A Novel 2-Phenylamino-Quinazoline-Based Compound Expands the Neural Stem Cell Pool and Promotes the Hippocampal Neurogenesis and the Cognitive Ability of Adult Mice. (12th May 2018)

• Record Type: Journal Article
• Authors: Lu, Hui; Cheng, Gang; Hong, Feng; Zhang, Lei; Hu, Youhong; Feng, Linyin
• Is Part Of: Stem cells. Volume 36:Number 8(2018)
• Page Start: 1273
• Page End: 1285
• Publication Date: 2018-05-12
• Subjects: Neural stem cells -- Notch signaling pathway -- Hes5 -- Adult hippocampal neurogenesis -- Learning and memory -- 2-phenylamino-quinazoline; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2843
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract : The adult neurogenesis occurs throughout the life of the mammalian hippocampus and is found to be essential for learning and memory. Identifying new ways to manipulate the number of neural stem cells (NSCs) and enhance endogenous neurogenesis in adults is very important. Here we found that a novel compound, N2-(4-isopropylphenyl)-5-(3-methoxyphenoxy)quinazoline-2, 4-diamine (code-named Yhhu-3792), enhanced the self-renewal capability of NSCs in vitro and in vivo. In vitro, Yhhu-3792 increased the ratio of 5-Bromo-2-deoxyuridine + /4′-6-diamidino-2-phenylindole + embryonic NSCs and accelerated the growth of neurospheres significantly. We demonstrated that Yhhu-3792 activated Notch signaling pathway and promoted the expression of Notch target genes, Hes3 and Hes5 . And the Notch signaling inhibitor DAPT could inhibit its function. Thus, we concluded Yhhu-3792 increased the number of embryonic NSCs via activating the Notch signaling pathway. We measured the effect of Yhhu-3792 on epidermal growth factor receptor signaling, which demonstrated Yhhu-3792 act via a different mechanism with the quinazoline parent chemical group. In the eight-week-old male C57BL/6 mice, chronic Yhhu-3792 administration expanded the NSCs pool and promoted endogenous neurogenesis in the hippocampal dentate gyrus (DG). It also increased the spatial and episodic memory abilities of mice, when evaluated with the Morris water maze and Fear conditioning tests. In conclusion, Yhhu-3792 could be a novel drug candidate to promote the self-renew of NSCs and adult neurogenesis. And it may have therapeutic potential in the impairment of learning and memory associated DG dysfunction. Abstract : A novel 2-phenylamino-quinazoline-based small molecular expands the neural stem cells pool, promotes adult hippocampal neurogenesis, and elevates the cognitive ability of adult mice.