Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome proliferator-activated receptor gamma activation.
In most neurodegenerative disorders, including multiple sclerosis, Parkinson disease, and Alzheimer disease, a massive neuronal cell death occurs as a consequence of an uncontrolled inflammatory response, where activated astrocytes and microglia and their cytotoxic agents play a crucial pathological role. Current treatments for these diseases are not effective. In the present study we investigate the effect of thiadiazolidinone derivatives, which have been recently suggested to play a role in neurodegenerative disorders. We have found that thiadiazolidinones are potent neuroprotector compounds. Thiadiazolidinones inhibited inflammatory activation of cultured brain astrocytes and microglia by diminishing lipopolysaccharide-induced interleukin 6, tumor necrosis factor alpha, inducible nitric-oxide synthase, and inducible cyclooxygenase type 2 expression. In addition, thiadiazolidinones inhibited tumor necrosis factor-alpha and nitric oxide production and, concomitantly, protected cortical neurons from cell death induced by the cell-free supernatant from activated microglia. The neuroprotective effects of thiadiazolidinones are completely inhibited by the peroxisome proliferator-activated receptor gamma antagonist GW9662. In contrast the glycogen synthase kinase 3beta inhibitor LiCl did not show any effect. These findings suggest that thiadiazolidinones potently attenuate lipopolysaccharide-induced neuroinflammation and reduces neuronal death by a mechanism dependent of peroxisome proliferator-activated receptor gamma activation.
Luna-Medina
Rosario
R
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Rutónoma de Madrid, 28029 Madrid, Spain.
Cortes-Canteli
Marta
M
Alonso
Mercedes
M
Santos
Angel
A
Martínez
Ana
A
Perez-Castillo
Ana
A
D000077556:Alitretinoin; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D002474:Cell-Free System; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000737:chemistry / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D019311:Staurosporine / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009573:Nitrites; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077556:Alitretinoin; D018698:Glutamic Acid; D014212:Tretinoin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D019311:Staurosporine