Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Sweden.
Neurobiol Dis. 2011 Oct;44(1):142-51. doi: 10.1016/j.nbd.2011.06.016. Epub 2011 Jul 2.
Histone deacetylase (HDAC) inhibitors have promising neuroprotective and anti-inflammatory properties although the exact mechanisms are unclear. We have earlier showed that factors from lipopolysaccharide (LPS)-activated microglia can down-regulate the astroglial nuclear factor-erythroid 2-related factor 2 (Nrf2)-inducible anti-oxidant defence. Here we have evaluated whether histone modification and activation of GSK3β are involved in these negative effects of microglia. Microglia were cultured for 24 h in serum-free culture medium to achieve microglia-conditioned medium from non-activated cells (MCM(0)) or activated with 10 ng/mL of LPS to produce MCM(10). Astrocyte-rich cultures treated with MCM(10) showed a time-dependent (0-72 h) increase in astroglial HDAC activity that correlated with lower levels of acetylation of histones H3 and H4 and decreased levels of the transcription factor Nrf2 and γ-glutamyl cysteine ligase modulatory subunit (γGCL-M) protein levels. The HDAC inhibitors valproic acid (VPA) and trichostatin-A (TSA) elevated the histone acetylation levels, restored the Nrf2-inducible anti-oxidant defence and conferred protection from oxidative stress-induced (H(2)O(2)) death in astrocyte-rich cultures exposed to MCM(10). Inhibitors of GSK3β (lithium) and p38 MAPK (SB203580) signaling pathways restored the depressed histone acetylation and Nrf2-related transcription whereas an inhibitor of Akt (Ly294002) caused a further decrease in Nrf2-related transcription. In conclusion, the study shows that well tolerated drugs such as VPA and lithium can restore an inflammatory induced depression in the Nrf2-inducible antioxidant defence, possibly via normalised histone acetylation levels.
组蛋白去乙酰化酶（HDAC）抑制剂具有有前景的神经保护和抗炎特性，尽管确切机制尚不清楚。我们之前已经表明，脂多糖（LPS）激活的小胶质细胞中的因子可以下调星形胶质细胞核因子-红细胞 2 相关因子 2（Nrf2）诱导的抗氧化防御。在这里，我们评估了组蛋白修饰和 GSK3β 的激活是否参与了小胶质细胞的这些负性效应。小胶质细胞在无血清培养基中培养 24 小时，以从非激活细胞（MCM(0)）产生小胶质细胞条件培养基或用 10 ng/mL LPS 激活以产生 MCM(10)。用 MCM(10)处理的星形胶质细胞丰富的培养物显示出星形胶质细胞 HDAC 活性的时间依赖性（0-72 小时）增加，与组蛋白 H3 和 H4 的乙酰化水平降低以及转录因子 Nrf2 和γ-谷氨酰半胱氨酸连接酶调节亚基（γGCL-M）蛋白水平降低相关。HDAC 抑制剂丙戊酸（VPA）和曲古抑菌素 A（TSA）提高了组蛋白乙酰化水平，恢复了 Nrf2 诱导的抗氧化防御，并在暴露于 MCM(10)的星形胶质细胞丰富的培养物中提供了对氧化应激诱导的（H2O2）死亡的保护。GSK3β（锂）和 p38 MAPK（SB203580）信号通路的抑制剂恢复了被抑制的组蛋白乙酰化和 Nrf2 相关转录，而 Akt（Ly294002）抑制剂导致 Nrf2 相关转录进一步降低。总之，该研究表明，像 VPA 和锂这样的耐受性良好的药物可以通过正常化组蛋白乙酰化水平来恢复 Nrf2 诱导的抗氧化防御的炎症诱导性抑制。
