Study of Mechanism Underlying the Effects of Novel Histone Deacetylase 8 Inhibitors on Neural Plasticity and LearningMemory in Mice

• Main Authors: Min-Hsuan Hsun, 孫旻萱
• Other Authors: Yang, Ying-Chen
• Format: Others
• Language: zh-TW
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/356n3d

碩士 === 國立宜蘭大學 === 生物技術與動物科學系生物技術碩士班 === 107 === The definition of epigenetic regulation is the heritable changes in gene function and phenotype that do not involve changes in the DNA sequence. The modification includes acetylation, phosphorylation, methylation and ubiquitination especially acetylation which is the most important modification of epigenetic regulation. Histone acetyltransferase (HAT) can acetylate histones and non-histone proteins to facilitate the chromatin structure release from the binding histones and increases gene expression/transcription and the function of non-histone proteins. In contrast, histone deacetylase (HDAC) can remove the acetyl groups on the histone/non-histone proteins. The recent researches have showed that histone deacetylase inhibitors (HDACi) also has the potential in treatment of the central nervous system diseases. However, the side effects are often concerned after treating by HDACi. Therefore, developing a selective HDACi might be reduce the toxicity and side effects. It’s has been showed that many available class I HDACi cannot inhibit HDAC8, or they need higher dose to inhibit HDAC8 because of the enzymatic pocket of HDAC8 may be different from the other class I members. Thus, it worths to develop a selective HDAC8 inhibitor. In our study, PCI-34051 is adopted as a positive control since it is the currently most effective and selective HDAC8 inhibitor. In the past, our lab has screened a series of selective HDAC8 inhibitors including compounds series A and F. Both of A2 and F3 have been identified to have better effect on neural plasticity as well as to demonstrate their capability in enhancement of learning and memory in animal models. The aim of the study is to investigate the mechanism of the selective HDAC8 inhibitors on neural plasticity and the effects of learning and memory in mice. The results show that in the nucleus, A2 and F3 up-regulate the secretion of brain-derived neurotrophic factor (BDNF) by up-regulating BDNF promoter IV, and acetylated tubulin assists BDNF transport to the extracellular membrane. Through the tropomyosin-related kinase B (TrkB) receptor BDNF can enter the cytoplasmic regulation downstream signaling pathway. In cytoplasm, A2 and F3 regulate HDAC8 phosphorylation and distribution to alter HDAC8 activity, which in turn affects the TrkB receptor downstream signaling pathway, including up-regulating PI3K and MAPK-ERK signaling pathways and downstream AKT and CREB proteins to promote neural plasticity and learning memory. In summary, A2 and F3 can influence neuronal plasticity and learning memory expression by regulating the secretion of BDNF, affecting the TrkB receptor downstream signaling pathway PI3K, MAPK-ERK and regulating the degree of HDAC8 phosphorylation and distribution to alter HDAC8 activity.