Zhao Yijing, Li Tong, Jiang Zige, Gai Chengcheng, Yu Shuwen, Xin Danqing, Li Tingting, Liu Dexiang, Wang Zhen
Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.
Department of Neurosurgery, Qingdao Municipal Hospital, Qingdao, Shandong Province, China.
Neural Regen Res. 2024 May;19(5):1084-1094. doi: 10.4103/1673-5374.382860.
We previously showed that hydrogen sulfide (HS) has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice. However, the precise mechanism underlying the role of HS in this situation remains unclear. In this study, we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine, a HS precursor, attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionine β synthase (a major HS synthetase in the brain) in the prefrontal cortex. We also found that an miR-9-5p inhibitor blocked the expression of cystathionine β synthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia. Furthermore, miR-9-5p overexpression increased cystathionine-β-synthase and HS expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury. L-cysteine decreased the expression of CXCL11, an miR-9-5p target gene, in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3, FSTL1, SOCS2 and SOCS5, while treatment with an miR-9-5p inhibitor reversed these changes. These findings suggest that HS can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoring β-synthase expression, thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.
我们之前的研究表明，硫化氢（HS）在新生小鼠缺氧缺血性脑损伤的情况下具有神经保护作用。然而，HS在这种情况下发挥作用的精确机制仍不清楚。在本研究中，我们使用了新生小鼠缺氧缺血性脑损伤模型和脂多糖刺激的BV2细胞模型，发现用HS前体L-半胱氨酸处理可减轻缺氧缺血诱导的脑梗死和脑萎缩，并增加前额叶皮质中miR-9-5p和胱硫醚β合酶（大脑中主要的HS合成酶）的表达。我们还发现，miR-9-5p抑制剂可阻断缺氧缺血性脑损伤小鼠前额叶皮质中胱硫醚β合酶的表达。此外，miR-9-5p过表达可增加缺氧缺血性脑损伤小鼠受损前额叶皮质中胱硫醚-β-合酶和HS的表达。L-半胱氨酸降低了小鼠模型前额叶皮质和脂多糖刺激的BV-2细胞中miR-9-5p靶基因CXCL11的表达，并增加了促炎细胞因子BNIP3、FSTL1、SOCS2和SOCS5的水平，而用miR-9-5p抑制剂处理可逆转这些变化。这些发现表明，HS可通过调节miR-9-5p/CXCL11轴并恢复β合酶表达，减轻新生小鼠缺氧缺血性脑损伤模型中的神经炎症，从而在减轻缺氧缺血性脑损伤中的神经炎症方面发挥作用。
