title: Valproic Acid Arrests Proliferation but Promotes Neuronal Differentiation of Adult Spinal NSPCs from SCI Rats.
abstract: Although the adult spinal cord contains a population of multipotent neural stem/precursor cells (NSPCs) exhibiting the potential to replace neurons, endogenous neurogenesis is very limited after spinal cord injury (SCI) because the activated NSPCs primarily differentiate into astrocytes rather than neurons. Valproic acid (VPA), a histone deacetylase inhibitor, exerts multiple pharmacological effects including fate regulation of stem cells. In this study, we cultured adult spinal NSPCs from chronic compressive SCI rats and treated with VPA. In spite of inhibiting the proliferation and arresting in the G0/G1 phase of NSPCs, VPA markedly promoted neuronal differentiation (β-tubulin III(+) cells) as well as decreased astrocytic differentiation (GFAP(+) cells). Cell cycle regulator p21(Cip/WAF1) and proneural genes Ngn2 and NeuroD1 were increased in the two processes respectively. In vivo, to minimize the possible inhibitory effects of VPA to the proliferation of NSPCs as well as avoid other neuroprotections of VPA in acute phase of SCI, we carried out a delayed intraperitoneal injection of VPA (150 mg/kg/12 h) to SCI rats from day 15 to day 22 after injury. Both of the newborn neuron marker doublecortin and the mature neuron marker neuron-specific nuclear protein were significantly enhanced after VPA treatment in the epicenter and adjacent segments of the injured spinal cord. Although the impaired corticospinal tracks had not significantly improved, Basso-Beattie-Bresnahan scores in VPA treatment group were better than control. Our study provide the first evidence that administration of VPA enhances the neurogenic potential of NSPCs after SCI and reveal the therapeutic value of delayed treatment of VPA to SCI.
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 29, Gaotanyan Street, Shapingba District, Chongqing, 400038, China, weihua9871@163.com.
authors.forename: Weihua
authors.initials: W
authors.lastname: Chu
authors.forename: Jichao
authors.initials: J
authors.lastname: Yuan
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Xin
authors.initials: X
authors.lastname: Xiang
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhu
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Chen
authors.forename: Jiangkai
authors.initials: J
authors.lastname: Lin
authors.forename: Hua
authors.initials: H
authors.lastname: Feng
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D000089662:Doublecortin Protein; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000473:pathology*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D014635:Valproic Acid