APX3330 promotes neurorestorative effects after stroke in type one diabetic rats

Tao Yan, Poornima Venkat, Michael Chopp, Alex Zacharek, Peng Yu, Ruizhuo Ning, Xiaoxi Qiao, Mark Kelley, Jieli Chen

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)453-466
Number of pages14
JournalAging and Disease
Volume9
Issue number3
DOIs
StatePublished - Jun 1 2018

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Stroke
Middle Cerebral Artery Infarction
Plasminogen Activator Inhibitor 1
Oligodendroglia
Matrix Metalloproteinase 9
Blood-Brain Barrier
Therapeutics
Cell Death
Macrophages
Glucose
Chemokine CCL2
Brain
Neuroprotective Agents
Therapeutic Uses
Myelin Sheath
Vascular Endothelial Growth Factor A
Oxidation-Reduction
Wistar Rats
Real-Time Polymerase Chain Reaction
Permeability

Keywords

  • APX3330
  • Neuroprotection
  • Neurorestoration
  • Stroke
  • Type 1 Diabetes Mellitus

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Geriatrics and Gerontology
  • Clinical Neurology
  • Cell Biology

Cite this

Yan, T., Venkat, P., Chopp, M., Zacharek, A., Yu, P., Ning, R., ... Chen, J. (2018). APX3330 promotes neurorestorative effects after stroke in type one diabetic rats. Aging and Disease, 9(3), 453-466. https://doi.org/10.14336/AD.2017.1130

APX3330 promotes neurorestorative effects after stroke in type one diabetic rats. / Yan, Tao; Venkat, Poornima; Chopp, Michael; Zacharek, Alex; Yu, Peng; Ning, Ruizhuo; Qiao, Xiaoxi; Kelley, Mark; Chen, Jieli.

In: Aging and Disease, Vol. 9, No. 3, 01.06.2018, p. 453-466.

Research output: Contribution to journalArticle

Yan, T, Venkat, P, Chopp, M, Zacharek, A, Yu, P, Ning, R, Qiao, X, Kelley, M & Chen, J 2018, 'APX3330 promotes neurorestorative effects after stroke in type one diabetic rats', Aging and Disease, vol. 9, no. 3, pp. 453-466. https://doi.org/10.14336/AD.2017.1130
Yan, Tao ; Venkat, Poornima ; Chopp, Michael ; Zacharek, Alex ; Yu, Peng ; Ning, Ruizhuo ; Qiao, Xiaoxi ; Kelley, Mark ; Chen, Jieli. / APX3330 promotes neurorestorative effects after stroke in type one diabetic rats. In: Aging and Disease. 2018 ; Vol. 9, No. 3. pp. 453-466.
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