Department of Anesthesiology, The Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
Department of Physiology, China Medical University, Shenyang, Liaoning, China.
J Neuroinflammation. 2024 May 17;21(1):132. doi: 10.1186/s12974-024-03121-8.
Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common neurological problems occurring in the perinatal period. However, there still is not a promising approach to reduce long-term neurodevelopmental outcomes of HIE. Recently, itaconate has been found to exhibit anti-oxidative and anti-inflammatory effects. However, the therapeutic efficacy of itaconate in HIE remains inconclusive. Therefore, this study attempts to explore the pathophysiological mechanisms of oxidative stress and inflammatory responses in HIE as well as the potential therapeutic role of a derivative of itaconate, 4-octyl itaconate (4OI).
We used 7-day-old mice to induce hypoxic-ischemic (HI) model by right common carotid artery ligation followed by 1 h of hypoxia. Behavioral experiments including the Y-maze and novel object recognition test were performed on HI mice at P60 to evaluate long-term neurodevelopmental outcomes. We employed an approach combining non-targeted metabolomics with transcriptomics to screen alterations in metabolic profiles and gene expression in the hippocampal tissue of the mice at 8 h after hypoxia. Immunofluorescence staining and RT-PCR were used to evaluate the pathological changes in brain tissue cells and the expression of mRNA and proteins. 4OI was intraperitoneally injected into HI model mice to assess its anti-inflammatory and antioxidant effects. BV2 and C8D1A cells were cultured in vitro to study the effect of 4OI on the expression and nuclear translocation of Nrf2. We also used Nrf2-siRNA to further validate 4OI-induced Nrf2 pathway in astrocytes.
We found that in the acute phase of HI, there was an accumulation of pyruvate and lactate in the hippocampal tissue, accompanied by oxidative stress and pro-inflammatory, as well as increased expression of antioxidative stress and anti-inflammatory genes. Treatment of 4OI could inhibit activation and proliferation of microglial cells and astrocytes, reduce neuronal death and relieve cognitive dysfunction in HI mice. Furthermore, 4OI enhanced nuclear factor erythroid-2-related factor (Nfe2l2; Nrf2) expression and nuclear translocation in astrocytes, reduced pro-inflammatory cytokine production, and increased antioxidant enzyme expression.
Our study demonstrates that 4OI has a potential therapeutic effect on neuronal damage and cognitive deficits in HIE, potentially through the modulation of inflammation and oxidative stress pathways by Nrf2 in astrocytes.
新生儿缺氧缺血性脑病（HIE）是围产期最常见的神经系统问题之一。然而，目前仍没有一种有前途的方法可以降低 HIE 的长期神经发育结局。最近，衣康酸已被发现具有抗氧化和抗炎作用。然而，衣康酸衍生物 4-辛基衣康酸（4OI）在 HIE 中的治疗效果仍不确定。因此，本研究试图探讨 HIE 中氧化应激和炎症反应的病理生理机制，以及 4OI 在其中的潜在治疗作用。
我们使用 7 日龄的小鼠通过右颈总动脉结扎和 1 小时缺氧来诱导缺氧缺血（HI）模型。在 HI 后 60 天对小鼠进行 Y 迷宫和新物体识别测试等行为实验，以评估长期神经发育结局。我们采用非靶向代谢组学与转录组学相结合的方法，筛选缺氧后 8 小时海马组织代谢谱和基因表达的变化。免疫荧光染色和 RT-PCR 用于评估脑组织细胞的病理变化以及 mRNA 和蛋白质的表达。将 4OI 腹腔注射到 HI 模型小鼠中，以评估其抗炎和抗氧化作用。在体外培养 BV2 和 C8D1A 细胞，研究 4OI 对 Nrf2 表达和核易位的影响。我们还使用 Nrf2-siRNA 进一步验证 4OI 在星形胶质细胞中诱导的 Nrf2 通路。
我们发现，在 HI 的急性期，海马组织中丙酮酸和乳酸积累，伴有氧化应激和促炎反应，以及抗氧化应激和抗炎基因表达增加。4OI 治疗可抑制小胶质细胞和星形胶质细胞的激活和增殖，减少 HI 小鼠的神经元死亡并缓解认知功能障碍。此外，4OI 增强了星形胶质细胞中核因子红细胞 2 相关因子 2（Nfe2l2；Nrf2）的表达和核易位，减少了促炎细胞因子的产生，增加了抗氧化酶的表达。
我们的研究表明，4OI 对 HIE 中的神经元损伤和认知缺陷具有潜在的治疗作用，可能通过调节星形胶质细胞中的 Nrf2 炎症和氧化应激途径。
