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Aging Dis. 2018 Jun 1;9(3):453-466. doi: 10.14336/AD.2017.1130. eCollection 2018 Jun.

APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats.

Author information

1
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.
2
2Department of Neurology, Henry Ford hospital, Detroit, MI, USA.
3
3Department of Physics, Oakland University, Rochester, MI, USA.
4
4Department of Neurology, First Hospital Harbin, Harbin, China.
5
5Department of Ophthalmology, Henry Ford Hospital, Detroit, MI, USA.
6
6Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.

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:

APX3330; Stroke; Type 1 Diabetes Mellitus; neuroprotection; neurorestoration

Conflict of interest statement

Conflicts of interest Mark R. Kelley has licensed APX3330 through Indiana University Research and Technology Corporation to Apexian Pharmaceuticals LLC. Apexian Pharmaceuticals had neither control nor oversight of the studies, interpretation, or presentation of the data in this manuscript. The other authors have no conflicts of interest to disclose.

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