The nonthiazolidinedione PPARgamma agonist L-796,449 is neuroprotective in experimental stroke.
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.
Pereira
Marta P
MP
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Spain.
Hurtado
Olivia
O
Cárdenas
Antonio
A
Alonso-Escolano
David
D
Boscá
Lisardo
L
Vivancos
José
J
Nombela
Florentino
F
Leza
Juan C
JC
Lorenzo
Pedro
P
Lizasoain
Ignacio
I
Moro
María A
MA
D000818:Animals; D001572:Benzofurans / Q000627:therapeutic use*; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000187:drug effects; D051547:Heme Oxygenase-1; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000187:drug effects; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010648:Phenylacetates / Q000627:therapeutic use*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats
D001572:Benzofurans; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; C436325:L 796449; D016328:NF-kappa B; D018696:Neuroprotective Agents; D047495:PPAR gamma; D010648:Phenylacetates; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D020780:Matrix Metalloproteinase 9