Phenotypic screen-based discovery of a small molecule that can increase adult neurogenesis and improve memory

Stem cells and neurogenesis persist in the postnatal and adult brain. Adult brain stem cells can be neuroprotective in disease and augment hippocampal-dependent cognitive function and thus are an important therapeutic target. Although many molecules have been discovered that regulate neurogenesis, few studies have attempted to amplify the process pharmacologically as a therapeutic goal. To address this gap, we used murine neurosphere cultures from the two major stem cell niches: the subventricular zone (SVZ) and the subgranular zone (SGZ). We screened compounds sharing pharmacophores with known inducers of neurogenesis and found several dozen proneurogenic compounds in an in vitro phenotypic screen. One, OXS-N1 was stable, and had acceptable absorption, distribution, metabolism, and excretion profiles in animal studies. OXS-N1 could increase neurogenesis in the SVZ and SGZ in WT mice after both intraperitoneal and oral administration. The number of newborn neurons (BrdU+/NeuN+) was increased; however, the number of activated stem cells (BrdU+/GFAP+) was not, suggesting an effect on neurogenesis independent of stem cell activation. This was supported by OXS-N1 increasing neurosphere differentiation but not proliferation. OXS-N1 also increased neurogenesis and improved performance in a Y maze cognitive task in PDGF-APPSw,Ind mice, a model of Alzheimer’s disease. RNAseq of SVZ and SGZ neurospheres in turn showed that genes associated with synaptic function were significantly increased by OXS-N1. Our study demonstrates the utility of phenotypic screening for the identification of molecules that increase neurogenesis and might be of therapeutic relevance.