The effect of Zataria multiflora hydroalcoholic extract on memory and lung changes induced by rats that inhaled paraquat.

Objectives: The effects of hydroalcoholic extract of Zataria multiflora (Z. multiflora) on memory changes, as well as lung injury due to inhaled paraqut (PQ) in rat, were examined.Method: Control group of rat with saline aerosol administration, PQ groups with PQ aerosol (27 and 54 mg/m3) administration, PQ groups treated with two doses of the extract (200 and 800 mg/kg/day) and dexamethasone (0.03 mg/kg/day) were studied. Shuttle box and Morris Water Maze (MWM) tests were carried out as well as oxidant, anti-oxidant markers, total and differential white blood cell (WBC) counts and cytokine levels in broncho-alveolar lavage (BALF).Results: Inhaled PQ significantly increased the escape latency and travelled distance in MWM test, but the time spent in the target quadrant on the probe day was significantly reduced (p < 0.05 to p < 0.001). The latency to enter the dark room at 3, 24, and 48 h after an electrical shock was reduced due to PQ (p < 0.05 to p < 0.001). Exposure to PQ significantly increased total WBC, neutrophil, eosinophil, lymphocyte, and monocyte counts, IL-10, interferon gama (INF-γ), nitrite (NO2), and malondialdehyde (MDA) levels, but catalase (CAT), superoxide dismutase (SOD), and thiol levels were decreased (p < 0.05 to p < 0.00). Z. multiflora and dexamethasone treatment significantly improved all behavioral as well as lung changes induced by inhaled PQ (p < 0.05 to p < 0.01).Conclusion: Z. multiflora treatment improved learning and memory impairment as well as lung inflammation and oxidative stress induced by inhaled PQ.

Losartan modulates brain inflammation and improves mood disorders and memory impairment induced by innate immune activation: The role of PPAR-γ activation.

In recent years, the role of angiotensin II (Ang II) and Ang II type 1 receptor (AT1) in the crosstalk between the immune system and the central nervous system has received more attention. The present study aimed to investigate the role of losartan, an AT1 receptor blocker, in the modulation of long-lasting adverse effects of repeated systemic lipopolysaccharide (LPS) injection in the brain function. For this purpose, 110 male BALB/c mice were administrated LPS (250 µg/kg) intraperitoneally (i.p.) for seven consecutive days. Mice were i.p. injected with losartan (1 and 3 mg/kg) three days before and during the LPS injection. To determine the role of PPAR-γ activation in the protective actions of losartan, GW9662, a PPAR-γ antagonist, was also co-administrated with losartan. Then, behavioral tests, including Morris water maze (MWM), novel object recognition test, passive avoidance, forced swim test (FST), elevated plus maze, and marble burying task, were conducted. The results demonstrated that losartan improved learning and memory impairment, attenuated anxiety-like behaviors, modulated brain inflammation and oxidative stress, and decreased amyloid-ß accumulation. Losartan was unable to improve hippocampal BDNF and IL-10 levels as well as the retention trial in the MWM task and depressive-like behaviors. In addition, the PPAR-γ antagonist did not significantly influence the beneficial effects of losartan. Our findings suggest that AT1R blockade can protect the brain against most long-lasting hallmark effects of systemic inflammation. Also, based on the results, the beneficial actions of losartan were not mediated through PPAR-γ activation.

The protective role of curcumin in myocardial ischemia-reperfusion injury.

Coronary artery disease (CAD) is a well-known pathological condition that is characterized by high morbidity and mortality. The main pathological manifestation of CAD is myocardial injury due to ischemia-reperfusion (I-R). Currently, no efficacious treatment of protecting the heart against myocardial I-R exists. Hence, it is necessary to discover or develop novel strategies to prevent myocardial-reperfusion injury to improve clinical outcomes in patients with CAD. A large body of experimental evidence supports cardioprotective properties of curcumin and the ability of this phytochemical to modify some cardiovascular risk factors. However, the detailed effects of curcumin in myocardial I-R injury are still unclear and there is a lack of evidence concerning which curcumin regimen may be ideal for myocardial I-R injury. This paper presents a brief review of the pathophysiology of myocardial I-R injury and the mechanisms of action of curcumin in reducing myocardial I-R injury.

The effect of captopril on lipopolysaccharide-induced lung inflammation.

PURPOSE: As an angiotensin converting enzyme (ACE) inhibitor, the effects of captopril on inflammation has been previously examined. Captopril has been shown to have anti-inflammatory and antioxidant effects. Imbalance in the oxidant/antioxidant system is one of the major causes of inflammation. In the present study, the effects of captopril on total and differential white blood cells (WBC), oxidative stress andlung histopathological changes produced by lipopolysaccharide (LPS) were investigated in rat. MATERIALS AND METHOD: The rats were divided into: control (saline-treated), LPS (1 mg/kg), 12.5, 25 or 50 mg/kg captopril-treated before LPS administration (LPS+Cap12.5, LPS+Cap25 and LPS+Cap50) and Cap-treated, 50 mg/kg before saline administration (as positive control group)groups. The levels of total and percentage of differential WBC in blood, and the oxidative stress index in the serum were evaluated. Lung histopathological changes were also examined. RESULTS: In the LPS group, total WBC count, percentage of neutrophils, basophils, eosinophils, and monocytes in the blood, oxidative stress indices in serum, lung pathological changes were significantly higher than the control group (p < 0.05 to p < 0.001). Pathological changes of lung, serum oxidative stress indices of LPS+Cap50 group, total WBC counts of LPS+Cap25 and LPS+Cap50 groups, as well as percentage of neutrophils, monocytes, and basophils in LPS+Cap50 group and percentage of eosinophils in LPS+Cap50 and LPS+Cap25 groups, were significantly decreased compared to the LPS group (p < 0.05 to p < 0.001). CONCLUSION: The results of this study showed that captopril dose-dependently reduced total and differential WBC counts, while it improved serum oxidant/antioxidant biomarkers and histopathological changes in LPS-treated rats. These results indicate a therapeutic potential for captopril on systemic inflammation and oxidative stress against LPS-induced lung injuries.

Therapeutic Potentials of BDNF/TrkB in Breast Cancer; Current Status and Perspectives.

Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to stimulate breast cancer cell growth and metastasis via tyrosine kinase receptors TrkA, TrkB, and the p75NTR death receptor. The aberrant activation of BDNF/TrkB pathways can modulate several signaling pathways, including Akt/PI3K, Jak/STAT, NF-kB, UPAR/UPA, Wnt/ß-catenin, and VEGF pathways as well as the ER receptor. Several microRNAs have been identified that are involved in the modulation of BDNF/TrkB pathways. These include miR-206, miR-204, MiR-200a/c, MiR-210, MiR-134, and MiR-191; and these may be of value as prognostic and predictive biomarkers for detecting patients at high risk of developing breast cancer. It has been also been demonstrated that a high expression of genes involved in the BDNF pathway in breast cancer is associated with poor clinical outcome and reduced survival of patients. Several approaches have been developed for targeting this pathway, for example TKr inhibitors (AZD6918, CEP-701) and RNA interference. The aim of the current review was to provide an overview of the role of BDNF/TrkB pathways in the pathogenesis of breast cancer and its value as a potential therapeutic target. J. Cell. Biochem. 118: 2502-2515, 2017. © 2017 Wiley Periodicals, Inc.

Systemic and Lung Inflammation and Oxidative Stress Associated With Behavioral Changes Induced by Inhaled Paraquat Are Ameliorated by Carvacrol.

Paraquat (PQ) is an herbicide toxin that induces injury in different organs. The anti-inflammatory and antioxidant effects of carvacrol were reported previously. The effects of carvacrol and pioglitazone (Pio) alone and their combination on inhaled PQ-induced systemic and lung oxidative stress and inflammation as well as behavioral changes were examined in rats. In this study, animals were exposed to saline (control [Ctrl]) or PQ (PQ groups) aerosols. PQ-exposed animals were treated with 0.03 mg/kg/day dexamethasone (Dexa), 20 and 80 mg/kg/day carvacrol (C-L and C-H), 5 mg/kg/day Pio, and Pio+C-L for 16 days. Inhaled PQ markedly enhanced total and differential white blood cell (WBC) counts, nitric oxide (NO), and malondialdehyde (MDA) levels but decreased catalase (CAT) and superoxide dismutase (SOD) activities and thiol levels both in the bronchoalveolar lavage fluid (BALF) and blood and increased interferon-gamma (INF-γ) and interleukin-10 (IL-10) levels in the BALF (p < 0.001 for all cases) except lymphocyte count in blood which was not significantly changed. The escape latency and traveled distance were increased in the PQ group. However, the time spent in the target quadrant in the Morris water maze (MWM) test and the duration of time latency in the dark room in the shuttle box test were reduced after receiving an electrical shock (p < 0.05-p < 0.001). Inhaled PQ-induced changes were significantly improved in carvacrol, Pio, Dexa, and especially in the combination of the Pio+C-L treated groups (p < 0.05-p < 0.001). Carvacrol and Pio improved PQ-induced changes similar to Dexa, but ameliorative effects produced by combination treatments of Pio+C-L were more prominent than Pio and C-L alone, suggesting a potentiating effect for the combination of the two agents.

Lactation ameliorates neurobehavioral outcomes in the ischemic rat dams.

AIMS: Cardiac arrest and stroke as a life-threatening event that may occur in throughout the female life, especially during pregnancy or after delivery. Previous studies demonstrated that cerebral ischemia during pregnancy or the puerperium is a rare occurrence but is associated with significant mortality and high morbidity. This study was designed to assess the effects of pregnancy and lactation on behavioral deficits, neural density, and angiogenesis in rat dams undergoing global ischemia. MATERIALS AND METHODS: Thirty-two female Wistar rats were divided into four groups: virgin-Sham (Vir-Sham) group, virgin-ischemic (Vir-Isc) group, pregnancy-lactation-sham (P-L-Sham) group, and pregnancy-lactation-ischemic (P-L-Isc) group. Global brain ischemia was induced in ischemic groups by using the 2-vessel occlusion (2-VO) model at the end of lactation phase. Seven days after 2-VO, anxiety-like signals and passive avoidance memory tests were assessed in animals. KEY FINDINGS: We found that the lactation significantly improved memory and reduced anxiety-like signals in P-L-Isc group as compared with Vir-Isc group. Moreover, angiogenesis and neural density significantly increased in the P-L-Isc group as compared with the Vir-Isc group. SIGNIFICANCE: This finding for the first time indicated that lactation protects the maternal brain against ischemic insult partly through promoting angiogenesis and neurogenesis.

Treadmill exercise ameliorates memory deficits and hippocampal inflammation in ovalbumin-sensitized juvenile rats.

The behavioral changes, including spatial learning and memory impairment as well as depressive- and anxiety-like behaviors in an animal model of asthma were demonstrated previously. On the other hand, there is increasing evidence that the anti-inflammatory actions of exercise are related to their neuroprotective properties against different insults in the brain. This study was aimed to explore the effects of moderate treadmill exercise on cognitive deficits and possible anti-inflammatory mechanisms in ovalbumin (OVA)-sensitized rats. The exercise groups were trained to run on the treadmill 30 min/day with an intensity of 12 m/min, 5 days/week for 4 weeks. Animals in the OVA groups were sensitized by two intraperitoneal (i.p.) injections of OVA (10 µg/injection) and challenged with OVA by inhalation during the treadmill running exercise period. Passive avoidance (PA) memory, levels of interleukin (IL)-10 and tumor necrosis factor (TNF)-α in the hippocampus, total and differential white blood cell (WBC) count in the blood as well as pathological changes of the lung were then evaluated. OVA-sensitization was resulted in cognitive deficits in the PA task, along with increased total and differential WBC in blood and TNF-α in the hippocampus. However, exercise ameliorated these changes and increased the IL-10 level in the hippocampus, suggesting that moderate treadmill exercise can improve memory impairment in OVA-sensitized rats due to its anti-inflammatory properties.

Vitamin D3 attenuates lipopolysaccharide-induced cognitive impairment in rats by inhibiting inflammation and oxidative stress.

AIMS: Vitamin D is a well-known endocrine regulator of calcium/phosphate homeostasis and has been reported as having a wide range of activities that are potentially beneficial for human health. This study aimed to investigate the effects of pretreatment of vitamin D3 (100, 1000, and 10,000 IU/kg) against lipopolysaccharide (LPS)-induced cognitive impairment in rats. MAIN METHODS: Male Wistar rats were divided into five groups. The passive avoidance test and Morris water maze (MWM) test were conducted to evaluate the learning and memory function. Oxidative stress markers including malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), total thiol content as well as interleukin (IL)-6 were evaluated in the hippocampus tissue. KEY FINDINGS: The intraperitoneal (i.p.) injection of LPS (1 mg/kg) correlates with deficits in passive avoidance and spatial learning in the systemic inflammation model. However, pretreatment with vitamin D3 improved LPS-induced cognitive impairment. In addition, vitamin D3 decreased IL-6 and MDA levels, whereas the activities of CAT, SOD, and total thiol content in the hippocampus tissue were significantly increased. SIGNIFICANCE: In conclusion, our results suggest that vitamin D3 plays a protective role against memory dysfunction caused by LPS-induced inflammation through inhibition of oxidative stress and inflammation in the hippocampus. Vitamin D may be a promising potential therapeutic supplement for the treatment or prevention of learning and memory disorders.

Treadmill exercise restores memory and hippocampal synaptic plasticity impairments in ovalbumin-sensitized juvenile rats: Involvement of brain-derived neurotrophic factor (BDNF).

Studies demonstrate that asthma, especially during childhood, affects the functions of the brain including learning and memory. Exercise is well known for its neuroprotective functions and for its beneficial effects on asthma. We aimed to assess the effects of exercise on cognitive function, synaptic plasticity, and hippocampal brain-derived neurotrophic factor (BDNF) levels in ovalbumin (OVA) sensitized juvenile rats. Rats were sensitized by intraperitoneal administration and inhaled OVA. Animals were subjected to treadmill running exercise during the OVA-challenged period. T-helper type 2 (Th2) cytokine [interleukin (IL)-4], Th1 cytokine (INF-γ) levels, and INF-γ/IL-4 (Th1/Th2) ratio in bronchoalveolar lavage fluid (BALF), and tracheal response to methacholine and OVA were measured. Further, memory behaviors and BDNF levels were measured in the hippocampus as well as long-term potentiation (LTP) was assessed by recording field excitatory postsynaptic potentials (fEPSPs) in the hippocampus. The levels of IL-4 and TGF-ß were decreased but INF-γ level and INF-γ/IL-4 ratio increased in the BALF due to exercise in the OVA-sensitized animals. In addition, exercise improved OVA-sensitization induced cognitive impairments, increased BDNF levels, and enhanced hippocampal LTP in OVA-sensitized rats. Exercise is not only effective in the alleviation of airway inflammation by restoring Th1/Th2 cytokines balance, but also is a candidate for improvement of memory and synaptic plasticity deficits partially through increasing the levels of hippocampal BDNF in OVA-sensitized rats.

The protective effect of Nigella sativa extract on lung inflammation and oxidative stress induced by lipopolysaccharide in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Oxidative stress during inflammation can increase inflammation and damage tissue. Nigella sativa L. (NS) showed many pharmacological properties including antioxidant and anti-inflammatory activities. AIM OF THE STUDY: In this study, the preventive effect of NS on lung inflammation and oxidative stress induced by lipopolysaccharide (LPS) in the rats was investigated. MATERIALS AND METHODS: Male rats were assigned to: Control, LPS (1 mg/kg, i.p.), LPS + NS (100, 200, 400 mg/kg, i.p.), (10 per group). Saline (1 ml/kg) was intra-peritoneal (i.p.) injected instead of LPS in the rats of the control group. LPS dissolved in saline and injected i.p. daily for 14 days. Treatment with NS extracts started two days before LPS administration and treatment continued during LPS administration. White blood cells (WBC), total and differential as well as oxidative stress index in bronchoalveolar fluid (BALF) and serum, TGF-ß1, IFN-γ, PGE2, and IL-4 levels in the BALF and lung histopathology were examined. RESULTS: LPS administration increased total WBC, eosinophils, neutrophils, basophils, and monocytes counts as well as oxidative stress markers in the BALF and serum as well as TGF-ß1, IFN-γ, PGE2, IL-4 levels in the BALF and pathological changes of the lung tissue. All of these effects were reduced by NS extract treatment dose-dependently. CONCLUSION: These results suggested the protective effects of NS extract on lung inflammation and oxidative stress as well as its effect on lung pathology induced by LPS dose-dependently.

Rosuvastatin Affects Tracheal Responsiveness, Bronchoalveolar Lavage Inflammatory Cells, and Oxidative Stress Markers in Hyperlipidemic and Asthmatic Rats.

Statins provide greater protection than predicted from just cholesterol-lowering effects, which is possibly mediated by other pleiotropic actions. This study aimed to examine the possible interaction effect of asthma on lipid profiles and evaluate the effect of rosuvastatin treatment on asthma. The animals were assigned into (1) control, (2) asthmatic, (3) hyperlipidemic, (4) asthmatic-hyperlipidemic, (5) rosuvastatin (40 mg/kg/day intraperitoneally, for 3 weeks)-treated asthmatic, (6) rosuvastatin-treated hyperlipidemic and (7) rosuvastatin-treated asthmatic-hyperlipidemic groups. Tracheal responsiveness to methacholine and ovalbumin, total and differential WBC (white blood cell) counts, and oxidative stress markers in bronchoalveolar lavage fluid (BALF) were evaluated. In the asthmatic and asthmatic-hyperlipidemic groups, tracheal responsiveness to ovalbumin, total WBC count, numbers of eosinophils, neutrophils, and monocytes were higher than the control group (p<0.001). A left-ward shift in the concentration-response curves to methacholine, an increase in nitrite and malondialdehyde concentrations, and a decrease in total thiol content, superoxide dismutase and catalase activities were also observed in the asthmatic and asthmatic-hyperlipidemic groups compared to control group (p<0.01 to p<0.001). Beyond lipid-lowering effect in the treated hyperlipidemic and asthmatic-hyperlipidemic groups, rosuvastatin treatment decreased tracheal responsiveness to methacholine, reduced total WBC count, the numbers of eosinophils, neutrophils, and monocytes, as well as decreased malondialdehyde concentration, and increased total thiol content, superoxide dismutase and catalase activities in treated asthmatic and asthmatic-hyperlipidemic groups (p<0.05 to p<0.001). The improving effect of rosuvastatin on asthmatic and asthmatic-hyperlipidemic animals was shown due to pleiotropic mechanisms including the effect on airway hyperresponsiveness, lung inflammation, and oxidative stress.

The effects of soy on scopolamine-induced spatial learning and memory impairments are comparable to the effects of estradiol.

Background Modulatory effects of soy extract and estradiol on the central nervous system (CNS) have been reported. The effect of soy on scopolamine-induced spatial learning and memory in comparison to the effect of estradiol was investigated. Materials and methods Ovariectomized rats were divided into the following groups: (1) control, (2) scopolamine (Sco), (3) scopolamine-soy 20 (Sco-S 20), (4) scopolamine-soy 60 (Sco-S 60), (5) scopolamine-estradiol 20 (Sco-E 20) and (6) scopolamine-estradiol 60 (Sco-E 60). Soy extract, estradiol and vehicle were administered daily for 6 weeks before training in the Morris water maze (MWM) test. Scopolamine (2 mg/kg) was injected 30 min before training in the MWM test. Results In the MWM, the escape latency and traveled path to find the platform in the Sco group was prolonged compared to the control group (p < 0.001). Treatment by higher doses of soy improved performances of the rats in the MWM (p < 0.05 - p < 0.001). However, treatment with both doses of estradiol (20 and 60 µg/kg) resulted in a statistically significant improvement in the MWM (p < 0.01 - p < 0.001). Cortical, hippocampal and serum levels of malondialdehyde (MDA), as an index of lipid peroxidation, were increased which was prevented by soy extract and estradiol (p < 0.001). Cortical, hippocampal as well as serum levels of the total thiol, superoxide dismutase (SOD) and catalase (CAT) in Sco group were lower than the control group (p < 0.001) while they were enhanced when the animals were treated by soy extract and estradiol (p < 0.01 - p < 0.001). Conclusions It was observed that both soy extract and estradiol prevented learning and memory impairments induced by scopolamine in ovariectomized rats. These effects can be attributed to their protective effects on oxidative damage of the brain tissue.

The effects of exercise on depressive- and anxiety-like behaviors as well as lung and hippocampus oxidative stress in ovalbumin-sensitized juvenile rats.

Allergic asthma during early life period has been reported to be associated with neurochemical and behavioral disorders, including anxiety and depression. We aimed to determine the effects of exercise on depressive- and anxiety-like behaviors as well as lung and hippocampus oxidative stress in ovalbumin (OVA)-sensitized juvenile rats. Animals were divided into 4 groups including control (non-exercised and non-sensitized), Exe (exercise and non-sensitized); OVA (non-exercised and OVA-sensitized); and OVA+Exe (exercised and OVA-sensitized). The rats were subjected to chronic OVA sensitization followed by 4 weeks of treadmill exercise training. Compared to the control group, the OVA group had an increase in anxiety- and depressive-like behavior, lung inflammation, and oxidative stress index in the lung and hippocampus. Compared to the OVA group, the OVA+Exe group had a decline in anxiety- and depressive-like behavior, lung inflammation, and oxidative stress index in the lung and hippocampus. No significant difference in terms of the above-mentioned parameters, were found between the control group and the Exe group. Exercise decreased depressive- and anxiety-like behaviors in OVA-sensitized juvenile rats; this effect might have been mainly mediated by improvement in antioxidant system.

Smooth muscle relaxant activity of Crocus sativus (saffron) and its constituents: possible mechanisms.

Saffron, Crocus sativus L. (C. sativus) is rich in carotenoids and used in traditional medicine for treatment of various conditions such as coughs, stomach disorders, amenorrhea, asthma and cardiovascular disorders. These therapeutic effects of the plant are suggested to be due to its relaxant effect on smooth muscles. The effect of C. sativus and its constituents on different smooth muscles and the underlying mechanisms have been studied. Several studies have shown the relaxant effects of C. sativus and its constituents including safranal, crocin, crocetin and kaempferol on blood vessels. In addition, it was reported that saffron stigma lowers systolic blood pressure. The present review highlights the relaxant effects of C. sativus and its constituents on various smooth muscles. The possible mechanisms of this relaxing effect including activation of ß2-adrenoceptors, inhibition of histamine H1 and muscarinic receptors and calcium channels and modulation of nitric oxide (NO) are also reviewed.

Effects of voluntary and treadmill exercise on spontaneous withdrawal signs, cognitive deficits and alterations in apoptosis-associated proteins in morphine-dependent rats.

Chronic exposure to morphine results in cognitive deficits and alterations of apoptotic proteins in favor of cell death in the hippocampus, a brain region critically involved in learning and memory. Physical activity has been shown to have beneficial effects on brain health. In the current work, we examined the effects of voluntary and treadmill exercise on spontaneous withdrawal signs, the associated cognitive defects, and changes of apoptotic proteins in morphine-dependent rats. Morphine dependence was induced through bi-daily administrations of morphine (10mg/kg) for 10 days. Then, the rats were trained under two different exercise protocols: mild treadmill exercise or voluntary wheel exercise for 10 days. After exercise training, their spatial learning and memory and aversive memory were examined by a water maze and by an inhibitory avoidance task, respectively. The expression of the pro-apoptotic protein Bax and the anti-apoptotic protein Bcl-2 in the hippocampus were determined by immunoblotting. We found that chronic exposure to morphine impaired spatial and aversive memory and remarkably suppressed the expression of Bcl-2, but Bax expression remained constant. Both voluntary and treadmill exercise alleviated memory impairment, increased the expression of Bcl-2 protein, and only the later suppressed the expression of Bax protein in morphine-dependent animals. Moreover, both exercise protocols diminished the occurrence of spontaneous morphine withdrawal signs. Our findings showed that exercise reduces the spontaneous morphine-withdrawal signs, blocks the associated impairment of cognitive performance, and overcomes morphine-induced alterations in apoptotic proteins in favor of cell death. Thus, exercise may be a useful therapeutic strategy for cognitive and behavioral deficits in addict individuals.