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Aging and disease    2018, Vol. 9 Issue (3) : 453-466     DOI: 10.14336/AD.2017.1130
Orginal Article |
APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats
Yan Tao1,2, Venkat Poornima2, Chopp Michael2,3, Zacharek Alex2, Yu Peng2, Ning Ruizhuo2,4, Qiao Xiaoxi5, Kelley Mark R.6, Chen Jieli2,*
1Gerontology Institute, Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China
2Department of Neurology, Henry Ford hospital, Detroit, MI, USA
3Department of Physics, Oakland University, Rochester, MI, USA
4Department of Neurology, First Hospital Harbin, Harbin, China.
5Department of Ophthalmology, Henry Ford Hospital, Detroit, MI, USA
6Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
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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.

Keywords Stroke      Type 1 Diabetes Mellitus      APX3330      neuroprotection      neurorestoration     
Corresponding Authors: Chen Jieli   
About author:

SZ and JZ denote equal first authorship contribution.

Issue Date: 05 June 2018
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Yan Tao
Venkat Poornima
Chopp Michael
Zacharek Alex
Yu Peng
Ning Ruizhuo
Qiao Xiaoxi
Kelley Mark R.
Chen Jieli
Cite this article:   
Yan Tao,Venkat Poornima,Chopp Michael, et al. APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats[J]. Aging and disease, 2018, 9(3): 453-466.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.1130     OR     http://www.aginganddisease.org/EN/Y2018/V9/I3/453
Figure 1.  APX3330 improves stroke outcome and decreases ischemic burden and BBB permeability in T1DM rats. Treatment with APX3330 significantly improves neurological functional outcome after stroke in T1DM rats as indicated by (A) Foot-fault test and (B) modified neurological severity score (mNSS). APX3330 treatment also significantly decreases (C) ischemic lesion volume and (D) BBB disruption after stroke in T1DM rats.
Figure 2.  APX3330 increases arterial density and decreases dysfunctional angiogenesis after stroke in T1DM rats. APX3330 significantly increases (A) arterial density and decreases (B) vascular density and (C) VEGF expression in the ischemic border zone after stroke in T1DM rats, as indicated by α-smooth muscle actin (α-SMA), Von Willebrand Factor (vWF) and vascular endothelial growth factor (VEGF) immunostaining and quantification data respectively.
Figure 3.  APX3330 significantly promotes white matter remodeling after stroke in T1DM rats. APX3330 significantly increases (A) myelin density (Luxol fast blue), (B) synaptic protein expression (Synaptophysin), (C) oligodendrocyte cell number (CNPase), and (D) oligodendrocyte progenitor cell (NG2) number in the ischemic border zone of T1DM stroke rats.
Figure 4.  APX3330 treatment significantly promotes M2 macrophage polarization in the ischemic brain of T1DM stroke rats. APX3330 significantly decreases (A) ED1 (M1 macrophage marker, and significantly increases (B) CD163 (M2 macrophage marker) in the ischemic border zone of T1DM stroke rats.
Figure 5.  APX3330 treatment significantly decreases inflammatory factors after stroke in T1DM rats. (A) An ELISA array was employed to measure inflammatory protein expression in the ischemic brain. APX3330 significantly decreases (B) plasminogen activator inhibitor type 1 (PAI-1), (C) monocyte chemotactic protein-1 (MCP1) and (D) MMP9 compared to control T1DM stroke rats.
Figure 6.  APX3330 treatment decreases inflammatory factor expression in the ischemic brain of T1DM stroke rats and significantly decreases primary cortical neurons cell death and inflammatory factor expression after stroke. (A) Western blot assay shows that APX3330 significantly decreases ischemic brain tissue expression of MMP9 and RAGE compared to control T1DM stroke rats. APX3330 treatment significantly decreases (B) primary cortical neuron cell death compared to control (untreated) cells as measured by LDH assay and (C) significantly decreases MMP9 and PAI-1 gene expression in primary cortical neurons subjected to high glucose and oxygen glucose deprivation, when compared to control (untreated) cells.
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