Mossakowski Medical Research Institute, Polish Academy of Sciences, 5, A. Pawinskiego Str., 02-106 Warsaw, Poland.
Int J Mol Sci. 2022 Jul 27;23(15):8287. doi: 10.3390/ijms23158287.
The histone deacetylase inhibitor (HDACi) Givinostat/ITF2357 provides neuroprotection in adult models of brain injury; however, its action after neonatal hypoxia-ischemia (HI) is still undefined. The aim of our study was to test the hypothesis that the mechanism of Givinostat is associated with the alleviation of inflammation. For this purpose, we analyzed the microglial response and the effect on molecular mediators (chemokines/cytokines) that are crucial for inducing cerebral damage after neonatal hypoxia-ischemia. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 60 min of hypoxia (7.6% O). Givinostat (10 mg/kg b/w) was administered in a 5-day regimen. The effects of Givinostat on HI-induced inflammation (cytokine, chemokine and microglial activation and polarization) were assessed with a Luminex assay, immunohistochemistry and Western blot. Givinostat treatment did not modulate the microglial response specific for HI injury. After Givinostat administration, the investigated chemokines and cytokines remained at the level induced by HI. The only immunosuppressive effect of Givinostat may be associated with the decrease in MIP-1α. Neonatal hypoxia-ischemia produces an inflammatory response by activating the proinflammatory M1 phenotype of microglia, disrupting the microglia-neuron (CX3CL1/CX3CR1) axis and elevating numerous proinflammatory cytokines/chemokines. Givinostat/ITF2357 did not prevent an inflammatory reaction after HI.
组蛋白去乙酰化酶抑制剂（HDACi）Givinostat/ITF2357 在成年脑损伤模型中提供神经保护；然而，其在新生儿缺氧缺血（HI）后的作用仍未确定。我们的研究目的是检验 Givinostat 的作用机制与炎症缓解有关的假设。为此，我们分析了小胶质细胞反应以及对分子介质（趋化因子/细胞因子）的影响，这些介质对于诱导新生儿缺氧缺血后的脑损伤至关重要。7 日龄大鼠幼仔接受单侧颈总动脉结扎，随后进行 60 分钟缺氧（7.6%O）。给予 Givinostat（10mg/kg b/w）5 天方案。通过 Luminex 测定、免疫组织化学和 Western blot 评估 Givinostat 对 HI 诱导的炎症（细胞因子、趋化因子和小胶质细胞激活和极化）的影响。Givinostat 治疗不会调节特定于 HI 损伤的小胶质细胞反应。给予 Givinostat 后，所研究的趋化因子和细胞因子仍保持 HI 诱导的水平。Givinostat 的唯一免疫抑制作用可能与 MIP-1α 的减少有关。新生儿缺氧缺血通过激活小胶质细胞的促炎 M1 表型产生炎症反应，破坏小胶质细胞-神经元（CX3CL1/CX3CR1）轴，并升高许多促炎细胞因子/趋化因子。Givinostat/ITF2357 不能预防 HI 后的炎症反应。
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