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J. Biol. Chem., Vol. 280, Issue 22, 21453-21462, June 3, 2005

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Regulation of Inflammatory Response in Neural Cells in Vitro by Thiadiazolidinones Derivatives through Peroxisome Proliferator-activated Receptor Activation^*

Rosario Luna-Medina, Marta Cortes-Canteli¶, Mercedes Alonso||, Angel Santos**, Ana Martínez||, and Ana Perez-Castillo

From the Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28029 Madrid, Spain, ^||Neuropharma, S.A. 28760, Tres Cantos, Madrid, Spain, and the ^**Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain

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 , inducible nitric-oxide synthase, and inducible cyclooxygenase type 2 expression. In addition, thiadiazolidinones inhibited tumor necrosis factor- 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 antagonist GW9662. In contrast the glycogen synthase kinase 3 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 activation.

Received for publication, December 21, 2004 , and in revised form, March 18, 2005.

^* This work was supported by Grants BMC2001-2342, SAF2004-06263-C02-01, and 95-0764.OP (to A. P.-C.) and SAF2003-02962 (to A. S.) from the Ministerio de Educación y Ciencia, and by Grant GR/SAL/0033/2004 from the Comunidad de Madrid (to A. P.-C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

A fellow of the Ministerio de Educación y Ciencia.

^¶ A post-doctoral fellow of the Consejo Superior de Investigaciones Científicas.

To whom correspondence should be addressed: Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier, 4, 28029 Madrid, Spain. Tel.: 34-91-585-4436; Fax: 34-91-585-4401; E-mail: aperez{at}iib.uam.es.

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