Oikawa Hirotaka, Goh Wilson W B, Lim Vania K J, Wong Limsoon, Sng Judy C G
Neuroepigenetics Laboratory, Singapore Institute for Clinical Sciences, Agency for Science and Technology (A*STAR), Singapore.
School of Pharmaceutical Science and Technology, Tianjin University, China; School of Computing, National University of Singapore, Singapore.
Neurochem Int. 2015 Dec;91:62-71. doi: 10.1016/j.neuint.2015.10.010. Epub 2015 Oct 27.
Valproic acid (VPA) is an anti-convulsant drug that is recently shown to have neuroregenerative therapeutic actions. In this study, we investigate the underlying molecular mechanism of VPA and its effects on Bdnf transcription through microRNAs (miRNAs) and their corresponding target proteins. Using in silico algorithms, we predicted from our miRNA microarray and iTRAQ data that miR-124 is likely to target at guanine nucleotide binding protein alpha inhibitor 1 (GNAI1), an adenylate cyclase inhibitor. With the reduction of GNAI1 mediated by VPA, the cAMP is enhanced to increase Bdnf expression. The levels of GNAI1 protein and Bdnf mRNA can be manipulated with either miR-124 mimic or inhibitor. In summary, we have identified a novel molecular mechanism of VPA that induces miR-124 to repress GNAI1. The implication of miR-124→GNAI1→BDNF pathway with valproic acid treatment suggests that we could repurpose an old drug, valproic acid, as a clinical application to elevate neurotrophin levels in treating neurodegenerative diseases.
丙戊酸（VPA）是一种抗惊厥药物，最近被证明具有神经再生治疗作用。在本研究中，我们通过微小RNA（miRNA）及其相应的靶蛋白，研究了VPA的潜在分子机制及其对脑源性神经营养因子（Bdnf）转录的影响。利用计算机算法，我们从miRNA微阵列和iTRAQ数据预测，miR-124可能靶向鸟嘌呤核苷酸结合蛋白α抑制因子1（GNAI1），一种腺苷酸环化酶抑制剂。随着VPA介导的GNAI1减少，环磷酸腺苷（cAMP）增加，从而增加Bdnf表达。miR-124模拟物或抑制剂均可调控GNAI1蛋白水平和Bdnf mRNA水平。总之，我们发现了VPA诱导miR-124抑制GNAI1的新分子机制。丙戊酸治疗中miR-124→GNAI1→BDNF途径的意义表明，我们可以将旧药丙戊酸重新用于临床，以提高神经营养因子水平来治疗神经退行性疾病。
