Cerebral ischemic/reperfusion injury is the most common neurological disorder and the second leading cause of death worldwide. Modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state has been suggested as a potential therapeutic approach in the treatment of this injury. SRT2104, a novel activator of histone deacetylase Sirtuin-1 (Sirt1), has recently been shown to have anti-inflammation properties. However, the effect of SRT2104 on cerebral ischemic/reperfusion injury has not been elucidated. Here, we found that SRT2104 inhibited neuron and microglia death directly and indirectly through microglia condition medium from an oxygen glucose deprivation/reoxygenation (OGD/R) -induced cell injury models. Moreover, SRT2104 treatment modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, we found that SRT2104 could significant inhibit the activation of NF-κB and enhanced Sirt1 expression in microglia. Mechanism studies using the BV2 microglial cell line confirmed that knockdown Sirt1 significantly reduced the effect of SRT2104 on the activation of NF-κB pathway and microglial phenotype shift. Altogether, our result shows SRT2104 protect OGD/R-induced injury through shifting microglia phenotype, which may have potential in further studies as a novel neuroprotective agent for cerebral ischemic/reperfusion injury therapy.

脑缺血/再灌注损伤是最常见的神经系统疾病，也是全球第二大死亡原因。调节小胶质细胞从促炎 M1 表型到抗炎 M2 状态的极化已被认为是治疗这种损伤的潜在治疗方法。 SRT2104 是一种新型组蛋白脱乙酰酶 Sirtuin-1 (Sirt1) 激活剂，最近被证明具有抗炎特性。然而，SRT2104对脑缺血/再灌注损伤的作用尚未阐明。在这里，我们发现 SRT2104 通过氧葡萄糖剥夺/复氧 (OGD/R) 诱导的细胞损伤模型的小胶质细胞条件培养基直接和间接抑制神经元和小胶质细胞死亡。此外，SRT2104 治疗调节小胶质细胞极化从 M1 表型的转变，并偏向 M2 表型。此外，我们发现SRT2104可以显着抑制小胶质细胞中NF-κB的激活并增强Sirt1的表达。使用 BV2 小胶质细胞系的机制研究证实，敲除 Sirt1 可显着降低 SRT2104 对 NF-κB 通路激活和小胶质细胞表型转变的影响。总而言之，我们的结果表明 SRT2104 通过改变小胶质细胞表型来保护 OGD/R 诱导的损伤，这可能在进一步研究中作为脑缺血/再灌注损伤治疗的新型神经保护剂具有潜力。