Inhibition of Phosphatase and Tensin Homolog Deleted on Chromosome 10 Decreases Rat Cortical Neuron Injury and Blood-Brain Barrier Permeability, and Improves Neurological Functional Recovery in Traumatic Brain Injury Model

Jun Ding,Jianyi Guo,Hengli Tian,Qiang Yuan,Hao Chen,Fang Yuan,Cesar V Borlongan

doi:10.1371/journal.pone.0080429

Jun Ding, Jianyi Guo + Show 5 more

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https://doi.org/10.1371/journal.pone.0080429

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Journal: PloS one	Publication Date: Nov 28, 2013
Citations: 26	License type: CC BY 3.0

Affiliation: Shanghai First People's Hospital

Abstract

Background and PurposeRecent evidence has supported the neuroprotective effect of bpV (pic), an inhibitor of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), in models of ischemic stroke. However, whether PTEN inhibitors improve long-term functional recovery after traumatic brain injury (TBI) and whether PTEN affects blood brain barrier (BBB) permeability need further elucidation. The present study was performed to address these issues.MethodsAdult Sprague-Dawley rats were subjected to fluid percussion injury (FPI) after treatment with a well-established PTEN inhibitor bpV (pic) or saline starting 24 h before FPI. Western blotting, real-time quantitative PCR, or immunostaining was used to measure PTEN, p-Akt, or MMP-9 expression. We determined the presence of neuron apoptosis by TUNEL assay. Evans Blue dye extravasation was measured to evaluate the extent of BBB disruption. Functional recovery was assessed by the neurological severity score (NSS), and Kaplan-Meier analysis was used for survival analysis.ResultsPTEN expression was up-regulated after TBI. After bpV (pic) treatment, p-Akt was also up-regulated. We found that bpV (pic) significantly decreased BBB permeability and reduced the number of TUNEL-positive cells. We further demonstrated that PTEN inhibition improved neurological function recovery in the early stage after TBI.ConclusionThese data suggest that treatment with the PTEN inhibitor bpV (pic) has a neuroprotective effect in TBI rats.

Highlights

Traumatic brain injury (TBI) is a leading cause of morbidity and disability in modern society, especially in young people
We investigated the role of PTEN in rats that underwent traumatic brain injury (TBI) induced by fluid percussion injury (FPI)
quantitative PCR (Q-PCR) showed that the PTEN mRNA level was about 10 fold that of the sham controls at an early stage, 2 h after TBI

Summary

Introduction

Traumatic brain injury (TBI) is a leading cause of morbidity and disability in modern society, especially in young people. After TBI, the subsequent development of mechanical injury or ischemia, hypoxia, ionic disequilibrium, and toxic effects of excitatory amino acids may damage or kill neurons or microvascular cells, leading to secondary edema, progressive hemorrhagic injury, and brain dysfunction. Protecting neurons and microvascular cells from damage and death is important for rescuing neurological function. The activation of phosphatidylinositol 3-kinase (PI3K) is correlated with increased cell survival, and this effect is largely mediated through the activation of a serine/threonine kinase Akt. The PI3K/Akt pathway promotes cellular survival in part by phosphorylating and inhibiting death-inducing proteins, including glycogen synthase kinase 3 (GSK-3), Bcl-2/Bcl-xL-associated death protein (BAD), and caspase- 9 [3,4,5,6].

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