Neuroprotection against focal ischemic brain injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone.
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.
Luo
Yumin
Y
Department of Neurology, University of Pittsburgh School of Medicine, PA 15213, USA.
Yin
Wei
W
Signore
Armando P
AP
Zhang
Feng
F
Hong
Zhen
Z
Wang
Suping
S
Graham
Steven H
SH
Chen
Jun
J
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002545:Brain Ischemia / Q000209:etiology / Q000517:prevention & control*; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D047495:PPAR gamma / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins; D015424:Reperfusion; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D016207:Cytokines; D007377:Interleukin-3; D037102:Lectins; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D047495:PPAR gamma; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D045162:Thiazolidinediones; C404145:myelopoietin; D000077154:Rosiglitazone; D018799:Intercellular Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor; D009195:Peroxidase