Activation of the Akt/GSK3β signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats

Hidenori Endo, Chikako Nito, Hiroshi Kamada, Tatsuro Nishi, Pak H. Chan

研究成果: Article査読

153 被引用数 (Scopus)

抄録

Recent studies have revealed that the phosphatidylinositol 3-kinase (PI3-K) pathway is involved in apoptotic cell death after experimental cerebral ischemia. The serine-threonine kinase, Akt, functions in the PI3-K pathway and prevents apoptosis by phosphorylation at Ser473 after a variety of cell death stimuli. After phosphorylation, activated Akt inactivates other apoptogenic factors, including glycogen synthase kinase-3β (GSK3β), thereby inhibiting cell death. However, the role of Akt/GSK3β signaling in the delayed death of hippocampal neurons in the CA1 subregion after transient global cerebral ischemia (tGCI) has not been clarified. Transient global cerebral ischemia for 5 mins was induced by bilateral common carotid artery occlusion combined with hypotension. Western blot analysis showed a significant increase in phospho-Akt (Ser473) and phospho-GSK3β (Ser9) in the hippocampal CA1 subregion after tGCI. Immunohistochemistry showed that expression of phospho-Akt (Ser473) and phospho-GSK3β (Ser9) was markedly increased in the vulnerable CA1 subregion, but not in the ischemic-tolerant CA3 subregion. Double staining with phospho-GSK3β (Ser9) and terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling showed different cellular distributions in the CA1 subregion 3 days after tGCI. Phosphorylation of Akt and GSK3β was prevented by LY294002, a PI3-K inhibitor, which facilitated subsequent DNA fragmentation 3 days after tGCI. Moreover, transgenic rats that overexpress copper/zinc-superoxide dismutase, which is known to be neuroprotective against delayed hippocampal CA1 injury after tGCI, had enhanced and persistent phosphorylation of both Akt and GSK3β after tGCI. These findings suggest that activation of the Akt/GSK3β signaling pathway may mediate survival of vulnerable hippocampal CA1 neurons after tGCI.

本文言語English
ページ(範囲)1479-1489
ページ数11
ジャーナルJournal of Cerebral Blood Flow and Metabolism
26
12
DOI
出版ステータスPublished - 2006 12 8

ASJC Scopus subject areas

  • 神経学
  • 臨床神経学
  • 循環器および心血管医学

フィンガープリント

「Activation of the Akt/GSK3β signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル