Cyclooxygenase-1 and-2 in the different stages of Alzheimer's disease pathology
ABSTRACT Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta amyloid (Abeta) protein and the formation of neurofibrillary tangles. In addition, there is an increase of inflammatory proteins in the brains of AD patients. Epidemiological studies, indicating that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing AD, have encouraged the study on the role of inflammation in AD. The best-characterized action of most NSAIDs is the inhibition of cyclooxygenase (COX). The expression of the constitutively expressed COX-1 and the inflammatory induced COX-2 has been intensively investigated in AD brain and different disease models for AD. Despite these studies, clinical trials with NSAIDs or selective COX-2 inhibitors showed little or no effect on clinical progression of AD. The expression levels of COX-1 and COX-2 change in the different stages of AD pathology. In an early stage, when low-fibrillar Abeta deposits are present and only very few neurofibrillary tangles are observed in the cortical areas, COX-2 is increased in neurons. The increased neuronal COX-2 expression parallels and colocalizes with the expression of cell cycle proteins. COX-1 is primarily expressed in microglia, which are associated with fibrillar Abeta deposits. This suggests that in AD brain COX-1 and COX-2 are involved in inflammatory and regenerating pathways respectively. In this review we will discuss the role of COX-1 and COX-2 in the different stages of AD pathology. Understanding the physiological and pathological role of cyclooxygenase in AD pathology may facilitate the design of therapeutics for the treatment or prevention of AD.
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ABSTRACT: Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of often chemically unrelated compounds with some common therapeutic actions and side effects. They have potent anti-inflammatory, analgesic and antipyretic activity, and are among the most widely used drugs worldwide. It is generally thought that one of their main mechanisms of action is the inhibition of cyclo-oxygenase (COX), the enzyme responsible for biosynthesing the prostaglandins and thromboxane. NSAIDs are also associated with an increased risk of adverse gastrointestinal, renal and cardiovascular effects. This review describes the clinical pharmacology of NSAIDs, their classification, molecular mechanisms of action and adverse effects, including their possible contribution to neuro-inflammation and carcinogenesis, as well as some recent developments aimed at designing effective anti-inflammatory agents with improved safety and tolerability profiles.Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Cu rrent Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) 08/2012; 11(1):52-64. DOI:10.2174/187152312803476255
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ABSTRACT: Both amyloid-β peptide 1-42 (Aβ1-42) formation and cyclooxygenase-2 (COX-2) have been involved in the pathogenesis of Alzheimer's disease (AD), a devastating neurological disorder. However, the relationship between Aβ1-42 and COX-2 is unclear. We found that the addition of Aβ1-42 to astrocytoma cultures induced COX-2 mRNA and protein and PGE2 synthesis in primary human astrocytes and in human astrocytoma cell lines. Moreover, Aβ1-42 induced COX-2 promoter transcription. Deletion of nuclear factor-κB (NF-κB) sites of the promoter diminished Aβ1-42-COX-2 dependent transcription. In agreement with this, Aβ1-42 induced transcription of NF-κB reporter gene. In contrast, Aβ1-42 neither did not induce NFAT not AP-1 factors activation suggesting that both NFAT and AP-1 was not necessary to control COX-2 transcription induced by Aβ1-42. Over expression of NF-κB inhibitory subunit, IκB, completely abrogated Aβ1-42-induced COX-2 activity in U-87 cells, whereas the opposite effect was shown when p65/rel A NF-κB was over expressed. In addition, Aβ1-42 induced p65/rel A subunit translocation to the nucleus and binding to the distal site of the COX-2 promoter. The importance of NF-κB in COX-2 induction and PGE2 synthesis by Aβ1-42 was corroborated by using the pharmacological inhibitor of the NF-κB pathway, PDTC. In addition, Aβ1-42 treated astrocytoma supernatants were toxic for neuroblastoma cells, an effect which was blocked by PDTC. Summing up, our results indicate that Aβ1-42 was able to induce COX-2 and PGE2 synthesis in astrocytic cells through a NF-κB dependent mechanism. This may have implicated in our understanding of AD pathology.Journal of Alzheimer's disease: JAD 01/2010; 22(2):493-505. DOI:10.3233/JAD-2010-100309 · 3.61 Impact Factor
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ABSTRACT: Overproduction of pro-inflammatory mediators resulting from chronic activation of microglia has been implicated in many neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease. In this study, we investigated the effects of (3R) 1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol, or compound 049 on the production of pro-inflammatory mediators in lipopolysaccharide (LPS)-treated microglia. Compound 049 is a pure compound fractionated from the hexane extract of Curcuma comosa, an indigenous plant of Thailand traditionally used as an anti-inflammatory agent for the treatment of uterine inflammation. It was found that pretreatment of the highly aggressively proliferating immortalized (HAPI), rat microglial cell line, with compound 049, at the concentrations of 0.1, 0.5 and 1microM significantly decreased LPS-induced NO and PGE(2) production in a concentration-dependent manner. Parallel to the decreases in NO and PGE(2) production was a reduction in the expression of inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2) as measured by mRNA and protein levels. These results indicate that compound 049 possesses an anti-inflammatory activity and may have a therapeutic potential for the treatment of neurodegenerative diseases related to microglial activation.Neuroscience Letters 10/2009; 462(2):171-5. DOI:10.1016/j.neulet.2009.06.094 · 2.06 Impact Factor