Nimesulide limits kainate-induced oxidative damage in the rat hippocampus

Kainate induces a marked expression of cyclooxygenase-2 after its systemic administration. Because cyclooxygenase-2 activity is associated to the production of reactive oxygen species, we investigated the effects of nimesulide, a selective cyclooxygenase-2 inhibitor, on kainate-induced in vivo oxidative damage in the rat hippocampus. A clinically relevant dose of nimesulide (6 mg/kg, i.p. ) was administered three times following kainate application (9 mg/kg, i.p.). After 24 h of kainate administration, the drastic decrease in hippocampal glutathione content and the significant increase in lipid peroxidation were attenuated in nimesulide-treated rats, suggesting that the induction of cyclooxygenase-2 is involved in kainate-mediated free radicals formation

Cyclooxygenase-2 inhibitors. 1,5-diarylpyrrol-3-acetic esters with enhanced inhibitory activity toward cyclooxygenase-2 and improved cyclooxygenase-2/cyclooxygenase-1 selectivity.

he important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diarylpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3- acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain

Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia

Cyclooxygenase-2 is involved in the inflammatory component of the ischemic cascade, playing an important role in the delayed progression of the brain damage. The present study evaluated the pharmacological effects of the selective cyclooxygenase-2 inhibitor nimesulide on delayed neuronal death of hippocampal CA1 neurons following transient global cerebral ischemia in gerbils. Administration of therapeutically relevant doses of nimesulide (3, 6 and 12 mg/kg; i.p.) 30 min before ischemia and at 6, 12, 24, 48 and 72 h after ischemia significantly (P<0.01) reduced hippocampal neuronal damage. Treatment with a single dose of nimesulide given 30 min before ischemia also resulted in a significant increase in the number of healthy neurons in the hippocampal CA1 sector 7 days after ischemia. Of interest is the finding that nimesulide rescued CA1 pyramidal neurons from ischemic death even when treatment was delayed until 24 h after ischemia (34+/-9% protection). Neuroprotective effect of nimesulide is still evident 30 days after the ischemic episode, providing the first experimental evidence that cyclooxygenase-2 inhibitors confer a long-lasting neuroprotection. Oral administration of nimesulide was also able to significantly reduce brain damage, suggesting that protective effects are independent of the route of administration. The present study confirms the ability of cyclooxygenase-2 inhibitors to reduce brain damage induced by cerebral ischemia and indicates that nimesulide can provide protection when administered for up to 24 h post-ischemia

Antioxidant activity of Piper caninum and Cyclooxygenase-2 inhibition by methoxylated flavones.

Background: This study investigated on antioxidant activity of Piper caninum and cyclooxygenase-2 inhibition by methoxylated flavones.Materials and methods: The present study was carried out to quantify the total phenolic content and free radical scavenging activities of the crude extracts by Folin-Ciocalteu and 1,1-diphenyl-2-picrylhydrazyl free radical scavenging assay respectively.Results: Methanolic extracts of Piper caninum exhibited the highest total phenolic content and free radical scavenging activities. All the pure compounds possessed significant cyclooxygenase-2 inhibition at physiological concentrations.Conclusion: Based on in vitro and molecular docking, we therefore suggest that Piper caninum methoxylated flavones are potent inhibitors of cyclooxygenase-2 at physiological concentrationsKey words: Piper caninum; antioxidant; cyclooxygenase-2.List of abbreviations: COX-2, cyclooxygenase-2; DPPH, 2,2-diphenyl- 1-picrylhydrazyl; PGE2, prostaglandin E2

Cyclooxygenase-2 and prostaglandins in human endometrial function

A role for cyclooxygenase enzymes and prostaglandins (such as prostaglandin E2) has been observed in benign endometrial pathologies (endometriosis, excessive blood loss and dysmenorrhoea) and in adenocarcinoma. Cyclooxygenase and prostaglandin E synthase enzymes catalyse the conversion of arachidonic acid to prostaglandin E2. Once synthesised, prostaglandin E2 mediates its effects via four G protein coupled receptors namely EP1, EP2, EP3 and EP4. These receptors signal via alternate and sometimes opposing pathways. The initial aim of the research presented in this thesis was to investigate the temporal expression and signalling of the prostaglandin E2 pathway in the normal human endometrium across the menstrual cycle. Prostaglandin E synthase and prostaglandin E2 were localised to glandular epithelial and endothelial cells. Similarly, expression of the prostaglandin E2 receptors, namely EP2 and EP4, was temporally up regulated and co-localised to the glandular and vascular compartments. This was associated with enhanced cAMP turnover in response to exogenous prostaglandin E2. In order to investigate further the role of cyclooxygenase-2 and prostaglandin E2 in glandular epithelial cells we generated a stably transfected endometrial epithelial cell line (Ishikawa) overexpressing cyclooxygenase-2 in either the sense or antisense directions. Using these cell lines we observed enhanced secretion of prostaglandins E2 and F2tt into the culture media of the cyclooxygenase-2 sense cells compared with the cyclooxygenase-2 antisense and wild type cells in response to exogenous arachidonic acid. Co-incubation of the cells with NS398 (specific cyclooxygenase-2 inhibitor) abolished the increase in prostaglandin synthesis. Overexpression of cyclooxygenase-2 was accompanied with significantly elevated EP2/EP3 receptor expression. No differences were detected for EP1, EP4 and FP receptors. These results indicate a possible autocrine/paracrine action of cyclooxygenase-2 enzyme products on expression of prostanoid receptors such as EP2/EP3. During the course of my PhD, numerous reports were published implicating cyclooxygenase-2 and its products in angiogenesis through the expression of angiogenic factors such as vascular endothelial growth factor, basic fibroblast growth factor and angiopoietins. To investigate the potential role of cyclooxygenase-2 in regulation of endometrial angiogenesis, cDNA array technology was employed to identify differentially expressed genes that may be involved in vascular function. Using this technique, a total of 81 genes were differentially regulated including cathepsin D. Cathepsin D mRNA and protein expression were elevated in the cyclooxygenase-2 antisense cells compared with the sense and wild type cells. Cathepsin D is known to proteolytically cleave plasminogen to the antiangiogenic factor angiostatin. Hence, we investigated the generation of angiostatin from plasminogen in conditioned media collected from cyclooxygenase-2 sense, cyclooxygenase-2 antisense and wild type cells. The cleavage of angiostatin from plasminogen was markedly enhanced in conditioned media from cyclooxygenase-2 antisense cells compared with cyclooxygenase-2 sense and wild type cells. Co-incubation of plasminogen with pepstatin A, a selective cathepsin D inhibitor, markedly reduced the cleavage of angiostatin from plasminogen thus further implicating cathepsin D in the differential angiostatin production by the cyclooxygenase-2 sense and antisense cell lines.In conclusion data presented in this thesis outline the temporal regulation of prostaglandin E2 receptor expression and signalling in the human endometrium.Moreover, we report a novel role for cyclooxygenase-2 in promoting angiogenesis through suppression of production of antiangiogenic factors such as angiostatin. The elevated expression of cyclooxgenase-2 observed in numerous endometrial pathologies may therefore play a crucial role in regulation of angiogenesis through expression of pro-angiogenic genes and inhibition of production of anti-angiogenic factors

Cyclooxygenase-2 immunoexpression in breast cancer : progesterone receptor influence

In breast cancer cyclooxygenase-2 expression is related with high local estrogen receptor levels and consequent poor outcomes, but the clinical relevance of cyclooxygenase-2 is still unclear. We analyzed, by immunostaining, cyclooxygenase-2 and progesterone receptor expression in 31 cases of women with invasive ductal carcinoma, from Child and Women department of Cova da Beira Medical Center. Cyclooxygenase-2 and progesterone receptor expression was observed in 64.5% and 54.8% of the tumors, respectively. We verified that tumors with progesterone receptor expression had lower size and the majority of women with these tumors had no axillary node metastasis, when compared to tumors with positive progesterone receptor. Similar results were found when a correlation between progesterone receptor, cyclooxygenase-2 and clinicopathological factors was performed. These results suggest that progesterone receptor has a protective role in breast cancer by inflammatory pathway modulation. COX-2+/PR+ seems to be a marker of better behavior in ductal invasive breast cancer. We speculate if cyclooxygenase-2 determination may have be a clinical usefulness in clinical practice. It’s expected that further studies may clarify this issue

Expression of cyclooxygenase-2 (COX-2) in tumour and stroma compartments in cervical cancer: clinical implications

This study aims at investigating the relationship between cyclooxygenase-2 expression in tumour vs stroma inflammatory compartment and its possible clinical role. The study included 99 stage IB-IV cervical cancer patients: immunostaining of tumour tissue sections was performed with rabbit antiserum against cyclooxygenase-2. CD3, CD4, CD8, CD25, Mast Cell Tryptase monoclonal antibodies were used to characterise stroma inflammatory cells in nine cervical tumours. An inverse relation was found between cyclooxygenase-2 levels (cyclooxygenase-2 IDV) of tumour vs stroma compartment (r=−0.44, P<0.0001). The percentage of cases showing high tumour/stromal cyclooxygenase-2 IDV ratio was significantly higher in patients who did not respond to treatment (93.3%) with respect to patients with partial (60.5%), and complete (43.7%) response (P= 0.009). Cases with a high tumour/stroma cyclooxygenase-2 IDV ratio had a shorter overall survival rate than cases with a low tumour/stroma cyclooxygenase-2 IDV (P<0.0001). In the multivariate analysis advanced stage and the status of tumour/stroma cyclooxygenase-2 IDV ratio retained an independent negative prognostic role. The proportion of CD3+, CD4+, and CD25+ cells was significantly lower in tumours with high tumour/stroma cyclooxygenase-2 IDV ratio, while a higher percentage of mast cells was detected in tumours showing high tumour/stroma cyclooxygenase-2 IDV ratio. Our study showed the usefulness of assessing cyclooxygenase-2 status both in tumour and stroma compartment in order to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant therapy and unfavourable prognosis

Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine : novel explanation of cardiovascular side effects associated with anti-inflammatory drugs

© 2014 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.BACKGROUND: Cardiovascular side effects associated with cyclooxygenase-2 inhibitor drugs dominate clinical concern. Cyclooxygenase-2 is expressed in the renal medulla where inhibition causes fluid retention and increased blood pressure. However, the mechanisms linking cyclooxygenase-2 inhibition and cardiovascular events are unknown and no biomarkers have been identified.METHODS AND RESULTS: Transcriptome analysis of wild-type and cyclooxygenase-2(-/-) mouse tissues revealed 1 gene altered in the heart and aorta, but >1000 genes altered in the renal medulla, including those regulating the endogenous nitric oxide synthase inhibitors asymmetrical dimethylarginine (ADMA) and monomethyl-l-arginine. Cyclo-oxygenase-2(-/-) mice had increased plasma levels of ADMA and monomethyl-l-arginine and reduced endothelial nitric oxide responses. These genes and methylarginines were not similarly altered in mice lacking prostacyclin receptors. Wild-type mice or human volunteers taking cyclooxygenase-2 inhibitors also showed increased plasma ADMA. Endothelial nitric oxide is cardio-protective, reducing thrombosis and atherosclerosis. Consequently, increased ADMA is associated with cardiovascular disease. Thus, our study identifies ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction with nonsteroidal anti-inflammatory drug usage.CONCLUSIONS: We identify the endogenous endothelial nitric oxide synthase inhibitor ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction.Peer reviewedFinal Published versio