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Eur J Pharmacol [journal]
- Neuroprotective effect of curcumin on okadaic acid induced memory impairment in mice. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 May 16.
Okadaic acid (OKA) has been observed to cause memory impairment in human subjects having seafood contaminated with dinoflagellate (Helicondria okadai). OKA induces tau hyperphosphorylation and oxidative stress leading to memory impairment as our previous study has shown. Curcumin a natural antioxidant has demonstrated neuroprotection in various models of neurodegeneration. However, the effect of Curcumin has not been explored in OKA induced memory impairment. Therefore, present study evaluated the effect of Curcumin on OKA (100ng, intracerebrally) induced memory impairment in male Swiss albino mice as evaluated in Morris water maze (MWM) and passive avoidance tests (PAT). OKA administration resulted in memory impairment with a decreased cerebral blood flow (CBF) (measured by laser doppler flowmetry), ATP level and increased mitochondrial (Ca(2+))i, neuroinflammation (increased TNF-α, IL-1β, COX-2 and GFAP), oxidative-nitrosative stress, increased caspase-9 and cholinergic dysfunction (decreased AChE activity/expression and α7 nicotinic acetylcholine receptor expression) in cerebral cortex and hippocampus of mice brain. Oral administration of Curcumin (50mg/kg) for 13 days significantly improved memory function in both MWM and PAT along with brain energy metabolism, CBF and cholinergic function. It decreased mitochondrial (Ca(2+))i, and ameliorated neuroinflammation and oxidative-nitrostative stress in different brain regions of OKA treated mice. Curcumin also inhibited astrocyte activation as evidenced by decreased GFAP expression. This neuroprotective effect of Curcumin is due to its potent anti-oxidant action thus confirming previous studies. Therefore, use of Curcumin should be encouraged in people consuming sea food (contaminated with dinoflagellates) to prevent cognitive impairment.
- Topically applied substance P enhanced healing of open excision wound in rats. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 May 15.
Significant social and financial burden due to wounds need newer drugs/formulations to speed up the healing process. Substance P (SP), a Neuropeptide, is associated with release of various cytokines and growth factors from inflammatory, epithelial and endothelial cells. In the present study, temporal effects of topically applied SP (10(-7)M in normal saline) were evaluated in the modulation of various cytokines and growth factors that participate in cutaneous wound healing. Gross examination of full thickness open excision wound in rats revealed that once daily topical application of SP significantly increased the wound closure, as compared to control group. SP treatment significantly increased tumor necrosis factor- α (TNF-α) and decreased interleukin 10 (IL-10) levels on day 3. On the contrary, on day 7 level of TNF-α decreased and that of IL-10 increased. The mRNA and protein expressions of vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) increased on days 3 and 7, and decreased on day 14 in SP-treated wounds. Histopathological evaluation of hematoxylin and eosin stained wound sections showed that SP treatment produced increased early leukocytes infiltration, fibroblast proliferation, angiogenesis, collagen deposition and re-epithelialization. Results of the present study demonstrate that topical application of SP enhanced wound healing by modulating cytokines, growth factors and cells. Based on the results, it is suggested that SP could be of beneficial use in diabetic wounds where levels of VEGF, TGF-β1 and SP decrease along with impairment of inflammatory reaction.
- Sprengerinin C exerts anti-tumorigenic effects in hepatocellular carcinoma via inhibition of proliferation and angiogenesis and induction of apoptosis. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 May 15.
The multi-targeted therapy for liver cancer has been considered as a novel strategy to fight hepatocellular carcinoma. In this study, we first found that sprengerinin C, a naturally derived compound strongly suppressed tumor angiogenesis on human umbilical vein endothelial cells. Mechanism study revealed that sprengerinin C blocked vascular endothelial growth factor receptor 2-dependent phosphoinositide 3-kinase/Akt/mTOR/matrix metalloproteinase and p38 MAPK/matrix metalloproteinase pathways, two major pathways for tumor angiogenesis. Moreover, sprengerinin C inhibited vascular endothelial growth factor release, a vital event for early angiogenesis response, from hypoxic HepG-2/BEL7402 cells by suppressing hypoxia-inducible factor-1α transcriptional activity. Furthermore, sprengerinin C induced HepG-2/BEL7402 cell apoptosis by activating NADPH oxidase/reactive oxygen species-dependent caspase apoptosis pathway and suppressed HepG-2/BEL7402 cell growth through p53-mediated G2/M-phase arrest. Sprengerinin C also showed significant anti-tumor effect in the nude mouse xenograft model of human hepatocellular carcinoma. These results provide new insights into development of potent candidate compounds for liver cancer through affecting multiple tumor progression steps of angiogenesis, apoptosis and proliferation.
- Riluzole attenuates excitatory amino acid transporter type 3 activity in Xenopus oocytes via protein kinase C inhibition. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 May 13.
This study aimed to evaluate the effect of riluzole on the activity of excitatory amino acid transporter type 3 (EAAT3), a neuronal glutamate transporter, and to investigate the role of protein kinase C (PKC) in this effect. EAAT3 expression was induced in Xenopus oocytes by injecting EAAT3 mRNA. Using the two-electrode voltage clamping method, membrane currents were recorded before, during, and after applying l-glutamate (30μM) in the absence and presence of prior incubation with riluzole (0.3-100μM). To study the effect of PKC on the riluzole-induced change in EAAT3 activity, oocytes were preincubated with 100μM phorbol-12-myristate-13-acetate (PMA), a PKC activator, or PKC inhibitors (2µM staurosporine and 100µM chelerythrine) before the recording. Responses were quantified by integrating current traces and are reported in microCoulombs (μC). Riluzole reduced EAAT3 activity in a concentration-dependent manner (0.3-100μM). Treatment of oocytes with PMA significantly increased the baseline and riluzole-reduced EAAT activity (P<0.05). In addition, treatment of oocytes with PKC inhibitors reduced basal transporter currents, but did not show a further significant decrease in the riluzole-reduced EAAT3 activity. These results suggest that riluzole reduces EAAT3 activity through PKC inhibition.
- Involvement of N-methyl-d-aspartate glutamate receptor and nitric oxide in cardiovascular responses to dynamic exercise in rats. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 May 14.
Dynamic exercise evokes sustained cardiovascular responses, which are characterized by arterial pressure and heart rate increases. Although it is well accepted that there is central nervous system mediation of cardiovascular adjustments during exercise, information on the role of neural pathways and signaling mechanisms is limited. It has been reported that glutamate, by acting on NMDA receptors, evokes the release of nitric oxide through activation of neuronal nitric oxide synthase (nNOS) in the brain. In the present study, we tested the hypothesis that NMDA receptors and nNOS are involved in cardiovascular responses evoked by an acute bout of exercise on a rodent treadmill. Moreover, we investigated possible central sites mediating control of responses to exercise through the NMDA receptor-nitric oxide pathway. Intraperitoneal administration of the selective NMDA glutamate receptor antagonist dizocilpine maleate (MK-801) reduced both the arterial pressure and heart rate increase evoked by dynamic exercise. Intraperitoneal treatment with the preferential nNOS inhibitor 7-nitroindazole reduced exercise-evoked tachycardiac response without affecting the pressor response. Moreover, treadmill running increased NO formation in the medial prefrontal cortex (MPFC), bed nucleus of the stria teminalis (BNST) and periaqueductal gray (PAG), and this effect was inhibited by systemic pretreatment with MK-801. Our findings demonstrate that NMDA receptors and nNOS mediate the tachycardiac response to dynamic exercise, possibly through an NMDA receptor-NO signaling mechanism. However, NMDA receptors, but not nNOS, mediate the exercise-evoked pressor response. The present results also provide evidence that MPFC, BNST and PAG may modulate physiological adjustments during dynamic exercise through NMDA receptor-NO signaling.
- Effect of atorvastatin and methotrexate on solid Ehrlich tumor. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 May 10.
Hydroxymethyl glutaryl CoA reductase is the key enzyme in cholesterol synthesis. A relationship was found between cholesterol and the development of many types of cancer. Atorvastatin is a hypolipidemic drug that may have a role in treatment of cancer. Moreover, atorvastatin was reported to decrease the resistance of cancer cells to many chemotherapeutic agents. The aim of this work was to study the effect of each of methotrexate (MTX) and atorvastatin alone and in combination on solid Ehrlich carcinoma (SEC) in mice. Fifty BALB/c mice were divided into five equal groups: control untreated group, SEC, SEC+MTX, SEC+atorvastatin, SEC+MTX+atorvastatin. Tumor volume, tissue glutathione reductase (GR), catalase, malondialdehyde (MDA), cholesterol and tumor necrosis factor alpha (TNF-α) were determined. A part of the tumor was examined for histopathological and immunohistochemical study. MTX or atorvastatin alone or in combination induced significant increase in tissue catalase and GR with significant decrease in tumor volume, tissue MDA, cholesterol and TNF-α and alleviated the histopathological changes with significant increase in p53 expression and apoptotic index compared to SEC group. In conclusion, the combination of MTX and atorvastatin had a better effect than each of MTX or atorvastatin alone against solid Ehrlich tumor in mice.
- Daidzein inhibits carbohydrate digestive enzymes in vitro and alleviates postprandial hyperglycemia in diabetic mice. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 May 10.
This study was designed to investigate whether daidzein inhibits α-glucosidase and α-amylase activities and alleviates postprandial hyperglycemia in streptozotocin-induced diabetic mice. Daidzein showed prominent inhibitory effects against α-glucosidase and α-amylase. The IC50 values of daidzein against α-glucosidase and α-amylase were 0.048 and 0.301mmol, respectively, which showed that daidzein was more effective than acarbose. The increase in postprandial blood glucose levels was more significantly suppressed in the daidzein-administered group than in the water group of both streptozotocin-induced diabetic and normal mice. Moreover, the area under the curve was significantly lowered following daidzein administration (2043 versus 2475mmolminl) in the streptozotocin-induced diabetic mice. These results indicated that daidzein may be a potent α-glucosidase inhibitor and suppress the postprandial hyperglycemia caused by starch.
- Time course of the effects of lipopolysaccharide on prepulse inhibition and brain nitrite content in mice. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 May 9.
The systemic administration of lipopolysaccharide (LPS) induces time-dependent behavioral alterations, which are related to sickness behavior and depression. The time-course effects of LPS on prepulse inhibition (PPI) remain unknown. Furthermore, the time-dependent effects of LPS on central nitrite content had not been investigated. Therefore, we studied alterations induced by single LPS (0.5mg/kg, i.p.) administration to mice on parameters, such as PPI, depressive- and anxiety-like behaviors, working memory, locomotor activity and motor coordination, 1.5 and 24h post-LPS administration. IL-1β and TNFα in the blood and brain as well as brain nitrite levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST). An overall hypolocomotion was observed 1.5h post-LPS, along with depressive-like behaviors and deficits in working memory. Increments in IL-1β content in plasma and PFC, TNFα in plasma and decreases in nitrite levels in the ST and PFC were also verified. Twenty-four hours post-LPS treatment, depressive-like behaviors and working memory deficits persisted, while PPI levels significantly reduced along with increases in IL-1β content in the PFC and a decrease in nitrite levels in the HC, ST and PFC. Our data demonstrate that a delayed increase (i.e., 24h post-LPS) in PPI levels ensue, which may be useful behavioral parameter for LPS-induced depression. A decrease in nitrergic neurotransmission was associated with these behavioral findings.
- Synergistic, but not separate, stimulation of accumbal β1- and β2-adrenoceptors alters the accumbal dopamine efflux in freely moving rats. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 May 9.
The effects of intra-accumbal infusion of selective agonists for the β-adrenoceptor subtypes on the noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats were investigated, using in vivo microdialysis. Neither β1-(dobutamine: 0.06 and 0.12pmol) nor β2-adrenoceptor agonist (salbutamol: 0.36 and 3.6pmol) altered the basal noradrenaline and dopamine efflux in the nucleus accumbens. Co-administration of 0.06pmol of dobutamine with salbutamol (3.6pmol) did not affect the noradrenaline levels, but it increased the dopamine efflux to approximately 120%. Co-administration of 0.12pmol of dobutamine with salbutamol (0.36 or 3.6pmol) also increased DA efflux to approximately 120% without affecting noradrenaline levels. The non-selective β-adrenoceptor antagonist l-propranolol (1200pmol) that did not alter the basal noradrenaline and dopamine levels, suppressed the dopamine efflux, induced by co-administration of dobutamine (0.12pmol) and salbutamol (3.6pmol). The doses mentioned are the total amount of drug over the 60-min infusion period. The present results support our previously reported conclusion that stimulation of accumbal β-adrenoceptors which are suggested to be postsynaptically located on accumbal dopaminergic terminals, can enhance the dopamine efflux in the nucleus accumbens. The present study also provides in vivo neurochemical evidence that concomitant, but not separate, activation of accumbal β1- and β2-adrenoceptors synergistically increases the accumbal dopamine efflux.
- Up-regulation of monoamine oxidase activity in the striatum of rats following chronic treatment of thienorphine. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 May 9.
Thienorphine is a new, non-selective partial agonist of opioid receptors. In our previous study using microdialysis, thienorphine persistently increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of rats, without affecting the level of dopamine. This finding suggested that monoamine oxidase (MAO) activity in the striatum of rats increased by chronic thienorphine treatment. In the present study, we investigated whether chronic treatment of thienorphine affected MAO activity in the striatum of rats compared with morphine. Rats were treated subcutaneously (three times/day) with either saline (control), morphine, thienorphine, or a pre-treatment of thienorphine followed by morphine, for 3 or 5 continuous days. A 20-min naloxone challenge given to a sub-group of animals from each group occurred at the end of their 5-day treatment. The results showed that repeated administration of thienorphine significantly elevated MAO activity in the striatum, thus restoring MAO activity, which was inhibited by chronic morphine treatment. These results suggest that increased activity of MAO in the striatum may accelerate the metabolism of dopamine, leading to the elevations of DOPAC and HVA. Furthermore, these findings implicate the involvement of MAO in the pharmacological characteristics of thienorphine.