Research Article: APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats

Date Published: June 1, 2018

Publisher: JKL International LLC

Author(s): Tao Yan, Poornima Venkat, Michael Chopp, Alex Zacharek, Peng Yu, Ruizhuo Ning, Xiaoxi Qiao, Mark R. Kelley, Jieli Chen.

http://doi.org/10.14336/AD.2017.1130

Abstract

APX3330 is a selective inhibitor of APE1/Ref-1 redox activity. In this study, we investigate the therapeutic effects and underlying mechanisms of APX3330 treatment in type one diabetes mellitus (T1DM) stroke rats. Adult male Wistar rats were induced with T1DM and subjected to transient middle cerebral artery occlusion (MCAo) and treated with either PBS or APX3330 (10mg/kg, oral gavage) starting at 24h after MCAo, and daily for 14 days. Rats were sacrificed at 14 days after MCAo and, blood brain barrier (BBB) permeability, ischemic lesion volume, immunohistochemistry, cell death assay, Western blot, real time PCR, and angiogenic ELISA array were performed. Compared to PBS treatment, APX3330 treatment of stroke in T1DM rats significantly improves neurological functional outcome, decreases lesion volume, and improves BBB integrity as well as decreases total vessel density and VEGF expression, while significantly increases arterial density in the ischemic border zone (IBZ). APX3330 significantly increases myelin density, oligodendrocyte number, oligodendrocyte progenitor cell number, synaptic protein expression, and induces M2 macrophage polarization in the IBZ of T1DM stroke rats. Compared to PBS treatment, APX3330 treatment significantly decreases plasminogen activator inhibitor type-1 (PAI-1), monocyte chemotactic protein-1 and matrix metalloproteinase 9 (MMP9) and receptor for advanced glycation endproducts expression in the ischemic brain of T1DM stroke rats. APX3330 treatment significantly decreases cell death and MMP9 and PAI-1 gene expression in cultured primary cortical neurons subjected to high glucose and oxygen glucose deprivation, compared to untreated control cells. APX3330 treatment increases M2 macrophage polarization and decreases inflammatory factor expression in the ischemic brain as well as promotes neuroprotective and neurorestorative effects after stroke in T1DM rats.

Partial Text

All experiments followed the standards of the American Council on Animal Care and Institutional Animal Care and Use Committee of Henry Ford Health System.

In this study, we are the first to demonstrate that APX3330 treatment significantly improves neurological functional outcome and decreases lesion volume and BBB permeability after stroke in T1DM rats. APX3330 promotes WM remodeling and exerts myelin protective effects in the IBZ of T1DM stroke rats. By employing an angiogenic ELISA assay and Western blot analysis, we also confirmed that APX3330 treatment significantly decreases the expression of inflammatory factors such as MCP1, MMP9 and RAGE and pro-thrombotic factor PAI-1, in the ischemic brain of T1DM stroke rats. APX3330 significantly decreases gene expression of inflammatory factor MMP9 and pro-thrombotic PAI-1 in cultured primary cortical neurons subjected to high glucose and oxygen glucose deprivation conditions. These data indicate that APX3330 may be a novel treatment for T1DM stroke.

 

Source:

http://doi.org/10.14336/AD.2017.1130

 

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