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  • Combined Treatment Strategy to Enhance Neurogenesis After Stroke

    Final Number:

    Austin Barnett BS; Margaret Carmody BS, MD; Yu Luo PhD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2016 Annual Meeting

    Introduction: Current treatment strategies for stroke primarily focus on reducing the size of ischemic damage and on rescuing dying cells early after occurrence. Utilizing a specific p53 inhibitor (PFT-a), our group has enhanced the proliferation and survival of endogenous progenitor cells in-vivo, leading to enhanced functional recovery in stroke animals days and weeks after stroke onset. Recently, a role for amyloid-ß protein precursor (APP), best known for its role in Alzheimer’s disease (AD), has been implicated in synapse formation, neural plasticity, and the differentiation of neural stem cells. Our hypothesis is that upregulation and accumulation of APP fragments in ischemic brain may prevent neuronal differentiation of endogenous brain progenitor cells, leading to insufficient neural repair.

    Methods: To enhance the neuronal differentiation of endogenous progenitor cells, we utilized an amyloid precursor protein inhibitor, (+)-phenserine, in combination of PFT-a and will test whether stimulation of both proliferation and neural differentiation of endogenous neural progenitor cells will lead to enhanced functional outcome in stroke recovery in an animal stroke model , middle cerebral artery occlusion (MCAo). The effect of the post stroke treatment was evaluated using behavioral and cognitive testing to measure the functional deficits in the treated mice vs. control mice treated with saline after stroke.

    Results: The behavioral tests, spontaneous locomotion and RotaRod, as well as the cognitive testing showed an improved functional recovery in the treatment group. Our results also show that PFT-alpha administration resulted in a significant increase in the number of sub-ventricular zone (SVZ) and sub-granular zone (SGZ) neuronal stem cells. Additionally, combined treatment of PFT-a and (+)-phenserine resulted an increase in immature neuroblasts present post-infarct, indicating enhanced neuronal differentiation.

    Conclusions: Our data suggests that combined treatment strategy that enhances proliferation and neuronal differentiation can work synergistically and improve the functional recovery after stroke through increased neurogenesis.

    Patient Care: This research has the potential to improve outcomes from ischemic stroke by opening new avenues of treatment by shifting the focus from limiting the damage to actively working to promote healing and regaining of lost function.

    Learning Objectives: By the conclusion of the session, participants should be able to: 1) Describe the pathway of inflammation and damage that leads to cell death in an ischemic stroke. 2) Understand the effect of p53 and APP on neuronal stem cells.


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