gw9662 and Neurodegenerative-Diseases

Peroxisomes provide glial cells with protective functions against the harmful effects of H2O2 on neurons and peroxisome impairment results in nervous lesions. Agonists of the γ -subtype of the Peroxisome-Proliferator-Activated-Receptors (PPAR) have been proposed as neuroprotective agents in neurodegenerative disorders. Nevertheless, the role of PPAR- γ alterations in pathophysiological mechanisms and the relevance of peroxisome functions in the PPAR- γ effects are not yet clear. In a primary cell culture of rat astrocytes, the irreversible PPAR- γ antagonist GW9662 concentration-dependently decreased the activity of catalase, the most important antioxidant defense enzyme in peroxisomes. Catalase functionality recovered in a few days and the PPAR- γ agonist rosiglitazone promoted reversal of enzymatic damage. The reversible antagonist G3335 reduced both the activity and expression of catalase in a rosiglitazone-prevented manner. G3335 reduced also the glutathione reductase expression, indicating that enzyme involved in glutathione regeneration was compromised. Neither the PPAR- α target gene Acyl-Coenzyme-A-oxidase-1 nor the mitochondrial detoxifying enzyme NADH:ubiquinone-oxidoreductase (NDFUS3) was altered by PPAR- γ inhibition. In conclusion, PPAR- γ inhibition induced impairment of catalase in astrocytes. A general decrease of the antioxidant defenses of the cell suggests that a PPAR- γ hypofunction could participate in neurodegenerative mechanisms through peroxisomal damage. This series of experiments could be a useful model for studying compounds able to restore peroxisome functionality.

Topics: Anilides; Animals; Antioxidants; Astrocytes; Cells, Cultured; Nerve Tissue Proteins; Neurodegenerative Diseases; Oxidoreductases; Peroxisomes; PPAR alpha; PPAR gamma; Primary Cell Culture; Rats; Rats, Sprague-Dawley

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.

Topics: Alitretinoin; Anilides; Animals; Anti-Inflammatory Agents; Apoptosis; Astrocytes; Brain; Cell Death; Cell Line; Cell-Free System; Cells, Cultured; Cyclooxygenase 2; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glutamic Acid; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Immunohistochemistry; In Vitro Techniques; Inflammation; Interleukin-6; Lipopolysaccharides; Lithium Chloride; Mice; Microscopy, Confocal; Microscopy, Fluorescence; Models, Chemical; Neurodegenerative Diseases; Neuroglia; Neurons; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; PPAR gamma; Prostaglandin-Endoperoxide Synthases; Rats; Staurosporine; Thiazolidinediones; Time Factors; Transfection; Tretinoin; Tumor Necrosis Factor-alpha