ISX-9

ISX-9 (Isoxazole 9) is a potent inducer of adult neural stem cell differentiation. ISX-9 activates Ca²⁺ influx through both voltage-gated Ca²⁺ channels and NMDA receptors and increases neuroD expression. ISX-9 also induces cardiomyogenic differentiation of Notch-activated epicardium-derived cells (NECs)^[1][2][3]. In Vitro: ISX-9 promotes neurogenesis in vivo, enhancing the proliferation and differentiation of hippocampal subgranular zone (SGZ) neuroblasts, and the dendritic arborization of adult-generated dentate gyrus neurons. At 2.5-20 μM, ISX-9 has been shown to dose-dependently trigger neurogenesis and block gliogenesis in adult rat hippocampal stem cells through a calcium-activated signaling pathway dependent on myocyte-enhancer factor 2-dependent gene expression^[1].
Molecular exploration of ISX-9-induced regulation of neurogenesis (via FACS and microarray of SGZ stem and progenitor cells) suggested the involvement of the myocyte-enhancer family of proteins (Mef2)^[1]. In Vivo: ISX-9 (20 mg/kg; for 12 days; mice) treatment improves hippocampal function. ISX-9 enhances spatial memory ability in the Morris water maze test. ISX-9 enhances hippocampal neurogenesis and memory in vivo, and its effects are reliant on Mef2^[1].