Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China.
J Cell Biochem. 2019 Jun;120(6):10175-10185. doi: 10.1002/jcb.28302. Epub 2019 Jan 6.
Hypoxic-ischemic brain damage (HIBD), frequently occurring in infancy and childhood, is a major cause of mortality and severe neurologic impairment. This study was performed to examine the effect of the PI3K/Akt signaling pathway on HIBD in a neonatal rabbit model.
Uterine artery occlusion was used to establish HIBD models in neonatal rabbits, which were then subjected to sham operation, dimethyl sulfoxide (2 mL) or LY294002 (inhibitor of PI3K/Akt signaling pathway, 6.4 μg/kg). Behavioral neurological assessment was performed in neonatal rabbits delivered by cesarean section, after which serum neuron-specific enolase (NSE) level and cerebral water content were determined. The level of cleaved caspase-3 level and apoptosis of neurons were observed by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. Furthermore, the expression of PI3K/Akt signaling pathway- and apoptosis-related factors was examined.
In neonatal rabbits, HIBD increased the fetal death rate; reduced neurological scores of posture, righting reflex, and deglutition reflex; elevated serum NSE levels, cerebral water content, cleaved caspase-3-positive expression in hippocampal CA1 region and apoptotic neurons; inactivated PI3K/Akt signaling pathway as well as reduced Bcl-2 expression and increased BAD and Bax expression. Notably, the treatment of LY294002 further aggravated neurological impairment in neonatal rabbits in response to HIBD.
Following the HIBD caused by intrauterine asphyxia, the LY294002 administered through auricular vein infusion into pregnant rabbits exacerbates neurological impairment of neonatal rabbits, suggesting that inhibition of PI3K/Akt signaling pathway may serve as a candidate therapeutic target for neurological recovery.
缺氧缺血性脑损伤（HIBD）常发生于婴儿和儿童时期，是导致死亡和严重神经功能障碍的主要原因。本研究旨在探讨 PI3K/Akt 信号通路对新生兔 HIBD 的影响。
采用子宫动脉夹闭法建立新生兔 HIBD 模型，再进行假手术、二甲基亚砜（2mL）或 LY294002（PI3K/Akt 信号通路抑制剂，6.4μg/kg）处理。通过剖宫产娩出的新生兔进行行为神经学评估，然后测定血清神经元特异性烯醇化酶（NSE）水平和脑含水量。通过免疫组织化学和末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记（TUNEL）染色观察裂解 caspase-3 水平和神经元凋亡情况。此外，还检测了 PI3K/Akt 信号通路和凋亡相关因子的表达。
在新生兔中，HIBD 增加了胎儿死亡率；降低了姿势、翻正反射和吞咽反射的神经评分；升高了血清 NSE 水平、脑含水量、海马 CA1 区裂解 caspase-3 阳性表达和凋亡神经元；激活了 PI3K/Akt 信号通路，并降低了 Bcl-2 表达，增加了 BAD 和 Bax 表达。值得注意的是，LY294002 的治疗进一步加重了 HIBD 新生兔的神经损伤。
宫内窒息导致 HIBD 后，通过耳静脉输注 LY294002 加重了新生兔的神经损伤，提示抑制 PI3K/Akt 信号通路可能成为神经恢复的候选治疗靶点。
