Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 cause potent neuroprotection after experimental stroke through noncompletely overlapping mechanisms.
Stroke triggers an inflammatory cascade which contributes to a delayed cerebral damage, thus implying that antiinflammatory strategies might be useful in the treatment of acute ischaemic stroke. Since two unrelated peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, the thiazolidinedione rosiglitazone (RSG) and the cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), have been shown to possess antiinflammatory properties, we have tested their neuroprotective effects in experimental stroke. Rosiglitazone or 15d-PGJ2 were administered to rats 10 mins or 2 h after permanent middle cerebral artery occlusion (MCAO). Stroke outcome was evaluated by determination of infarct volume and assessment of neurological scores. Brains were collected for protein expression, gene array analyses and gene shift assays. Our results show that both compounds decrease MCAO-induced infarct size and improve neurological scores. At late times, the two compounds converge in the inhibition of MCAO-induced brain expression of inducible NO synthase and the matrix metalloproteinase 9. Interestingly, at early times, complementary DNA microarrays and gene shift assays show that different mechanisms are recruited. Analysis of early nuclear p65 and late cytosolic IkappaBalpha protein levels shows that both compounds inhibit nuclear factor-kappaB signalling, although at different levels. All these results suggest both PPARgamma-dependent and independent pathways, and might be useful to design both therapeutic strategies and prognostic markers for stroke.
Pereira
Marta P
MP
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain.
Hurtado
Olivia
O
Cárdenas
Antonio
A
Boscá
Lisardo
L
Castillo
José
J
Dávalos
Antoni
A
Vivancos
José
J
Serena
Joaquín
J
Lorenzo
Pedro
P
Lizasoain
Ignacio
I
Moro
María A
MA
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000517:prevention & control*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009566:Nitrates / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D047495:PPAR gamma / Q000819:agonists / Q000096:biosynthesis / Q000187:drug effects; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage*; D013997:Time Factors
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000893:Anti-Inflammatory Agents; D020672:I-kappa B Proteins; D016328:NF-kappa B; D018696:Neuroprotective Agents; C000606206:Nfkbia protein, rat; D009566:Nitrates; D009573:Nitrites; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; D015230:Prostaglandin D2