title: Tubastatin A, an HDAC6 inhibitor, alleviates stroke-induced brain infarction and functional deficits: potential roles of α-tubulin acetylation and FGF-21 up-regulation.
abstract: Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-tubulin. HDAC6 dysfunction is associated with several pathological conditions in the central nervous system. This study investigated the beneficial effects of tubastatin A (TubA), a novel specific HDAC6 inhibitor, in a rat model of transient middle cerebral artery occlusion (MCAO) and an in vitro model of excitotoxicity. Post-ischemic TubA treatment robustly improved functional outcomes, reduced brain infarction, and ameliorated neuronal cell death in MCAO rats. These beneficial effects lasted at least three days after MCAO. Notably, when given at 24 hours after MCAO, TubA still exhibited significant protection. Levels of acetylated α-tubulin were decreased in the ischemic hemisphere on Days 1 and 3 after MCAO, and were significantly restored by TubA. MCAO markedly downregulated fibroblast growth factor-21 (FGF-21) and TubA significantly reversed this downregulation. TubA also mitigated impaired FGF-21 signaling in the ischemic hemisphere, including up-regulating β-Klotho, and activating ERK and Akt/GSK-3β signaling pathways. In addition, both TubA and exogenous FGF-21 conferred neuroprotection and restored mitochondrial trafficking in rat cortical neurons against glutamate-induced excitotoxicity. Our findings suggest that the neuroprotective effects of TubA likely involve HDAC6 inhibition and the subsequent up-regulation of acetylated α-tubulin and FGF-21.
authors.affiliation: School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China.|Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA.
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Leng
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA.
authors.forename: Junyu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA.
authors.forename: Hsiao-Mei
authors.initials: HM
authors.lastname: Liao
authors.affiliation: Drug Discovery Program, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Bergman
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Leeds
authors.affiliation: Drug Discovery Program, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Kozikowski
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA.
authors.forename: De-Maw
authors.initials: DM
authors.lastname: Chuang
mesh_terms: D000107:Acetylation; D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D018696:Neuroprotective Agents; D014404:Tubulin; C414620:fibroblast growth factor 21; C553587:tubastatin A; D018698:Glutamic Acid; D005346:Fibroblast Growth Factors