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

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.

组蛋白去乙酰化酶（HDAC）6 仅存在于细胞质中，可使诸如α - 微管蛋白等细胞质蛋白去乙酰化。HDAC6 功能障碍与中枢神经系统的多种病理状况相关。本研究在短暂大脑中动脉闭塞（MCAO）大鼠模型及兴奋性毒性体外模型中，探究了新型特异性 HDAC6 抑制剂图巴他汀 A（TubA）的有益作用。缺血后给予 TubA 能显著改善 MCAO 大鼠的功能预后，减少脑梗死面积，并减轻神经元细胞死亡。这些有益作用在 MCAO 后至少持续三天。值得注意的是，在 MCAO 后 24 小时给予 TubA，仍显示出显著的保护作用。MCAO 后第 1 天和第 3 天，缺血半球中乙酰化α - 微管蛋白水平降低，而 TubA 可使其显著恢复。MCAO 显著下调成纤维细胞生长因子 - 21（FGF - 21），TubA 则显著逆转这种下调。TubA 还减轻了缺血半球中受损的 FGF - 21 信号传导，包括上调β - Klotho，以及激活 ERK 和 Akt/GSK - 3β信号通路。此外，TubA 和外源性 FGF - 21 均对大鼠皮质神经元具有神经保护作用，并恢复了其在谷氨酸诱导的兴奋性毒性下的线粒体运输。我们的研究结果表明，TubA 的神经保护作用可能涉及抑制 HDAC6 以及随后乙酰化α - 微管蛋白和 FGF - 21 的上调。