title: Early Activation of Phosphatidylinositol 3-Kinase after Ischemic Stroke Reduces Infarct Volume and Improves Long-Term Behavior.
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 mm3and 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.
authors: Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea.
authors: Young Seo
authors: YS
authors: Kim
authors: Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea.
authors: Arum
authors: A
authors: Yoo
authors: Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea.
authors: Jeong Woo
authors: JW
authors: Son
authors: Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea.
authors: Hyun Young
authors: HY
authors: Kim
authors: Department of Radiology, Hanyang University College of Medicine, Seoul, South Korea.
authors: Young-Jun
authors: YJ
authors: Lee
authors: Department of Anatomy, Hanyang University College of Medicine, Seoul, South Korea.
authors: Sejin
authors: S
authors: Hwang
authors: Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea.
authors: Kyu-Yong
authors: KY
authors: Lee
authors: Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea.
authors: Young Joo
authors: YJ
authors: Lee
authors: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street Room 6405, Charlestown, MA, 02129, USA.
authors: Cenk
authors: C
authors: Ayata
authors: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street Room 6405, Charlestown, MA, 02129, USA. Kim.HyungHwan@mgh.harvard.edu.
authors: Hyung-Hwan
authors: HH
authors: Kim
authors: Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea. ksh213@hanyang.ac.kr.|Department of Neurology, Hanyang University College of Medicine, 249-1 Gyomun-dong, Guri-si, Gyeonggi-do, 471-701, Republic of Korea. ksh213@hanyang.ac.kr.
authors: Seong-Ho
authors: http://orcid.org/0000-0001-5419-5761
authors: SH
authors: Koh
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D038524:Diffusion Magnetic Resonance Imaging; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy / Q000201:enzymology*; D013995:Time
chemical_list: D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D038362:Glycogen Synthase Kinase 3; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: Acute stroke; Animal models; Diffusion-weighted MRI; Neuroprotection; PI3K