title: 1-Phenil-6,7-dihydroxy-isochroman inhibits inflammatory activation of microglia.
abstract: Inflammation plays a central role in the pathogenesis of several brain disorders and neuronal injury, and it develops as a consequence of glial cell activation. Activated microglial cells generate potentially damaging nitric oxide, oxygen free radicals, prostanoids, and pro-inflammatory cytokines. Naturally occurring polyphenols have recently received attention for their potential protective effect on neurodegenerative disorders characterized by microglial activation, due to their anti-inflammatory and antioxidant properties. In the present study, we investigated, using an in vitro model of primary microglia, the ability of 1-phenyl-6,7-dihydroxy-isochroman (encoded L 137), a natural polyphenolic compound, to inhibit microglia activation induced by an inflammatory insult. So, L137 effects (1-100 μM) on production of pro-inflammatory mediators in lipopolysaccharide (LPS)-activated microglial cells were evaluated. The expression of inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) as well as of the nuclear transcription Factor-kappa B (NF-κB) was also performed in cellular lysates by Immunoblot. L137 significantly reduced tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 secretion, as well as nitric oxide (NO) and prostanoids [Thromboxane (TX)B2, prostaglandin (PG)E2] production in activated microglial cells. Western blot analyses showed an inhibitory effect of L137 on the iNOS and COX-2 expression, mediated by a modulation of redox-sensitive nuclear transcriptional factor (NF)-κB, known to control a wide array of genes involved in inflammation. In conclusion, this study demonstrate that L137 is able to inhibit the production of pro-inflammatory and neurotoxic mediators by LPS-activated microglial cells thus suggesting L137 as a potential lead compound for drug development for neurodegenerative disorders where microglia-mediated inflammatory responses play an important pathogenic role.
authors.affiliation: Department of Physiology and Pharmacology Vittorio Erspamer, Italy.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Togna
authors.forename: Valentina
authors.initials: V
authors.lastname: Latina
authors.forename: Giuliana
authors.initials: G
authors.lastname: Trefiletti
authors.forename: Marcella
authors.initials: M
authors.lastname: Guiso
authors.forename: Sabina
authors.initials: S
authors.lastname: Moschini
authors.forename: Giuseppina I
authors.initials: GI
authors.lastname: Togna
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C477354:1-phenyl-6,7-dihydroxy-isochroman; D000893:Anti-Inflammatory Agents; D002839:Chromans; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone