrocephalic rats increased reactive astrocytes and reactive microglia compared to the OEO-treated animals based on GFAP and Iba-1 immunoreactivity results. The findings were confirmed by western blot. There were significant differences between the hydrocephalus control and the 200 mg/kg/day OEO-treated rats in terms of GFAP and Iba-1 expression levels. Conclusions:In nonclusions, the OEO treated groups had stabilized ventricular expansion compared to hydrocephalus rats. Findings of the study showed that OEO can restrain the hydrocephalus-associated damage in rat brain induced by kaolin, likely by reducing GFAP and Iba-1 and therefore the OEO intervention, might be useful as a new treatment strategy.

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.

Plantago major (P. major) has traditionally been used in Iranian Persian medicine to treat gastrointestinal ulcers and bleeding.This study aimed to investigate the anti-inflammatory effects of the leaf and seed extracts of P. major in rats with acetic acid-induced ulcerative colitis (UC).To this end, 49 rats were randomly divided into seven groups. UC was induced in all groups but the control (vehicle) group using a single intra-rectal administration of 2 ml of 4% acetic acid. Other groups received daily intraperitoneal (i.p.) injections of the seed extract of P. major (400 mg/kg and 700 mg/kg), the leaf extract of P. major (400 mg/kg and 700 mg/kg), and sulfasalazine (400 mg/kg) for seven consecutive days, respectively. The rats' rectum was surgically removed and evaluated for macroscopic and microscopic damage. The tissue levels of oxidative stress and inflammatory markers were measured using the ELISA method.The high-dose leaf extract significantly decreased ulcer index and histopathologic damage as well as the tissue levels of IL-6, TNF-α, PGE2, IL-1β, MPO, and MDA compared to the damage group. The low-dose leaf extract also significantly reduced the levels of some markers. The seed extract in the two used doses caused a modest decrease in the histopathological damages and ulcer index.P. major leaf extract effectively reduces inflammation and mucosal damage in rats with UC, especially when administered in high doses. P. major seed extract has minimal protective effects on UC.

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.

In order to conduct an effective chemotherapy session as a treatment modality for glioblastoma tumors, a nanocarrier platform is required for the drug to cross the blood brain barrier (BBB) successfully and properly target glioma cells. Dual-targeting Temozolomide (TMZ) loaded triblock polymer coated magnetic nanoparticles (MNPs) were synthesized with a SPION core and by conjugating the surface with folic acid (FA), which were shown to effectively pass the BBB and target tumor cells. Two principal methods, dynamic light scattering (DLS) and transmission electron microscopy (TEM) were employed for characterization of the synthesized nanoparticles. TMZ-loaded MNP-FA nanoparticles presented with a size of 58.61 nm, a zeta potential of -29.85 ± 0.47 mV, and a drug loading content of 6.85 ± 0.46%. Data gathered from inductively coupled plasma optical emission spectrometry (ICP-OES) and Prussian blue staining indicated effective dual-targeting, which subsequently led to an appreciably enhanced penetration through the BBB and accumulation of MNPs-FA in rat glioma cells. The anticancer effect of the dual-targeting MNPs-FA was also indicated by the increased survival time (>100%, p < 0.001) and decreased tumor volume (p < 0.001). In conclusion, the dual-targeting TMZ-loaded MNPs-FA are able to improve therapeutic efficiency toward brain gliomas in rats.

The T-cell immunoglobulin and mucin-3 (TIM-3)/galectin-9 (Gal-9) autocrine loop is an indispensable signaling in acute myeloid leukemia (AML) cells, which induces their self-renewal through activation of nuclear factor-kappa b (NF-kB) and β-catenin pathways. In this study, we evaluated the effects of oridonin and doxorubicin on the TIM-3/Gal-9 autocrine loop. We also evaluated oridonin anti-inflammatory and anti-cancer properties on U937 cells, as an AML cell line in comparison to doxorubicin as a common anthracycline drug for AML treatment. Cell counting kit-8 (CCK-8) was applied to evaluate the cytotoxicity of oridonin and doxorubicin on U937 cells and also to determine the impact of galectin-9 (Gal-9) on their proliferation. The effects of oridonin and doxorubicin on Gal-9, TIM-3, and interleukin-1β (IL-1β) gene expression were determined by real-time polymerase chain reaction (RT-PCR). The Gal-9 secretion level was measured by enzyme-linked immunosorbent assay (ELISA) and activation of NF-kB pathway was assessed by western blotting. In a dose-dependent manner, oridonin and doxorubicin were capable to eradicate U937 cells while Gal-9 expanded them. Following the treatment of U937 cells with oridonin, the expression of Gal-9, TIM-3, and IL-1β genes was down-regulated, and the Gal-9 secretion and NF-kB phosphorylation were diminished, whereas doxorubicin increased all of these factors. Doxorubicin is a common treatment agent in AML, but it may induce inflammation and up-regulate the TIM3/Gal-9 autocrine loop, consequently can enhance the possibility of disease relapse. Meanwhile, oridonin is capable to inhibit the essential signaling pathways in AML cells and reduce the inflammation and expansion of tumor cells and postpone AML recurrence.

Due to side-effects and inefficiency of the drugs used in malaria treatment, finding alternative medicine with less side-effects has attracted much attention. In this regard, in the present study, nanocomposite synthesized and its effects on the metabolites of P. falciparum were investigated. Subsequent to synthesis of nanocomposites, characterization was carried out using nuclear magnetic resonance (NMR), liquid chromatography-mass spectrometry (LC-MS), scanning electron microscopy, dynamic light scattering and Fourier-transform infrared tests. Solubility and drug release were measured and its toxicity on Vero cell was assessed using the MTT assay. The antiparasitic effect of the nanocomposite on the metabolites of P. falciparum was investigated by 1H NMR spectroscopy. Among synthesized nanocomposites, the average size of 239 nm showed suitable solubility in water as well as slow drug release. The MTT assay showed no toxicity for Vero cell lines. Concentrations of 2.5 μg mL-1 of nanocomposite eliminated 82.6% of the total parasites. The most effected metabolic cycles were glyoxylate and dicarboxylate metabolism. In this study, 1H NMR spectroscopy was used with untargeted metabolomics to study the effect of the nanocomposite on P. falciparum. Playing an essential role in understanding drug-target interactions and characterization of mechanism of action or resistance exhibited by novel antiprotozoal drugs, can be achieved by targeting metabolic using LC-MS.

Due to side-effects and inefficiency of the drugs used in malaria treatment, finding alternative medicine with less side-effects has attracted much attention. In this regard, in the present study, nanocomposite synthesized and its effects on the metabolites of P. falciparum were investigated. Subsequent to synthesis of nanocomposites, characterization was carried out using nuclear magnetic resonance (NMR), liquid chromatography-mass spectrometry (LC-MS), scanning electron microscopy, dynamic light scattering and Fourier-transform infrared tests. Solubility and drug release were measured and its toxicity on Vero cell was assessed using the MTT assay. The antiparasitic effect of the nanocomposite on the metabolites of P. falciparum was investigated by 1H NMR spectroscopy. Among synthesized nanocomposites, the average size of 239 nm showed suitable solubility in water as well as slow drug release. The MTT assay showed no toxicity for Vero cell lines. Concentrations of 2.5 μg mL−1 of nanocomposite eliminated 82.6% of the total parasites. The most effected metabolic cycles were glyoxylate and dicarboxylate metabolism. In this study, 1H NMR spectroscopy was used with untargeted metabolomics to study the effect of the nanocomposite on P. falciparum. Playing an essential role in understanding drug-target interactions and characterization of mechanism of action or resistance exhibited by novel antiprotozoal drugs, can be achieved by targeting metabolic using LC-MS.

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.

The effect of maternal forced exercise on central disorders in offsprings has been shown but the mechanism is still unclear. In this study, the role of 5-HT2 and D2 receptors in neuroprotective effects of maternal forced exercise on offspring neurodevelopment and neurobehavioral symptoms is evaluated. Sixty pregnant rats were trained by forced exercise and some behavioral and molecular aspects in their offspring were evaluated in presence of 5-HT2 and D2 receptors agonists and antagonists. The results showed that maternal forced exercise causes increase of pain tolerability and increase latency of pain perception in offspring in hot plate test, writhing test and tail flick test. Also maternal forced exercise causes decrease of depression and anxiety like behavior in offsprings. On the other hand, treatment of mothers by forced exercise in combination with 5-HT2 and D2 receptor antagonists inhibited the protective effects of forced exercise and cause disturbance in pain perception and tolerability and increase depression and anxiety in offsprings. Also expression of cyclic AMP response element binding protein (CREB) was changed in all experimental groups. In conclusion, our data suggested that maternal forced exercise causes neurobehavioral protective effect on offsprings and this effect might probably be mediated by 5-HT2 and D2 receptors and activation of CREB gene expression.

Many obstacles compromise the efficacy of bone marrow mesenchymal stem cells (BM-MSCs) by inducing apoptosis in the grafted BM-MSCs. The current study investigates the effect of melatonin on important mediators involved in survival of BM-MSCs in hydrogen peroxide (H2O2) apoptosis model. In brief, BM-MSCs were isolated, treated with melatonin, and then exposed to H2O2. Their viability was assessed by MTT assay and apoptotic fractions were evaluated through Annexin V, Hoechst staining, and ADP/ATP ratio. Oxidative stress biomarkers including ROS, total antioxidant power (TAP), superoxide dismutase (SOD) and catalase (CAT) activity, glutathione (GSH), thiol molecules, and lipid peroxidation (LPO) levels were determined. Secretion of inflammatory cytokines (TNF-α and IL-6) were measured by ELISA assay. The protein expression of caspase-3, Bax, and Bcl-2, was also evaluated by Western blotting. Melatonin pretreatment significantly increased viability and decreased apoptotic fraction of H2O2-exposed BM-MSCs. Melatonin also decreased ROS generation, as well as increasing the activity of SOD and CAT enzymes and GSH content. Secretion of inflammatory cytokines in H2O2-exposed cells was also reduced by melatonin. Expression of caspase-3 and Bax proteins in H2O2-exposed cells was diminished by melatonin pretreatment. The findings suggest that melatonin may be an effective protective agent against H2O2-induced oxidative stress and apoptosis in MSC.

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.

Prolonged abuse of methylphenidate (MPH) often causes neuronal damage. Topiramate (TPM) has neuroprotective properties, but its mechanism of action remains unclear. The current study evaluates in vivo role of various doses of TPM (10, 30, 50, 70 and 100mg/kg) and its possible mechanisms against MPH-induced hippocampal oxidative stress, inflammation and apoptosis, in absence and presence of different receptor agonists and antagonists. Domoic acid (DOM) as AMPA/kainate receptor agonist, bicuculline (BIC) as GABAA receptor antagonist, ketamine (KET) as NMDA receptor antagonist, yohimbine (YOH) as ɑ2 adrenergic receptor antagonist and haloperidole (HAL) as D2 dopamine receptor antagonist was used. Open Field Test (OFT) was used to investigate the disturbances in motor activity. Hippocampal oxidative, anti-oxidant and inflammatory parameters and apoptotic factors were studied. Expressions of BDNF at gene and protein levels were also evaluated. Crystal violet staining was performed to determine neuronal cell density. TPM (70 and 100mg/kg) reduced MPH-induced rise in lipid peroxidation, oxidized form of glutathione (GSSG), IL-1β and TNF-α levels, Bax expression and motor activity disturbances. In addition, TPM treatment increased BDNF gene and protein expressions, Bcl-2 expression, the level of reduced form of glutathione (GSH) and activities of enzymes superoxide dismutase, glutathione peroxidase and glutathione reductase.TPM also inhibited MPH-induced hippocampal degeneration. Pretreatment of animals with DOM, BIC, KET and YOH inhibited TPM-induced neuroprotection and increased oxidative stress, neuroinflammation, neuroapoptosis and neurodegeneration while reducing BDNF expressions. Thus, TPM by interacting with AMPA/kainate, GABAA, NMDA and ɑ2-adrenergic receptors improves BDNF expression and acts as a neuroprotective agent against MPH-induced neurodegeneration.

Chronic abuse of methylphenidate (MPH) can cause serious neurotoxicity. The neuroprotective effects of topiramate (TPM) were approved, but its putative mechanism remains unclear. In current study the role of CREB/BDNF signaling pathway in TPM protection against methylphenidate-induced neurotoxicity in rat hippocampus was evaluated. 60 adult male rats were divided randomly into six groups. Groups received MPH (10 mg/kg) only and concurrently with TPM (50 mg/kg and 100 mg/kg) and TPM (50 and 100 mg/kg) only for 14 days. Open field test (OFT) was used to investigate motor activity. Some biomarkers of apoptotic, anti-apoptotic, oxidative, antioxidant and inflammatory factors were also measured in hippocampus. Expression of total (inactive) and phosphorylated (active) CREB and BDNF were also measured in gene and protein levels in dentate gyrus (DG) and CA1 areas of hippocampus. MPH caused significant decreases in motor activity in OFT while TPM (50 and 100 mg/kg) inhibited MPH-induced decreases in motor activity. On the other hand, MPH caused remarkable increases in Bax protein level, lipid peroxidation, catalase activity, IL-1β and TNF-α levels in hippocampal tissue. MPH also caused significant decreases of superoxide dismutase, activity and also decreased CREB, in both forms, BDNF and Bcl-2 protein levels. TPM, by the mentioned doses, attenuated these effects and increased superoxide dismutase, glutathione peroxidase and glutathione reductase activities and also increased CREB, in both forms, BDNF and Bcl-2 protein levels and inhibited MPH induced increase in Bax protein level, lipid peroxidation, catalase activity, IL-1β and TNF-α levels. TPM also inhibited MPH induced decreases in cell number and changes in cell shapes in DG and CA1 areas. TPM can probably act as a neuroprotective agent against MPH induced neurotoxicity and this might have been mediated by CREB/BDNF signaling pathway.

Background Alcohol abuse causes severe damage to the brain neurons. Studies have reported the neuroprotective effects of curcumin against alcohol-induced neurodegeneration. However, the precise mechanism of action remains unclear. Methods Seventy rats were equally divided into 7 groups (10 rats per group). Group 1 received normal saline (0.7 ml/rat) and group 2 received alcohol (2 g/kg/day) for 21 days. Groups 3, 4, 5 and 6 concurrently received alcohol (2 g/kg/day) and curcumin (10, 20, 40 and 60 mg/kg, respectively) for 21 days. Animals in group 7 self- administered alcohol for 21 days. Group 8 treated with curcumin (60 mg/kg, i.p.) alone for 21 days. Open Field Test (OFT) was used to investigate motor activity in rats. Hippocampal oxidative, antioxidative and inflammatory factors were evaluated. Furthermore, brain cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and brain derived neurotrophic factor (BDNF) levels were studied at gene level by reverse transcriptase polymerase chain reaction (RT-PCR). In addition, protein expression for BDNF, CREB, phosphorylated CREB (CREB-P), Bax and Bcl-2 was determined by western blotting. Result Voluntary and involuntary administration of alcohol altered motor activity in OFT, and curcumin treatment inhibited this alcohol-induced motor disturbance. Also, alcohol administration augmented lipid peroxidation, mitochondrial oxidized glutathione (GSSG), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and Bax levels in isolated hippocampal tissues. Furthermore, alcohol-induced significant reduction were observed in reduced form of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities and CREB, BDNF and Bcl-2 levels. Also curcumin alone did not change the behavior and biochemical and molecular parameters. Conclusion Curcumin can act as a neuroprotective agent against neurodegenerative effects of alcohol abuse, probably via activation of CREB-BDNF signaling pathway.

This study investigated the anticonvulsant activity and possible mechanism of action of an aqueous solution of Dorema ammoniacum gum (DAG) which has been used traditionally in the treatment of convulsions.In this study, the anticonvulsant activity of DAG was examined using the pentylentetrazole (PTZ) model in mice. Thirty male albino mice were divided randomly and equally to 5 groups, and pretreated with normal saline, diazepam, or various doses of DAG (500, 700, and 1000 mg/kg, i.p.), prior to the injection of PTZ (60 mg/kg, i.p.). The latency and duration of seizures were recorded 30 min after PTZ injection. Pretreatments with naloxone and flumazenil in different groups were studied to further clarify the mechanisms of the anticonvulsant action. Phytochemical screening and thin layer chromatography (TLC) fingerprinting of ammoniacum gum was also determined. DAG showed significant anticonvulsant activity at all doses used. The gum delayed both the onset and the duration of seizures induced by PTZ. Treatment with flumazenil before DAG (700 mg/kg) inhibited the effect of gum on seizure duration and latency to some extent and administration of naloxone before DAG also significantly inhibited changes in latency and duration of seizure produced by DAG. The percentage inhibition was greater with naloxone than with flumazenil. This study showed that DAG had significant anticonvulsant activity in PTZ-induced seizures, and GABAergic and opioid systems may be involved. More studies are needed to further investigate its detailed mechanism.

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.

Methylphenidate (MPH) is a neural stimulant with unclear neurochemical and behavioral effects. Lithium is a neuroprotective agent in use clinically for the management of manic-depressive and other neurodegenerative disorders. This study investigated the protective effect of lithium on MPH-induced oxidative stress, anxiety, depression and cognition impairment. Forty-eight adult male rats were divided randomly and equally into 6 groups. Treatment groups were received MPH (10mg/kg) and various doses of lithium (75, 150 and 300mg/kg) simultaneously and also lithium (150mg/kg) alone for 21 days. Elevated Plus Maze and Forced Swim Test were used to determine the level of anxiety and depression in animals. Morris Water Maze was used to evaluate spatial learning and memory. The hippocampi of rats were isolated and the level and activity of oxidative, anti-oxidant and inflammatory factors were measured. Also brain derived neurotropic factor expression level was measured by RT-PCR and western blotting. MPH (10mg/kg) caused behaviors indicative of anxiety and depression-like phenotypes in EPM and FST and cognition impairment in MWM. While lithium in all mentioned doses inhibited these effects. Treatment with MPH significantly increased lipid peroxidation, mitochondrial GSH content and IL-1β and TNF-α levels in isolated hippocampal cells. Moreover superoxide dismutase and glutathione peroxidase activities and BDNF expression remarkably decreased. Various doses of lithium attenuated these effects and significantly mitigated MPH-induced oxidative damage, inflammation and increased BDNF expression level. Lithium has the potential to act as a neuroprotective agent against MPH induced toxicity in rat brain and this might be mediated by BDNF expression in hippocampus of rats.

Abuses of methylphenidate (MPH) as psychostimulant cause neural damage of brain cells. Neuroprotective properties of topiramate (TPM) have been indicated in several studies but its exact mechanism of action remains unclear. The current study evaluates protective role of various doses of TPM and its mechanism of action in MPH induced oxidative stress and inflammation. The neuroprotective effects of various doses of TPM against MPH induced oxidative stress and inflammation were evaluated and then the action of TPM was studied in presence of domoic acid (DOM), as AMPA/kainate receptor agonist and bicuculline (BIC) as GABA A receptor antagonist, in isolated rat hippocampus. Open Field Test (OFT) was used to investigate motor activity changes. Oxidative, antioxidant and inflammatory factors were measured in isolated hippocampus. TPM (70 and 100 mg/kg) decreased MPH induced motor activity disturbances and inhibit MPH induced oxidative stress and inflammation. On the other hand pretreatment of animals with DOM or BIC, inhibit this effect of TPM and potentiate MPH induced motor activity disturbances and increased lipid peroxidation, mitochondrial oxidized form of glutathione (GSSG) level, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in isolated hippocampal cells and decreased reduced form of glutathione (GSH) level, superoxide dismutase, glutathione peroxidase and glutathione reductase activity. It seems that TPM can protect cells of hippocampus from oxidative stress and neuroinflammation and it could be partly by activation of GABA A receptor and inhibition of AMPA/kainite receptor.

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.