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.
Highlights
Hyperglycemia and insulin resistance are major risk factors for ischemic stroke, atherosclerosis, and vascular and cardiac complications [1]
APX3330 treatment significantly improves functional outcome after stroke in T1DM rats and the data show that the overall group effect was significant on day 14 after stroke (p
Total vascular density was significantly reduced in APX3330 treatment rats compared with PBS treated control T1DM stroke rats (p
Summary
Hyperglycemia and insulin resistance are major risk factors for ischemic stroke, atherosclerosis, and vascular and cardiac complications [1]. Myelin degradation following ischemic stroke is attenuated in MMP9 knockout mice [10], implicating MMP’s in post-stroke WM injury Inflammatory factors such as the receptor for advanced glycation endproducts (RAGE) play a vital role in promoting inflammation and diabetic complications [11, 12]. In T1DM stroke rats, suppressing NFκB signaling pathway significantly decreases inflammatory factors such as RAGE and TLR4 expression in the ischemic brain and improves stroke outcome [25]. While neuroprotective therapies that up regulate HIF-1α activity have been reported to promote pro-angiogenic responses and improve stroke outcome in diabetic mice [26], several reports indicate that DM up regulates HIF-1α protein levels and increases HIF-1α transcriptional activity in endothelial cells, which in turn can adversely affect tight junction proteins and BBB permeability [27, 28]. We are the first to investigate whether APX330 treatment could improve functional outcome after stroke in Type one diabetic (T1DM) rats, whether APX3330 induces neurorestorative effects, and what mechanisms are involved in APX330 treatment induced beneficial effects in T1DM stroke rats
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