Early activation of phosphatidylinositol 3-kinase for neuroprotective effect against ischemic stroke and behavior functional test

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) are many-sided survival related kinases, and have recently been implicated in apoptosis and ischemic stroke. In this study, we aimed to identify the effects of early intervention with PI3K activator. After surgery in an ischemic stroke model with SD rats, the most effective dose, 24 µg/kg, was determined. This dose was most effective at 2 hours after ischemic stroke. Diffusion-weighted MRI (DWI), performed 1 hour after ischemic stroke surgery, and stroke models with lesion size within a certain range, were randomized to both PI3K activator and control groups. We performed molecular work, fluid-attenuated inversion recovery (FLAIR) MRI, and neurological function tests, using blinded assessment to increase the accuracy of the experiment. Also, DWI was used as a randomization to reduce biased selection in the experimental group. There was no difference between control and PI3K groups in DWI images after ischemic stroke. Conversely, 48-hour FLAIR (146 ± 81 mm3 and 211 ± 96 mm3, p = 0.045) images showed significantly reduced infarct volume in the PI3K activator-treated group. In addition, long-term neurological function tests showed better behavior scores than the control group. Molecular work revealed increased expression of pAkt and GSK-3β, and decreased expression of cleaved caspase-9 and caspase-3. In TUNEL staining, PI3K activator decreased the number of apoptotic cells compared with that in the control group. These studies show that early activation of PI3K has a neuroprotective effect against apoptosis due to ischemic stroke.