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

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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.

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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).

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Authors and Affiliations

  1. Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea

    Young Seo Kim, Arum Yoo, Jeong Woo Son, Hyun Young Kim, Kyu-Yong Lee, Young Joo Lee & Seong-Ho Koh

  2. Department of Radiology, Hanyang University College of Medicine, Seoul, South Korea

    Young-Jun Lee

  3. Department of Anatomy, Hanyang University College of Medicine, Seoul, South Korea

    Sejin Hwang

  4. Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street Room 6405, Charlestown, MA, 02129, USA

    Cenk Ayata & Hyung-Hwan Kim

  5. Department of Neurology, Hanyang University College of Medicine, 249-1 Gyomun-dong, Guri-si, Gyeonggi-do, 471-701, Republic of Korea

    Seong-Ho Koh

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  1. Young Seo Kim
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Correspondence to Hyung-Hwan Kim or Seong-Ho Koh.

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Young Seo Kim, Arum Yoo, and Jeong Woo Son contributed equally to this work.

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Kim, Y.S., Yoo, A., Son, J.W. et al. Early Activation of Phosphatidylinositol 3-Kinase after Ischemic Stroke Reduces Infarct Volume and Improves Long-Term Behavior. Mol Neurobiol 54, 5375–5384 (2017). https://doi.org/10.1007/s12035-016-0063-4

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