The natural dual cyclooxygenase and 5-lipoxygenase inhibitor flavocoxid is protective in EAE through effects on Th1/Th17 differentiation and macrophage/microglia activation

Kong, Weimin; Hooper, Kirsten M.; Ganea, Doina

doi:10.1016/j.bbi.2015.11.002

Cited by 45 publications

(33 citation statements)

References 43 publications

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“…Thus, COX-2 and 5-LOX inhibitors seem to possess the greatest potential anti-inflammatory effect in human fetal microglia. This confirms the importance of these enzymes in regulating proinflammatory responses in certain inflammatory conditions, including some neurodegenerative diseases (Phillis et al, 2006; Hwang et al, 2013; Palumbo and Bosetti, 2013; Kong et al, 2016). Based on our results, it seems that these enzymes exert similar beneficial anti-inflammatory effects during the early stage of glial cell development.…”

Section: Discussionsupporting

confidence: 68%

The Anti-Inflammatory Effects of Lipoxygenase and Cyclo-Oxygenase Inhibitors in Inflammation-Induced Human Fetal Glia Cells and the Aβ Degradation Capacity of Human Fetal Astrocytes in an Ex vivo Assay

2017

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Chronic inflammation is a common phenomenon present in the background of multiple neurodegenerative diseases, including Alzheimer's disease (AD). The arachidonic acid pathway overproduces proinflammatory eicosanoids during these states and glial cells in the brain gradually lose their vital functions of protecting and supporting neurons. In this study, the role of different key enzymes of the eicosanoid pathway mediating inflammatory responses was examined in vitro and ex vivo using human fetal glial cells. Astrocytes and microglia were exposed to proinflammatory agents i.e., cytokines interleukin 1-β (IL-1β) and tumor necrosis factor (TNF-α). ELISA assays were used to examine the effects of inhibitors of key enzymes in the eicosanoid pathway. Inhibitors for 5-lipoxygenase (5-LOX) and cyclo-oxygenase 2 (COX-2) in both cell types and 5-, 12-, and 15-LOX-inhibitor in astrocytes reduced significantly IL-6 secretion, compared to exposed glial cells without inhibitors. The cytokine antibody array showed that especially treatments with 5, -12, and -15 LOX inhibitor in astrocytes, 5-LOX inhibitor in microglia and COX-2 inhibitor in both glial cell types significantly reduced the expression of multiple proinflammatory cytokines. Furthermore, human fetal astrocytes and microglia were cultured on top of AD-affected and control human brain sections for 30 h. According to the immunochemical evaluation of the level of total Aβ, astrocytes were very efficient at degrading Aβ from AD-affected brain sections ex vivo; simultaneously added enzyme inhibitors did not increase their Aβ degradation capabilities. Microglia were not able to reduce the level of total Aβ during the 30 h incubation time.

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Section: Discussionsupporting

confidence: 68%

The Anti-Inflammatory Effects of Lipoxygenase and Cyclo-Oxygenase Inhibitors in Inflammation-Induced Human Fetal Glia Cells and the Aβ Degradation Capacity of Human Fetal Astrocytes in an Ex vivo Assay

2017

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“…Furthermore, this botanically based mixture appears to exert a protective action in cadmium‐induced testicular toxicity and gentamicin‐induced nephrotoxicity . Finally, flavocoxid exhibited neuroprotective effects in rodent models of cerebral ischemia, autoimmune encephalomyelitis, and brain injury …”

Section: Identification Of Novel Targets In the Arachidonic Acid Cascadementioning

confidence: 98%

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Pereira-Leite

Nunes

Jamal

et al. 2016

Medicinal Research Reviews

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The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy.

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“…In fact, Arg1 is the most-significantly up-regulated gene in the CNS at peak EAE 28 . Adoptive transfer of AAMC- polarized macrophages or microglia can ameliorate EAE 29,30 , and the therapeutic effects of estrogen, glatiramer acetate and other agents in EAE were found to correlate with the expansion of AAMC in the periphery and/or CNS 31–34 . Less is known about endogenous AAMC that spontaneously accumulate in the CNS during the course of EAE or MS.…”

Section: Introductionmentioning

confidence: 99%

Myeloid cell plasticity in the evolution of central nervous system autoimmunity

Giles

Washnock-Schmid

Duncker

et al. 2018

Annals of Neurology

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These observations demonstrate the heterogeneity of CNS myeloid cells, their evolution during the course of autoimmune demyelinating disease, and their plasticity on the single cell level. Future therapeutic strategies for disease modification in individuals with MS may be focused on accelerating the transition of CNS myeloid cells from a proinflammatory to a noninflammatory phenotype. Ann Neurol 2018;83:131-141.

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The natural dual cyclooxygenase and 5-lipoxygenase inhibitor flavocoxid is protective in EAE through effects on Th1/Th17 differentiation and macrophage/microglia activation

Cited by 45 publications

References 43 publications

The Anti-Inflammatory Effects of Lipoxygenase and Cyclo-Oxygenase Inhibitors in Inflammation-Induced Human Fetal Glia Cells and the Aβ Degradation Capacity of Human Fetal Astrocytes in an Ex vivo Assay

The Anti-Inflammatory Effects of Lipoxygenase and Cyclo-Oxygenase Inhibitors in Inflammation-Induced Human Fetal Glia Cells and the Aβ Degradation Capacity of Human Fetal Astrocytes in an Ex vivo Assay

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Myeloid cell plasticity in the evolution of central nervous system autoimmunity

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