Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China; Department of Geriatrics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China.
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China.
Exp Neurol. 2024 Dec;382:114986. doi: 10.1016/j.expneurol.2024.114986. Epub 2024 Oct 4.
Intracerebral hemorrhage (ICH) is a common and devastating type of stroke, marked by significant morbidity and a grim prognosis. The inflammation cascade triggered by astrocytes plays a critical role in secondary brain injury (SBI) following ICH, leading to detrimental effects such as cell death. However, effective intervention strategies are currently lacking. This study aims to investigate the role of the astrocyte cascade reaction following ICH and identify potential intervention targets. Utilizing the GSE216607 and GSE206971 databases for analysis, we established a mouse autologous blood model. Firstly, our research revealed a significant activation of the autophagy pathway following intracerebral hemorrhage (ICH), with a notable upregulation of Lamp2a, a key factor in chaperone-mediated autophagy (CMA), primarily localized in astrocytes. Additionally, the downregulation of Lamp2a resulted in a significant augmentation of A1 reactive astrocytes, concomitant with a reduction in myelin coverage area, heightened neuronal injury, exacerbated motor and sensory deficits, and diminished neurological scores after ICH in mice. Conversely, CA77.1, an activator of CMA, could reverse ICH-induced augmentation of A1 reactive astrocytes, myelin damage, neuronal death, and neurobehavioral disorders. In conclusion, the activation of astrocyte CMA following ICH can exert neuroprotective effects. Lamp2a represents a promising therapeutic target for post-ICH treatment.
脑出血 (ICH) 是一种常见且具有破坏性的中风类型，其发病率高，预后差。星形胶质细胞引发的炎症级联反应在 ICH 后的继发性脑损伤 (SBI) 中起着关键作用，导致细胞死亡等有害影响。然而，目前缺乏有效的干预策略。本研究旨在探讨 ICH 后星形胶质细胞级联反应的作用，并确定潜在的干预靶点。本研究利用 GSE216607 和 GSE206971 数据库进行分析，建立了小鼠自体血模型。首先，我们的研究表明，脑出血后自噬途径明显激活，伴侣介导的自噬 (CMA) 的关键因子 Lamp2a 显著上调，主要定位于星形胶质细胞。此外，Lamp2a 的下调导致 A1 反应性星形胶质细胞显著增加，同时髓鞘覆盖面积减少，神经元损伤加剧，运动和感觉功能障碍恶化，以及脑出血后小鼠的神经评分降低。相反，CMA 的激活剂 CA77.1 可以逆转 ICH 诱导的 A1 反应性星形胶质细胞、髓鞘损伤、神经元死亡和神经行为障碍的增加。总之，ICH 后星形胶质细胞 CMA 的激活可以发挥神经保护作用。Lamp2a 可能是 ICH 后治疗的一个有前途的治疗靶点。
