Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.
Scott & White Clinic-Temple, Temple, TX, USA.
CNS Neurosci Ther. 2017 Jul;23(7):554-566. doi: 10.1111/cns.12703. Epub 2017 May 19.
This study aimed to evaluate the roles of autophagy and endoplasmic reticulum (ER) stress in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) in rats.
Autophagy inducer (rapamycin) and inhibitor (3-methyladenine), as well as ER stress activator (tunicamycin, TM) and inhibitor (tauroursodeoxycholic acid, TUDCA), were used. Bafilomycin A1, an inhibitor of autophagosome-lysosome fusion, was used to assess autophagic flux.
Autophagy and ER stress were enhanced in the week after ICH. At 6 hours after ICH, autophagy was excessive, while the autophagic flux was damaged at 72 hours and return to be intact at 7 days after ICH. At 6 hours after ICH, ER stress induction by TM could enhance autophagy and lead to caspase 12-mediated apoptosis and neuronal degeneration, which was further aggravated by autophagy induction. At 7 days after ICH, ER stress inhibition by TUDCA still could suppress ICH-induced SBI. And, the effects of TUDCA were enhanced by autophagy induction.
At 6 hours after ICH, excessive autophagy may participate in ER stress-induced brain injury; at 7 days after ICH, autophagy could enhance the protection of ER stress inhibitor possibly via clearing up the cell rubbish generated due to the early-stage damaged autophagic flux.
本研究旨在评估自噬和内质网（ER）应激在大鼠脑出血（ICH）继发性脑损伤（SBI）中的作用。
使用自噬诱导剂（雷帕霉素）和抑制剂（3-甲基腺嘌呤），以及 ER 应激激活剂（衣霉素，TM）和抑制剂（牛磺熊脱氧胆酸，TUDCA）。使用巴弗洛霉素 A1 作为自噬体-溶酶体融合的抑制剂来评估自噬流。
ICH 后一周内自噬和 ER 应激增强。ICH 后 6 小时，自噬过度，而自噬流在 72 小时受损，并在 ICH 后 7 天恢复完整。ICH 后 6 小时，TM 诱导的 ER 应激可增强自噬并导致半胱天冬酶 12 介导的细胞凋亡和神经元变性，而自噬诱导进一步加重了这种情况。ICH 后 7 天，TUDCA 抑制 ER 应激仍可抑制 ICH 诱导的 SBI。并且，自噬诱导增强了 TUDCA 的作用。
ICH 后 6 小时，过度自噬可能参与 ER 应激诱导的脑损伤；ICH 后 7 天，自噬可能通过清除早期受损自噬流产生的细胞垃圾来增强 ER 应激抑制剂的保护作用。
