Department of Nursing, Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan.
Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
CNS Neurosci Ther. 2019 Feb;25(2):175-186. doi: 10.1111/cns.13029. Epub 2018 Jul 5.
Recently, histone deacetylase (HDAC) inhibitors are considered a possible therapeutic strategy in Alzheimer's disease (AD). However, HDACi treatments exhibit diverse functions with unfavorable effects in AD. Thus, the development of selective HDACi without side effects is urgently needed.
HDACi, namely, BML210, MGCD0103, PXD101, and Droxinostat, were screened in mouse hippocampal primary cultures incubated with oligomeric Aβ (50 μmol/L). MGCD0103 was chosen for in vivo tests and was intraperitoneally injected into C57BL/6J mice (0.5 mg/kg, once per day) for 4 weeks following an intrahippocampal CA1 injection of oligomeric Aβ . Brain samples were collected for pathological analyses after the behavioral analyses including open- field test (OFT), elevated plus maze (EPM), Y-maze, and Morris water maze (MWM).
Among the HDACi, MGCD0103 exhibited significant neuroprotection against the Aβ toxicity in primary cultures. MGCD0103 coattenuated cognitive deficits and anxiety against Aβ damage in mice. MGCD0103 further ameliorated pathological features such as the levels of acetylated histone 3 at Lys 9 site (H3K9) and α-tubulin, synaptophysin, Aβ, tau protein phosphorylation, and serotonergic neuron loss against Aβ toxicity. Furthermore, chronic MGCD0103 treatment did not show liver or kidney toxicity in mice.
These results reveal MGCD0103 could be a potential therapeutic agent against AD.
最近，组蛋白去乙酰化酶（HDAC）抑制剂被认为是阿尔茨海默病（AD）的一种潜在治疗策略。然而，HDACi 治疗在 AD 中表现出多种功能，并有不良反应。因此，迫切需要开发无副作用的选择性 HDACi。
在培养的含有寡聚体 Aβ（50 μmol/L）的小鼠海马原代培养物中筛选 HDACi，即 BML210、MGCD0103、PXD101 和 Droxinostat。选择 MGCD0103 进行体内试验，并在海马 CA1 内注射寡聚体 Aβ 后，对 C57BL/6J 小鼠（0.5 mg/kg，每天一次）进行腹腔内注射，持续 4 周。在进行行为分析（包括旷场试验（OFT）、高架十字迷宫（EPM）、Y 迷宫和 Morris 水迷宫（MWM））后，收集脑样本进行病理分析。
在这些 HDACi 中，MGCD0103 对原代培养物中的 Aβ 毒性表现出显著的神经保护作用。MGCD0103 减轻了 Aβ 损伤小鼠的认知功能障碍和焦虑。MGCD0103 进一步改善了病理特征，如乙酰化组蛋白 3 在赖氨酸 9 位（H3K9）和微管相关蛋白的水平、突触小体蛋白、Aβ、tau 蛋白磷酸化和 5-羟色胺能神经元丢失，减轻了 Aβ 毒性。此外，慢性 MGCD0103 治疗在小鼠中未显示出肝或肾毒性。
这些结果表明，MGCD0103 可能是一种治疗 AD 的潜在药物。
