脳虚血ストレスによる高血糖と神経障害発現に及ぼす抗糖尿病治療薬メトホルミンの有効性

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タイトル別名
  • Effectiveness of Metformin in Prevention of Development of Hyperglycemia and Neuronal Damage Caused by Ischemic Stress
  • ノウキョケツ ストレス ニ ヨル コウケットウ ト シンケイ ショウガイ ハツゲン ニ オヨボス コウトウニョウビョウ チリョウヤク メトホルミン ノ ユウコウセイ

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  Hyperglycemia is a known exacerbating factor in ischemic stroke. It has been reported that hyperglycemia and post-ischemic glucose intolerance can develop after stroke and be involved in the development of neuronal damage, as we described previously. Here, we focus on the effectiveness of metformin, a hypoglycemic drug, in preventing the development of neuronal damage using the middle cerebral artery occlusion (MCAO) model mice. 5′-AMP-activated protein kinase (AMPK) is a serine/threonine kinase that plays a key role in the hypoglycemic effects of metformin. Recently, it has been reported that centrally activated AMPK is involved in the development of ischemic neuronal damage, while the effect of peripherally activated AMPK on ischemic neuronal damage is not known. In the liver, AMPK activity was not affected by MCAO, while the administration of intraperitoneal metformin (250 mg/kg), an AMPK activator, significantly activated hepatic AMPK and suppressed both the development of post-ischemic glucose intolerance and ischemic neuronal damage without alteration of central AMPK activity. On the other hand, the administration of intracerebroventricular metformin (100 μg/mouse) significantly exacerbated the development of neuronal damage observed on day 1 after MCAO. These effects were significantly blocked by compound C, a specific AMPK inhibitor. These results suggest that central AMPK is activated by ischemic stress per se, although peripheral AMPK is not altered. Furthermore, the regulation of post-ischemic glucose intolerance by metformin-induced activation of peripheral AMPK contributes to the reduction of cerebral ischemic neuronal damage.<br>

収録刊行物

  • 薬学雑誌

    薬学雑誌 131 (4), 533-538, 2011-04-01

    公益社団法人 日本薬学会

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