title: PPAR- γ impairment alters peroxisome functionality in primary astrocyte cell cultures.
abstract: 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.
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino-(Neurofarba)-Sezione di Farmacologia e Tossicologia, Università di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino-(Neurofarba)-Sezione di Farmacologia e Tossicologia, Università di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Zanardelli
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino-(Neurofarba)-Sezione di Farmacologia e Tossicologia, Università di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino-(Neurofarba)-Sezione di Farmacologia e Tossicologia, Università di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D010088:Oxidoreductases / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020675:Peroxisomes / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000975:Antioxidants; D009419:Nerve Tissue Proteins; D047493:PPAR alpha; D047495:PPAR gamma; D010088:Oxidoreductases
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