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COX Isoforms (cox + isoform)
Selected AbstractsDopaminergic neurotoxicity by 6-OHDA and MPP+: Differential requirement for neuronal cyclooxygenase activityJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2005Emilce Carrasco Abstract Cyclooxygenase (COX), a key enzymatic mediator of inflammation, is present in microglia and surviving dopaminergic neurons in Parkinson's disease (PD), but its role and place in the chain of neurodegenerative events is unclear. Epidemiologic evidence showed that regular use of nonsteroidal antiinflammatory drugs (NSAIDs), specifically non-aspirin COX inhibitors like ibuprofen, lowers the risk for PD; however, the putative cause-and-effect relationship between COX activity in activated microglia and neuronal loss was challenged recently. We examined whether neuronal COX activity is involved directly in dopaminergic cell death after neurotoxic insult. Using low concentrations of 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridium ion (MPP+), neurotoxicants used to model selective dopaminergic cell loss in PD, and cultures of embryonic rat mesencephalic neurons essentially devoid of glia, we tested whether the nonselective COX inhibitor ibuprofen attenuated 6-OHDA and MPP+ neurotoxicity. At levels close to its IC50 for both COX isoforms, ibuprofen protected dopaminergic neurons against 6-OHDA but not MPP+ toxicity. Experiments with selective inhibitors of COX-1 (SC-560) and COX-2 (NS-398 and Cayman 10404), indicated that COX-2, but not COX-1, was involved in 6-OHDA toxicity. Accordingly, 6-OHDA, but not MPP+, increased prostaglandin (PG) levels twofold and this increase was blocked by ibuprofen. At concentrations well above its IC50 for COX, ibuprofen also prevented MPP+ toxicity, but had only limited efficacy against loss of structural complexity. Taken together, our data suggest that selective 6-OHDA toxicity to dopaminergic neurons is associated with neuronal COX-2, whereas MPP+ toxicity is COX independent. This difference may be important for understanding and manipulating mechanisms of dopaminergic cell death. © 2005 Wiley-Liss, Inc. [source] The Coxib NSAIDs: Potential Clinical and Pharmacologic Importance in Veterinary MedicineJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2005Mary Sarah Bergh Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to control acute and chronic pain as well as to manage oncologic and neurologic diseases in human and veterinary patients. Despite ongoing research and efforts to improve the safety and efficacy of existing drugs, adverse effects such as gastrointestinal irritation, renal and hepatic toxicity, interference with hemostasis, and reproductive problems persist. The true incidence of NSAID-induced adverse effects in animals is unknown, but is likely underestimated, because cats and dogs may be more sensitive than humans to NSAIDs due to alterations in drug metabolism, absorption, and enterohepatic recirculation. NSAIDs produce both analgesia and toxic adverse effects primarily by inhibiting cyclooxygenase (COX), thereby decreasing the production of prostaglandins that signal inflammation and pain as well as mediate physiologic functions such as platelet aggregation, gastric protection, and electrolyte balance in the kidney. The presence of at least 2 COX isoforms may account for variability in NSAID efficacy and toxicity both within and among species. This paper reviews and evaluates the published literature on the safety, pharmacology, uses, and complications of a subclass of COX-1,sparing drugs, the coxibs, in veterinary medicine. Coxibs and other COX-1,sparing drugs provide a clinically useful improvement over traditional NSAIDs, but data are incomplete and more in vivo species-specific, target-tissue, and clinical studies are needed. [source] Hit Identification and Biological Evaluation of Anticancer Pyrazolopyrimidines Endowed with Anti-inflammatory ActivityCHEMMEDCHEM, Issue 8 2010Stefano Alcaro Prof. Inhibiting COX: A small library of pyrazolopyriminines endowed with antiproliferative action was submitted to virtual screening against two COX isoforms. Three compounds were identified in silico as potentially selective COX-2 inhibitors. The biological assay confirmed one of them to be a COX-2 inhibitor with potency and selectivity comparable to known drugs. [source] Two inducible, functional cyclooxygenase-2 genes are present in the rainbow trout genomeJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2007Tomo-o Ishikawa Abstract The cyclooxygenases (Cox) catalyze the initial reactions in prostanoid biosynthesis, and produce the common prostanoids precursor, PGH2. Mammalian species have two Cox isoforms; constitutively expressed cyclooxygenase-1 (Cox-1) and inducible cyclooxygenase-2 (Cox-2). Database searches suggest three Cox genes are present in many fish species. In this study, we cloned and characterized a second Cox-2 cDNA, Cox-2b, from the rainbow trout. Rainbow trout Cox-2b protein contains all the functionally important conserved amino acids for Cox enzyme activity. Moreover, the Cox-2b message contains AU-rich elements (AREs) in the 3, untranslated region (3,UTR) characteristic of inducible Cox-2 mRNAs. We took advantage of the existence of a rainbow trout cell line to demonstrate that expression from both the originally reported Cox-2 (Cox-2a) and Cox-2b genes is inducible. However, differential induction responses to alternative inducers are observed for rainbow trout Cox-2a and Cox-2b. Both Cox-2a and Cox-2b proteins expressed in COS cells are enzymatically active. Thus the rainbow trout has two functional, inducible Cox-2 genes. The zebrafish also contains two Cox-2 genes. However, genome structure analysis suggests diversion of the Cox-2a gene between zebrafish and rainbow trout. J. Cell. Biochem. 102: 1486,1492, 2007. © 2007 Wiley-Liss, Inc. [source] | ||||||||||