Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China.
Int Immunopharmacol. 2020 Feb;79:106180. doi: 10.1016/j.intimp.2019.106180. Epub 2020 Jan 8.
Ghrelin, a brain-gut peptide, has been proven to exert neuroprotection in different kinds of neurological diseases; however, its role and the potential molecular mechanisms in secondary brain injury (SBI) after intracerebral hemorrhage (ICH) are still unknown. In this study, we investigate whether treatment with ghrelin may attenuate SBI in a murine ICH model, and if so, whether the neuroprotective effects are due to the inhibition of nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation and promotion of nuclear factor-E2-related factor 2 (Nrf2)/antioxidative response element (ARE) signaling pathway. Stereotactically intrastriatal infusion of autologous blood was performed to mimic ICH. Ghrelin was given intraperitoneally immediately following ICH and again 1 h later. Results showed that ghrelin attenuated neurobehavioral deficits, brain edema, hematoma volume, and perihematomal cell death post-ICH. Ghrelin inhibited the NLRP3 inflammasome activation and subsequently suppressed the neuroinflammatory response as evidenced by reduced microglia activation, neutrophil infiltration, and pro-inflammatory mediators release after ICH. Additionally, ghrelin alleviated ICH-induced oxidative stress according to the chemiluminescence of luminol and lucigenin, malondialdehyde (MDA) content, and total superoxide dismutase (SOD) activity assays. These changes were accompanied by upregulation of Nrf2 expression, Nrf2 nuclear accumulation, and enhanced Nrf2 DNA binding activity, as well as by increased expressions of Nrf2 downstream target antioxidative genes, including NAD(P)H quinine oxidoreductase-1 (NQO1), glutathione cysteine ligase regulatory subunit (GCLC), and glutathione cysteine ligase modulatory subunit (GCLM). Together, our data suggested that ghrelin protected against ICH-induced SBI by inhibiting NLRP3 inflammasome activation and promoting Nrf2/ARE signaling pathway.
胃饥饿素是一种脑肠肽，已被证明在多种神经疾病中具有神经保护作用；然而，其在脑出血（ICH）后继发性脑损伤（SBI）中的作用和潜在的分子机制尚不清楚。在本研究中，我们研究了给予胃饥饿素是否可以减轻小鼠 ICH 模型中的 SBI，如果是，其神经保护作用是否归因于抑制核苷酸结合寡聚化结构域样受体含pyrin 结构域蛋白 3（NLRP3）炎症小体激活和促进核因子-E2 相关因子 2（Nrf2）/抗氧化反应元件（ARE）信号通路。立体定向纹状体内注入自体血模拟 ICH。ICH 后立即腹腔内给予胃饥饿素，并在 1 小时后再次给予。结果表明，胃饥饿素减轻了 ICH 后的神经行为缺陷、脑水肿、血肿体积和血肿周围细胞死亡。胃饥饿素抑制了 NLRP3 炎症小体的激活，从而抑制了神经炎症反应，这表现在 ICH 后小胶质细胞激活、中性粒细胞浸润和促炎介质释放减少。此外，根据发光氨和光诺灵的化学发光、丙二醛（MDA）含量和总超氧化物歧化酶（SOD）活性测定，胃饥饿素减轻了 ICH 诱导的氧化应激。这些变化伴随着 Nrf2 表达的上调、Nrf2 核积累和增强的 Nrf2 DNA 结合活性，以及 Nrf2 下游抗氧化基因的表达增加，包括 NAD(P)H 醌氧化还原酶-1（NQO1）、谷胱甘肽半胱氨酸连接酶调节亚单位（GCLC）和谷胱甘肽半胱氨酸连接酶调节亚单位（GCLM）。总之，我们的数据表明，胃饥饿素通过抑制 NLRP3 炎症小体的激活和促进 Nrf2/ARE 信号通路来保护 ICH 引起的 SBI。
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