PDF(Pubmed)
Abstract：
A large body of evidence has demonstrated that neuronal apoptosis is involved in the pathological process of secondary brain injury following intracerebral hemorrhage (ICH). Additionally, our previous studies determined that the inhibition of HDAC6 activity by tubacin or specific shRNA can attenuate neuronal apoptosis in an oxygen-glucose deprivation reperfusion model. However, whether the pharmacological inhibition of HDAC6-attenuated neuronal apoptosis in ICH remains unclear. In this study, we used hemin-induced SH-SY5Y cells to simulate a hemorrhage state in vitro and adopted a collagenase-induced ICH rat model in vivo to assess the effect of the HDAC6 inhibition. We found a significant increase in HDAC6 during the early stages of ICH. As expected, the acetylated α-tubulin significantly decreased in correlation with the expression of HDAC6. Medium and high doses (25, 40 mg/kg) of TubA, a selective inhibitor of HDAC6, both reduced neurological impairments, histological impairments, and ipsilateral brain edema in vivo. TubA or HDAC6 siRNA both alleviated neuronal apoptosis in vivo and in vitro. Finally, HDAC6 inhibition increased the level of acetylated α-tubulin and Bcl-2 and lowered the expression of Bax and cleaved caspase-3 post-ICH. In general, these results suggested that the pharmacological inhibition of HDAC6 may act as a novel and promising therapeutic target for ICH therapy by up-regulating acetylated α-tubulin and reducing neuronal apoptosis.
摘要：
大量证据表明，神经元凋亡参与了脑出血（ICH）后继发性脑损伤的病理过程。此外,我们之前的研究确定,在氧-葡萄糖剥夺再灌注模型中,通过tubacin或特异性shRNA抑制HDAC6活性可以减弱神经元凋亡.然而,HDAC6的药理学抑制是否能减弱ICH中的神经元凋亡尚不清楚.在这项研究中,我们使用血红素诱导的SH-SY5Y细胞在体外模拟出血状态,并在体内采用胶原酶诱导的ICH大鼠模型来评估HDAC6抑制作用.我们发现在ICH的早期阶段HDAC6显著增加。不出所料,乙酰化α-微管蛋白显著降低,与HDAC6的表达相关。中高剂量（25，40mg/kg）的TubA，HDAC6的选择性抑制剂，两者都减少了神经损伤，组织学损伤，和体内同侧脑水肿。TubA或HDAC6siRNA均在体内和体外减轻神经元凋亡。最后,HDAC6抑制增加了ICH后乙酰化α-微管蛋白和Bcl-2的水平，并降低了Bax和裂解的caspase-3的表达。总的来说,这些结果表明，通过上调乙酰化α-微管蛋白和减少神经元凋亡，HDAC6的药理学抑制可能成为ICH治疗的新的和有前景的治疗靶点。
