Published Online
on December 23, 2004

A more recent version of this article appeared on February 1, 2005

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Submitted on June 2, 2004
Revised on November 3, 2004
Accepted on November 22, 2004

A Peroxisome Proliferator-Activated Receptor- Agonist Reduces Infarct Size in Transient but not in Permanent Ischemia

Tomokazu Shimazu MD, PhD; Ikuo Inoue MD, PhD; Nobuo Araki MD, PhD; Yoshio Asano MD, PhD; Masahiko Sawada MD, PhD; Daisuke Furuya MD, PhD; Harumitsu Nagoya MD; and Joel H. Greenberg PhD^*

From the Cerebrovascular Research Center, Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia (T.S., J.H.G.); the Fourth Department of Internal Medicine (I.I.) and the Department of Neurology (N.A., Y.A., M.S., D.F., H.N.), Saitama Medical School, Japan.

^* To whom correspondence should be addressed. E-mail: joel{at}mail.med.upenn.edu.

Background and Purpose--Activators of peroxisome proliferator-activated receptor- (PPAR), 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 PPAR 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 PPAR 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 PPAR agonist reduces infarct size in transient but not permanent MCAO, suggest that the role of PPAR is specific to events occurring during reperfusion. Our data point to CuZn-SOD as the mediator of this neuroprotection.

Key words: cerebral ischemia, focal • reperfusion • superoxide dismutase

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