Published Online
on September 20, 2007

A more recent version of this article appeared on November 1, 2007

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Submitted on February 27, 2007
Revised on April 18, 2007
Accepted on April 24, 2007

Pioglitazone Exerts Protective Effects Against Stroke in Stroke-Prone Spontaneously Hypertensive Rats, Independently of Blood Pressure

Taishi Nakamura MD; Eiichiro Yamamoto MD; Keiichiro Kataoka MD; Takuro Yamashita MD; Yoshiko Tokutomi PhD; Yi-Fei Dong MD; Shinji Matsuba MD; Hisao Ogawa MD; and Shokei Kim-Mitsuyama MD^*

From the Department of Pharmacology and Molecular Therapeutics (T.N., E.Y., K.K., T.Y., Y.T., Y.-F.D., S.M., S.K.-M.) and the Department of Cardiovascular Medicine (H.O.), Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

^* To whom correspondence should be addressed. E-mail: kimmitsu{at}gpo.kumamoto-u.ac.jp.

Background and Purpose—Very recent subgroup analysis from the PROspective pioglitAzone Clinical Trial In macroVascular Events has shown that pioglitazone reduces the risk of recurrent stroke in type 2 diabetic patients. However, the underlying mechanism of stroke prevention by pioglitazone is unknown. Our aim was to examine the effect of pioglitazone on hypertension-based stroke in rats.

Methods—Methods-Pioglitazone (1 mg · kg^-1 · d^-1) was orally administered to stroke-prone spontaneously hypertensive rats (SHRSP) to examine the effect on incidental stroke, cerebrovascular injury, brain inflammation, oxidative stress, and vascular endothelial dysfunction induced by hypertension.

Results—Treatment of SHRSP with pioglitazone for 4 weeks, without affecting blood pressure and blood glucose values, improved vascular endothelial dysfunction (P<0.05), suppressed remodeling of the middle cerebral artery (P<0.05) and brain microvessels (P<0.05), and inhibited brain macrophage infiltration (P<0.05) and the upregulation of brain monocyte chemoattractant protein-1 and tumor necrosis factor-a expression (P<0.01). Furthermore, pioglitazone treatment significantly delayed the onset of stroke signs and death in SHRSP (P<0.05). These beneficial effects of pioglitazone on cerebrovascular injury and stroke in SHRSP were associated with a reduction of brain and vascular superoxide via the inhibition of NADPH oxidase activity.

Conclusions—Our work provides the first evidence that pioglitazone significantly protects against hypertension-induced cerebrovascular injury and stroke by improving vascular endothelial dysfunction, inhibiting brain inflammation, and reducing oxidative stress. These beneficial effects of pioglitazone were independent of blood pressure or blood sugar values. Thus, pioglitazone appears to be a potential therapeutic agent for stroke in type 2 diabetes with hypertension.

Key words: endothelium • hypertension • inflammation • stroke

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