Peroxisome proliferator-activated receptor-gamma agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents.
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.
Tureyen
Kudret
K
Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA.
Kapadia
Ramya
R
Bowen
Kellie K
KK
Satriotomo
Irawan
I
Liang
Jin
J
Feinstein
Douglas L
DL
Vemuganti
Raghu
R
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077205:Pioglitazone; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D013482:Superoxide Dismutase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000187:drug effects / Q000378:metabolism; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D016207:Cytokines; D018696:Neuroprotective Agents; D047495:PPAR gamma; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D018799:Intercellular Adhesion Molecule-1; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000077205:Pioglitazone