http://stroke.ahajournals.org/content/38/11/3016.short
- 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;
- Shokei Kim-Mitsuyama, MD
+ Author Affiliations
- Correspondence to Shokei Kim-Mitsuyama, MD, PhD, Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan. E-mail kimmitsu@gpo.kumamoto-u.ac.jp
Abstract
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— 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-α 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.
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