A peroxisome proliferator-activated receptor-gamma agonist reduces infarct size in transient but not in permanent ischemia.
OBJECTIVE
Activators of peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the PPAR family, increase levels of CuZn-superoxide dismutase (SOD) in cultured endothelium, suggesting a mechanism by which it may exert its protective effect within the brain. These properties raise the question of whether a PPARgamma agonist may be neuroprotective in models of ischemia without reperfusion, in which oxidative injury is less prevalent.


METHODS
In 2 groups of rats, 90 minutes of middle cerebral artery (MCA) occlusion was followed by 1 day of reperfusion, with 1 group receiving pioglitazone (a PPARgamma agonist) starting 72 hours before MCA occlusion (MCAO) and continuing through the day of occlusion, whereas the other group received vehicle only. In 2 comparable groups, the MCA was occluded permanently. One day after occlusion, the animals were tested neurologically and infarct volumes were calculated. In a separate group, rats were treated with pioglitazone or vehicle for 4 days. Tissue was obtained from the cortex and the striatum 2 hours into reperfusion after 90 minutes of MCAO, and the tissue was examined for CuZn-SOD by Western blot.


RESULTS
Results show a significant reduction in infarct size in the treated rats, with transient MCAO but not permanent MCAO. There was also an improvement in neurological score in the treated animals after transient MCAO. The level of CuZn-SOD was increased in the cortex in treated animals.


CONCLUSIONS
These data, which show that a PPARgamma agonist reduces infarct size in transient but not permanent MCAO, suggest that the role of PPARgamma is specific to events occurring during reperfusion. Our data point to CuZn-SOD as the mediator of this neuroprotection.
Shimazu
Tomokazu
T
Cerebrovascular Research Center, Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia 19104-6063, USA.
Inoue
Ikuo
I
Araki
Nobuo
N
Asano
Yoshio
Y
Sawada
Masahiko
M
Furuya
Daisuke
D
Nagoya
Harumitsu
H
Greenberg
Joel H
JH
D000818:Animals; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D002560:Cerebrovascular Circulation; D004727:Endothelium / Q000201:enzymology*; D006863:Hydrogen-Ion Concentration; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*; D000077205:Pioglitazone; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow; D015427:Reperfusion Injury; D013482:Superoxide Dismutase / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors
D047495:PPAR gamma; D045162:Thiazolidinediones; D013482:Superoxide Dismutase; D000077205:Pioglitazone