title: 4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor.
abstract: This letter describes the mechanism behind the protective effect of 4-phenylbutyric acid (4-PBA) against endoplasmic reticulum (ER) stress-induced neuronal cell death using three simple 4-(p-substituted phenyl) butyric acids (4-PBA derivatives). Their relative human histone deacetylase (HDAC) inhibitory activities were consistent with a structural model of their binding to HDAC7, and their ability to suppress neuronal cell death and activity of chemical chaperone in vitro. These data suggest that 4-PBA protects against neuronal cell death mediated by the chemical chaperone activity rather than by inhibition of histone deacetylase.
authors.affiliation: Department of Pharmaceutical and Life Sciences, Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan.
authors.forename: Seisuke
authors.initials: S
authors.lastname: Mimori
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ohtaka
authors.forename: Yukari
authors.initials: Y
authors.lastname: Koshikawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawada
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kaneko
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Okuma
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nomura
authors.forename: Yasuoki
authors.initials: Y
authors.lastname: Murakami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hamana
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology*; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors; D018832:Molecular Chaperones; D010654:Phenylbutyrates; D020011:Protective Agents; C075773:4-phenylbutyric acid
keywords: 4-phenylbutyric acid (4-PBA); Acetyl histone H3; Chemical chaperone; Endoplasmic reticulum (ER) stress; Histone deacetylase (HDAC)