Peroxisome proliferator-activated receptor-gamma ligands reduce inflammation and infarction size in transient focal ischemia.
Newly developed insulin-sensitizing agents, which target the nuclear receptor peroxisome proliferator-activated receptor-gamma have recently been appreciated to exhibit potent anti-inflammatory actions. Since stroke is associated with an intense inflammatory response, we reasoned that these agents may ameliorate injury from stroke. We report that administration of troglitazone or pioglitazone 24 h before and at the time of cerebral infarction dramatically reduced infarction volume and improved neurological function following middle cerebral artery occlusion in rats. Furthermore, we find that delayed therapy also significantly reduced infarct volume. The brains of the drug-treated animals displayed reduced inflammation as evidenced by decreased immunoreactivity for microglial/macrophage markers and reduced protein and mRNA for interleukin-1beta, cyclooxygenase-2 and inducible nitric oxide synthase. We argue that the beneficial effects of these drugs are likely due to reduced expression of these inflammatory mediators, which are known to exacerbate ischemic injury following stroke. These results are of particular relevance to diabetic patients chronically treated with these agents who may benefit from the neuroprotective actions of these drugs.
Sundararajan
S
S
Department of Neurology, Case Western Reserve University and University Hospitals of Cleveland, 11100 Euclid Ave, Cleveland, OH 44106, USA. sophia.sundararajan@case.edu
Gamboa
J L
JL
Victor
N A
NA
Wanderi
E W
EW
Lust
W D
WD
Landreth
G E
GE
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D002452:Cell Count; D002560:Cerebrovascular Circulation / Q000502:physiology; D002839:Chromans / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008024:Ligands; D008264:Macrophages / Q000187:drug effects; D008297:Male; D017628:Microglia / Q000187:drug effects; D020768:Middle Cerebral Artery / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D047495:PPAR gamma / Q000187:drug effects*; D000077205:Pioglitazone; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000627:therapeutic use*; D000077288:Troglitazone
D001786:Blood Glucose; D002839:Chromans; D008024:Ligands; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077288:Troglitazone; D000077205:Pioglitazone