The nonthiazolidinedione PPARgamma agonist L-796,449 is neuroprotective in experimental stroke.

Abstract

Some agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma) belonging to the thiazolidinedione (TZD) family, as well as the cyclopentenone prostaglandin 15-dPGJ2, have been shown to cause neuroprotection in animal models of stroke. We have tested whether the TZD-unrelated PPARgamma agonist L-796,449 is neuroprotective after permanent middle cerebral artery occlusion (MCAO) in the rat brain. Our results show that L-796,449 decreases MCAO-induced infarct size and improves neurologic scores. This protection is concomitant to inhibition of MCAO-induced brain expression of inducible NO synthase (iNOS) and the matrix metalloproteinase MMP-9 and to upregulation of the cytoprotective stress protein heme oxygenase-1 (HO-1). Analysis of the NF-kappaB p65 monomer and the NF-kappaB inhibitor IkappaBalpha protein levels as well as gel mobility shift assays indicate that L-796,449 inhibits NF-kappaB signaling, and that it may be recruiting both PPARgamma-dependent and independent pathways. In summary, our results provide new insights for stroke treatment.

• Authors: Marta P Pereira, Olivia Hurtado, Antonio Cárdenas, David Alonso-Escolano, Lisardo Boscá, José Vivancos, Florentino Nombela, Juan C Leza, Pedro Lorenzo, Ignacio Lizasoain, María A Moro
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 64 Issue 9 Pg. 797-805 (Sep 2005) ISSN: 0022-3069 [Print] England
• PMID: 16141790 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzofurans
• I kappa B beta protein
• I-kappa B Proteins
• L 796449
• NF-kappa B
• Neuroprotective Agents
• PPAR gamma
• Phenylacetates
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Heme Oxygenase (Decyclizing)
• Heme Oxygenase-1
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Casp3 protein, rat
• Caspase 3
• Caspases
• Matrix Metalloproteinase 9

Topics

• Animals
• Benzofurans (therapeutic use)
• Blotting, Western
• Brain Ischemia (drug therapy)
• Caspase 3
• Caspases (metabolism)
• Cyclooxygenase 2
• Disease Models, Animal
• Electrophoretic Mobility Shift Assay
• Heme Oxygenase (Decyclizing) (biosynthesis, drug effects)
• Heme Oxygenase-1
• I-kappa B Proteins (drug effects, metabolism)
• Inflammation (prevention & control)
• Male
• Matrix Metalloproteinase 9 (biosynthesis, drug effects)
• NF-kappa B (drug effects, metabolism)
• Neuroprotective Agents (therapeutic use)
• Nitric Oxide Synthase (biosynthesis, drug effects)
• Nitric Oxide Synthase Type II
• PPAR gamma (agonists, metabolism)
• Phenylacetates (therapeutic use)
• Prostaglandin-Endoperoxide Synthases (biosynthesis, drug effects)
• Rats