The neuroprotection of insulin on ischemic brain injury in rat hippocampus through negative regulation of JNK signaling pathway by PI3K/Akt activation

Liang Hui, Dong Sheng Pei, Quan Guang Zhang, Qiu Hua Guan, Guang Yi Zhang

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97 Citations (Scopus)

Abstract

Current studies demonstrated that cell survival is determined by a balance among signaling cascades, including those that recruit the Akt and JNK pathways. In our present work, the relationship between Akt1 and JNK1/2 was evaluated after cerebral ischemia-reperfusion in the hippocampus in a four-vessel occlusion model of Sprague-Dawley rats. This paper was based on our present and previous studies. Firstly, Akt1 had one active peak during reperfusion following 15 min ischemia. Secondly, two peaks of JNK1/2 activation occurred during reperfusion, respectively. Thirdly, the phosphorylation of JNK substrates c-Jun and Bcl-2, and the activation of a key protease of caspase-3 were detected. They only had one active peak, respectively, during reperfusion. To clarify the mechanism of Akt1 activation and further define whether JNK1/2 activation could be regulated by Akt1 through PI3K pathway, LY294002 and insulin were, respectively, administrated to the rats prior to ischemia. Our research indicated that LY294002, a PI3K inhibitor, significantly suppressed Akt1 activation. Furthermore, LY294002 significantly strengthened both peaks of JNK1/2 activation, c-Jun activation, Bcl-2 phosphorylation, and the activation of caspase-3 during reperfusion. In contrast, insulin, a PI3K agonist, not only obviously activated Akt1 during early and later reperfusion, but also inhibited phosphorylation of JNK1/2, c-Jun, and Bcl-2 and attenuated the activation of caspase-3. In addition, pretreatment of insulin significantly increased the number of the surviving CA1 pyramidal cells at 5 days of reperfusion. Consequently, our results indicated that the cross-talk between Akt1 and JNK1/2 could be mediated by insulin receptor through PI3K in rat hippocampus during reperfusion. This signaling pathway might play a neuroprotective role against ischemic insults via inhibition of the JNK pathway, involving the death effector of caspase-3.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalBrain Research
Volume1052
Issue number1
DOIs
StatePublished - Aug 2 2005

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MAP Kinase Signaling System
Phosphatidylinositol 3-Kinases
Brain Injuries
Reperfusion
Hippocampus
Insulin
Caspase 3
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Phosphorylation
Ischemia
Effector Caspases
Neuroprotection
Pyramidal Cells
Insulin Receptor
Brain Ischemia
Sprague Dawley Rats
Cell Survival
Peptide Hydrolases
Research

Keywords

  • Akt1
  • Bcl-2
  • Caspase-3
  • Cerebral ischemia/reperfusion (I/R)
  • Hippocampus
  • Insulin
  • JNK1/2
  • LY294002
  • Phosphatidylinositol 3-kinase (PI3K)
  • c-Jun

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Cite this

The neuroprotection of insulin on ischemic brain injury in rat hippocampus through negative regulation of JNK signaling pathway by PI3K/Akt activation. / Hui, Liang; Pei, Dong Sheng; Zhang, Quan Guang; Guan, Qiu Hua; Zhang, Guang Yi.

In: Brain Research, Vol. 1052, No. 1, 02.08.2005, p. 1-9.

Research output: Contribution to journalArticle

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AU - Guan, Qiu Hua

AU - Zhang, Guang Yi

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