Abstract 60: Sequential Combined Treatment of Pifithrin-a and (+)-phenserine Enhances Neurogenesis and Functional Recovery After Stroke

Abstract

Background and Purpose: Due to the limitation in treatment window of the rtPA (recombinant tissue plasminogen activator), the development of delayed treatment for stroke is needed. Utilizing a specific p53 inhibitor (PFT-a), our group has previously reported enhanced 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) has been implicated in synapse formation, neural plasticity, and the differentiation of neural stem cells. In this study, we examined the efficacy of delayed post-stroke treatment of sequentially combined PFT-a (post-stroke day 5-12) and an amyloid precursor protein inhibitor, (+)-phenserine (post stroke day 13-27) on functional recovery after stroke and the response of endogenous neural progenitor cells in SVZ and SGZ in stroke animals. Methods: We utilized a genetically inducible NSC-specific reporter mouse line (nestin-CreERT2-R26R-YFP) to label and track neural stem cell proliferation, survival, and differentiation in ischemic brain. We evaluated functional recovery at 4 weeks after stroke using locomotion analysis, novel object recognition and Barnes maze tests for cognitive function. Results: Our results show that delayed and combined treatment with PFT-a and (+)-phenserine resulted in increased proliferation and differentiation of YFP positive neuronal stem cells in post-stroke mice compared to vehicle treated stroke mice. In addition, the combined treatment cohort showed improved functional recovery in both locomotor (open field) and cognitive functions (NOR and Barnes maze) starting at 2 weeks post stroke and sustained up to 4 weeks after stroke. Conclusions: Our data suggest that sequential combination treatment strategy that enhances proliferation and neuronal differentiation of endogenous neural stem cells can work synergistically and improve the functional recovery after stroke through increased neurogenesis. This may provide a prolonged treatment window for improving functional recovery after stroke.