Department of Neurosurgery and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.
Department of Neurosurgery, Chengdu Second People's Hospital, Chengdu, Sichuan, People's Republic of China.
Transl Stroke Res. 2023 Jun;14(3):364-382. doi: 10.1007/s12975-022-01026-3. Epub 2022 Jul 19.
Intraventricular hemorrhage (IVH) is a subtype of intracerebral hemorrhage (ICH) with high morbidity and mortality. Posthemorrhagic hydrocephalus (PHH) is a common and major complication that affects prognosis, but the mechanism is still unclear. Inflammation and fibrosis have been well established as the major causes of PHH after IVH. In this study, we aimed to investigate the effects of metformin on IVH in adult male mice and further explored the underlying molecular mechanisms of these effects. In the acute phase, metformin treatment exerted dose-dependent neuroprotective effects by reducing periependymal apoptosis and neuronal degeneration and decreasing brain edema. Moreover, high-dose metformin reduced inflammatory cell infiltration and the release of proinflammatory factors, thus protecting ependymal structure integrity and subependymal neurons. In the chronic phase, metformin administration improved neurocognitive function and reduced delayed hydrocephalus. Additionally, metformin significantly inhibited basal subarachnoid fibrosis and ependymal glial scarring. The ependymal structures partially restored. Mechanically, IVH reduced phospho-AMPK (p-AMPK) and SIRT1 expression and activated the phospho-NF-κB (p-NF-κB) inflammatory signaling pathway. However, metformin treatment increased AMPK/SIRT1 expression and lowered the protein expression of p-NF-κB and its downstream inflammation. Compound C and EX527 administration reversed the anti-inflammatory effect of metformin. In conclusion, metformin attenuated neuroinflammation and subsequent fibrosis after IVH by regulating AMPK /SIRT1/ NF-κB pathways, thereby reducing delayed hydrocephalus. Metformin may be a promising therapeutic agent to prevent delayed hydrocephalus following IVH.
脑室内出血 (IVH) 是脑出血 (ICH) 的一种亚型，具有高发病率和死亡率。出血后脑积水 (PHH) 是一种常见且主要的并发症，影响预后，但发病机制尚不清楚。炎症和纤维化已被证实是 IVH 后 PHH 的主要原因。在这项研究中，我们旨在研究二甲双胍对成年雄性小鼠 IVH 的影响，并进一步探讨这些影响的潜在分子机制。在急性期，二甲双胍通过减少室管膜周围细胞凋亡和神经元变性以及减少脑水肿，发挥剂量依赖性的神经保护作用。此外，高剂量的二甲双胍减少了炎性细胞浸润和促炎因子的释放，从而保护室管膜结构的完整性和室下神经元。在慢性期，二甲双胍给药改善了神经认知功能并减少了延迟性脑积水。此外，二甲双胍可显著抑制基底蛛网膜下腔纤维化和室管膜胶质瘢痕形成，部分恢复室管膜结构。在机制上，IVH 降低了磷酸化 AMPK (p-AMPK) 和 SIRT1 的表达，并激活了磷酸化 NF-κB (p-NF-κB) 炎症信号通路。然而，二甲双胍治疗增加了 AMPK/SIRT1 的表达，降低了 p-NF-κB 及其下游炎症的蛋白表达。化合物 C 和 EX527 的给药逆转了二甲双胍的抗炎作用。总之，二甲双胍通过调节 AMPK/SIRT1/NF-κB 通路减轻了 IVH 后的神经炎症和随后的纤维化，从而减少了延迟性脑积水。二甲双胍可能是预防 IVH 后延迟性脑积水的一种有前途的治疗药物。
