Tubastatin A, an HDAC6 inhibitor, alleviates stroke-induced brain infarction and functional deficits: Potential roles of α-tubulin acetylation and FGF-21 up-regulation

Zhifei Wang, Yan Leng, Junyu Wang, Hsiao Mei Liao, Joel Bergman, Peter Leeds, Alan Kozikowski, De Maw Chuang

Research output: Contribution to journalArticle

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 24hours 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.

Original languageEnglish (US)
Article number19626
JournalScientific Reports
Volume6
DOIs
StatePublished - Jan 21 2016
Externally publishedYes

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Brain Infarction
Tubulin
Acetylation
Middle Cerebral Artery Infarction
Up-Regulation
Stroke
Down-Regulation
Glycogen Synthase Kinase 3
Histone Deacetylases
fibroblast growth factor 21
tubastatin A
Neuroprotective Agents
Glutamic Acid
Cytoplasm
Cell Death
Central Nervous System
Neurons

ASJC Scopus subject areas

  • General

Cite this

Tubastatin A, an HDAC6 inhibitor, alleviates stroke-induced brain infarction and functional deficits : Potential roles of α-tubulin acetylation and FGF-21 up-regulation. / Wang, Zhifei; Leng, Yan; Wang, Junyu; Liao, Hsiao Mei; Bergman, Joel; Leeds, Peter; Kozikowski, Alan; Chuang, De Maw.

In: Scientific Reports, Vol. 6, 19626, 21.01.2016.

Research output: Contribution to journalArticle

Wang, Zhifei ; Leng, Yan ; Wang, Junyu ; Liao, Hsiao Mei ; Bergman, Joel ; Leeds, Peter ; Kozikowski, Alan ; Chuang, De Maw. / Tubastatin A, an HDAC6 inhibitor, alleviates stroke-induced brain infarction and functional deficits : Potential roles of α-tubulin acetylation and FGF-21 up-regulation. In: Scientific Reports. 2016 ; Vol. 6.
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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 24hours 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.",
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