Pioglitazone exerts protective effects against stroke in stroke-prone spontaneously hypertensive rats, independently of blood pressure.
OBJECTIVE
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 x kg(-1) x 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-alpha 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.
Nakamura
Taishi
T
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan.
Yamamoto
Eiichiro
E
Kataoka
Keiichiro
K
Yamashita
Takuro
T
Tokutomi
Yoshiko
Y
Dong
Yi-Fei
YF
Matsuba
Shinji
S
Ogawa
Hisao
H
Kim-Mitsuyama
Shokei
S
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D048909:Diabetes Complications / Q000503:physiopathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000074624:NADPH Oxidase 1; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D000077205:Pioglitazone; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D001786:Blood Glucose; D016207:Cytokines; D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D045162:Thiazolidinediones; D013481:Superoxides; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D000077205:Pioglitazone