gw9662 and Cerebral-Infarction

Thiazolidinediones (TZDs) are synthetic agonists of the ligand-activated transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). TZDs are known to curtail inflammation associated with peripheral organ ischemia. As inflammation precipitates the neuronal death after stroke, we tested the efficacy of TZDs in preventing brain damage following transient middle cerebral artery occlusion (MCAO) in adult rodents. As hypertension and diabetes complicate the stroke outcome, we also evaluated the efficacy of TZDs in hypertensive rats and type-2 diabetic mice subjected to transient MCAO. Pre-treatment as well as post-treatment with TZDs rosiglitazone and pioglitazone significantly decreased the infarct volume and neurological deficits in normotensive, normoglycemic, hypertensive and hyperglycemic rodents. Rosiglitazone neuroprotection was not enhanced by retinoic acid x receptor agonist 9-cis-retinoic acid, but was prevented by PPARgamma antagonist GW9662. Rosiglitazone significantly decreased the post-ischemic intercellular adhesion molecule-1 expression and extravasation of macrophages and neutrophils into brain. Rosiglitazone treatment curtailed the post-ischemic expression of the pro-inflammatory genes interleukin-1beta, interleukin-6, macrophage inflammatory protein-1alpha, monocyte chemoattractant protein-1, cyclooxygenase-2, inducible nitric oxide synthase, early growth response-1, CCAAT/enhancer binding protein-beta and nuclear factor-kappa B, and increased the expression of the anti-oxidant enzymes catalase and copper/zinc-superoxide dismutase. Rosiglitazone also increased the expression of the anti-inflammatory gene suppressor of cytokine signaling-3 and prevented the phosphorylation of the transcription factor signal transducer and activator of transcription-3 after focal ischemia. Thus, PPARgamma activation with TZDs might be a potent therapeutic option for preventing inflammation and neuronal damage after stroke with promise in diabetic and hypertensive subjects.

Topics: Anilides; Animals; Cerebral Infarction; Chemotaxis, Leukocyte; Cytokines; Diabetes Mellitus, Type 2; Disease Models, Animal; Encephalitis; Hypertension; Intercellular Adhesion Molecule-1; Ischemic Attack, Transient; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neuroprotective Agents; Pioglitazone; PPAR gamma; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rosiglitazone; Superoxide Dismutase; Superoxide Dismutase-1; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Thiazolidinediones

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a nuclear membrane-associated transcription factor that governs the expression of various inflammatory genes. PPAR-gamma agonists protect peripheral organs from ischemic injury. In the present study, we investigated whether the PPAR-gamma agonist rosiglitazone is neuroprotective against focal ischemic brain injury. C57/B6 mice underwent 1.5-h middle cerebral artery occlusion, and received either vehicle or rosiglitazone treatment of 0.75, 1.5, 3, 6 or 12 mg/kg (n = 9 per group). Cerebral infarct volume, neurological function, expression of pro-inflammatory proteins and neutrophil accumulation were assessed after ischemia and reperfusion. At 48 h after ischemia, infarct volume was significantly decreased with 3-12 mg/kg of rosiglitazone, with a time window of efficacy of 2 h after ischemia at the optimal dose (6 mg/kg). Neutrophil accumulation was significantly decreased in the brain parenchyma of rosiglitazone-treated mice. Ischemia-induced expression of several inflammatory cytokines and chemokines was markedly reduced in rosiglitazone-treated brains, as determined using proteomic-array analysis. Rosiglitazone treatment improved neurological function at 7 days after ischemia. Moreover, in cultured cortical primary microglia, rosiglitazone attenuated inflammatory responses by decreasing lipopolysaccharide-induced release of tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6. These results suggest that the PPAR-gamma agonist rosiglitazone has neuroprotective properties that are at least partially mediated via anti-inflammatory actions, and is thus a potential novel therapeutic agent for stroke.

Topics: Anilides; Animals; Animals, Newborn; Behavior, Animal; Blood Pressure; Body Temperature; Brain Ischemia; Cells, Cultured; Cerebral Infarction; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Gene Expression; Gene Expression Regulation; Granulocyte Colony-Stimulating Factor; Immunohistochemistry; Infarction, Middle Cerebral Artery; Intercellular Adhesion Molecule-1; Interleukin-3; Lectins; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Peroxidase; PPAR gamma; Psychomotor Performance; Recombinant Fusion Proteins; Recombinant Proteins; Reperfusion; Rosiglitazone; Thiazolidinediones