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Molecular Neurobiology

, Volume 54, Issue 7, pp 5375–5384 | Cite as

Early Activation of Phosphatidylinositol 3-Kinase after Ischemic Stroke Reduces Infarct Volume and Improves Long-Term Behavior

  • Young Seo Kim
  • Arum Yoo
  • Jeong Woo Son
  • Hyun Young Kim
  • Young-Jun Lee
  • Sejin Hwang
  • Kyu-Yong Lee
  • Young Joo Lee
  • Cenk Ayata
  • Hyung-Hwan KimEmail author
  • Seong-Ho KohEmail author
Article

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) have recently been implicated in apoptosis and ischemic cell death. We tested the efficacy of early intervention with a peptide PI3K activator in focal cerebral ischemia. After determining the most effective dose (24 μg/kg) and time window (2 h after MCAO) of treatment, a total of 48 rats were subjected to middle cerebral artery occlusion (MCAO). Diffusion weighted MRI (DWI) was performed 1 h after MCAO and rats with lesion sizes within a predetermined range were randomized to either PI3K activator or vehicle treatment arms. Fluid attenuated inversion recovery (FLAIR) MRI, neurological function, western blots, and immunohistochemistry were blindly assessed. Initial DWI lesion volumes were nearly identical between two groups prior to treatment. However, FLAIR showed significantly smaller infarct volumes in the PI3K activator group compared with vehicle (146 ± 81 mm3 and 211 ± 96 mm3, p = 0.045) at 48 h. The PI3K activator group also had better neurological function for up to 2 weeks. In addition, PI3K activator decreased the number of TUNEL-positive cells in the peri-infarct region compared with the control group. Western blot and immunohistochemistry showed increased expression of phosphorylated Akt (Ser473) and GSK-3β (Ser9) and decreased expression of cleaved caspase-9 and caspase-3. Our results suggest a neuroprotective role of early activation of PI3K in ischemic stroke. The use of DWI in the randomization of experimental groups may reduce bias.

Keywords

Acute stroke Diffusion-weighted MRI Animal models PI3K Neuroprotection 

Notes

Acknowledgments

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2015R1A2A2A04004865) and by a grant from the NanoBio R&D Program of the Korea Science and Engineering Foundation, funded by the Ministry of Education, Science and Technology (2006-2004670).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2016_63_MOESM1_ESM.doc (36 kb)
Supplementary Table 1 (DOC 36 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of NeurologyHanyang University College of MedicineSeoulSouth Korea
  2. 2.Department of RadiologyHanyang University College of MedicineSeoulSouth Korea
  3. 3.Department of AnatomyHanyang University College of MedicineSeoulSouth Korea
  4. 4.Neurovascular Research Laboratory, Department of RadiologyMassachusetts General Hospital, Harvard Medical SchoolCharlestownUSA
  5. 5.Department of NeurologyHanyang University College of MedicineGuri-siRepublic of Korea

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