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Neuroprotection against focal ischemic brain injury by the peroxisome proliferator‐activated receptor‐γ agonist rosiglitazone
Author(s) -
Luo Yumin,
Yin Wei,
Signore Armando P.,
Zhang Feng,
Hong Zhen,
Wang Suping,
Graham Steven H.,
Chen Jun
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03758.x
Subject(s) - rosiglitazone , neuroprotection , agonist , medicine , peroxisome proliferator activated receptor , ischemia , pharmacology , endocrinology , inflammation , receptor
Peroxisome proliferator‐activated receptor gamma (PPAR‐γ) is a nuclear membrane‐associated transcription factor that governs the expression of various inflammatory genes. PPAR‐γ agonists protect peripheral organs from ischemic injury. In the present study, we investigated whether the PPAR‐γ 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‐α, interleukin (IL)‐1β and IL‐6. These results suggest that the PPAR‐γ 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.