title: Effect of HDAC inhibitors on neuroprotection and neurite outgrowth in primary rat cortical neurons following ischemic insult.
abstract: Histone deacetylase inhibitors (HDACi)-valproic acid (VPA) and trichostatin A (TSA) promote neurogenesis, neurite outgrowth, synaptic plasticity and neuroprotection. In this study, we investigated whether VPA and TSA promote post-ischemic neuroprotection and neuronal restoration in rat primary cortical neurons. On 6 days in vitro (DIV), cortical neurons were exposed to oxygen-glucose deprivation for 90 min. Cells were returned to normoxic conditions and cultured for 1, 3, or 7 days with or without VPA and TSA. Control cells were cultured in normoxic conditions only. On 7, 9, and 13 DIV, cells were measured neurite outgrowth using the Axiovision program and stained with Tunel staining kit. Microtubule associated protein-2 immunostaining and tunel staining showed significant recovery of neurite outgrowth and post-ischemic neuronal death by VPA or TSA treatment. We also determined levels of acetylated histone H3, PSD95, GAP 43 and synaptophysin. Significant increases in all three synaptic markers and acetylated histone H3 were observed relative to non-treated cells. Post-ischemic HDACi treatment also significantly raised levels of brain derived neurotrophic factor (BDNF) expression and secreted BDNF. Enhanced BDNF expression by HDACi treatment might have been involved in the post-ischemic neuroprotection and neuronal restorative effects. Our findings suggest that both VPA and TSA treatment during reoxygenation after ischemia may help post-ischemic neuroprotection and neuronal regeneration via increased BDNF expression and activation.
authors.affiliation: Center for Neuroscience Research, SMART Institute of Advanced Biomedical Science, Konkuk University, Seoul, 143-701, Korea.
authors.forename: Mohammad Rakibul
authors.initials: MR
authors.lastname: Hasan
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Youn Jung
authors.initials: YJ
authors.lastname: Kim
authors.forename: Kyoung Ja
authors.initials: KJ
authors.lastname: Kwon
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.forename: Hahn Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Seol-Heui
authors.initials: SH
authors.lastname: Han
authors.forename: Dong-Hee
authors.initials: DH
authors.lastname: Choi
authors.forename: Jongmin
authors.initials: J
authors.lastname: Lee
mesh_terms: D000818:Animals; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D017931:DNA Primers; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D016501:Neurites; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017931:DNA Primers; D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents