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

doi:10.1038/srep19626

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.

Highlights

Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-tubulin
This study demonstrated that the selective HDAC6 inhibitor Tubastatin A (TubA) markedly reduced brain infarct volume, mitigated neuronal death, and improved functional deficits induced by focal cerebral ischemia in rats
The robust neuroprotective effects and behavioral benefits in conjunction with the long time window suggest that TubA has promising utility for the treatment of ischemic stroke, underscoring the mounting evidence that selective inhibition of HDAC6 is neuroprotective and promotes regeneration after injury in the CNS6

Summary

Introduction

Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-tubulin. HDAC6 is a unique member of the class IIb HDACs, with two catalytic domains and predominantly cytoplasmic localization[4] This HDAC isoform regulates various cellular processes, including microtubule-based transport, cell motility, endocytosis, cell migration, autophagy, and aggresome formation, by deacetylating non-histone proteins, such as α -tubulin, cortactin, and heat shock protein 90 (HSP90)[5]. In several experimental models of central and peripheral nervous diseases, TubA has exhibited neuroprotective effects It rescued neuronal death from oxidative stress induced by homocysteic acid, reversed axonal loss in a mouse model of Charcot-Marie-Tooth disease, improved cognitive deficits in a mouse model of Alzheimer’s disease, and facilitated BDNF trafficking in hippocampal neurons in a mouse model of Rett syndrome[12,14,15,16]

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