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The Journal of Neuroscience, May 23, 2007, 27(21):5766-5776; doi:10.1523/JNEUROSCI.1004-07.2007

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Neurobiology of Disease
NP031112, a Thiadiazolidinone Compound, Prevents Inflammation and Neurodegeneration under Excitotoxic Conditions: Potential Therapeutic Role in Brain Disorders

Rosario Luna-Medina,1 Marta Cortes-Canteli,1 Susana Sanchez-Galiano,1 Jose A. Morales-Garcia,1 Ana Martinez,2 Angel Santos,3 and Ana Perez-Castillo1

1Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain, 2Neuropharma, S.A. Avenida de la Industria, 28760 Madrid, Spain, and 3Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain

Correspondence should be addressed to either of the following: Ana Perez-Castillo, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Arturo Duperier, 4, 28029 Madrid, Spain, Email: aperez{at}iib.uam.es; or Angel Santos, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain, E-mail: Email: piedras3{at}med.ucm.es

Inflammation and neurodegeneration coexist in many acute damage and chronic CNS disorders (e.g., stroke, Alzheimer's disease, Parkinson's disease). A well characterized animal model of brain damage involves administration of kainic acid, which causes limbic seizure activity and subsequent neuronal death, especially in the CA1 and CA3 pyramidal cells and interneurons in the hilus of the hippocampus. Our previous work demonstrated a potent anti-inflammatory and neuroprotective effect of two thiadiazolidinones compounds, NP00111 (2,4-dibenzyl-[1,2,4]thiadiazolidine-3,5-dione) and NP01138 (2-ethyl-4-phenyl-[1,2,4]thiadiazolidine-3,5-dione), in primary cultures of cortical neurons, astrocytes, and microglia. Here, we show that injection of NP031112, a more potent thiadiazolidinone derivative, into the rat hippocampus dramatically reduces kainic acid-induced inflammation, as measured by edema formation using T2-weighted magnetic resonance imaging and glial activation and has a neuroprotective effect in the damaged areas of the hippocampus. Last, NP031112-induced neuroprotection, both in vitro and in vivo, was substantially attenuated by cotreatment with GW9662 (2-chloro-5-nitrobenzanilide), a known antagonist of the nuclear receptor peroxisome proliferator-activated receptor {gamma}, suggesting that the effects of NP031112 can be mediated through activation of this receptor. As such, these findings identify NP031112 as a potential therapeutic agent for the treatment of neurodegenerative disorders.

Key words: excitotoxicity; neurodegenerative diseases; neuroinflammation; neuroprotection; peroxisome proliferator-activated receptor; thiadiazolidinones

Received Oct. 6, 2006; revised April 18, 2007; accepted April 18, 2007.

Correspondence should be addressed to either of the following: Ana Perez-Castillo, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Arturo Duperier, 4, 28029 Madrid, Spain, Email: aperez{at}iib.uam.es; or Angel Santos, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain, E-mail: Email: piedras3{at}med.ucm.es






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