Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China.
Beijing Rehabilitation Medicine Academy, Capital Medical University, Beijing, China.
J Neurosci Res. 2024 Jan;102(1). doi: 10.1002/jnr.25275.
Chronic cerebral ischemia (CCI) can lead to vascular cognitive impairment, but therapeutic options are limited. Cognitive-exercise dual-task (CEDT), as a potential rehabilitation intervention, can attenuate cognitive impairment. However, the related mechanisms remain unclear. In this study, 2-vessel occlusion (2-VO) in male SD rats was performed to establish the CCI model. The rats were treated with cognitive, exercise, or CEDT intervention for 21 days. The Morris water maze (MWM) test was used to assess cognitive ability. TUNEL staining was used to detect the neuronal apoptosis. Immunofluorescence, RT-qPCR and Western blot were used to detect the protein or mRNA levels of EphrinA3, EphA4, p-PI3K, and p-Akt. The results showed that CEDT could improve performance in the MWM test, reverse the increased expression of EphrinA3 and EphA4, and the reduced expression of p-PI3K and p-Akt in CCI rats, which was superior to exercise and cognitive interventions. In vitro, oxygenglucose deprivation (OGD) challenge of astrocytes and neuronal cells were used to mimic cerebral ischemia. Immunofluorescence assay revealed that the levels of MAP-2, p-PI3K, and p-Akt were reduced in EphrinA3 overexpressed cells after OGD stimulation. Finally, the knock-down of EphrinA3 by shRNA significantly promoted the recovery of cognitive function and activation of PI3K/Akt after CEDT treatment in CCI rats. In conclusion, our study suggests that CEDT promotes cognitive function recovery after CCI by regulating the signaling axis of EphrinA3/EphA4/PI3K/Akt.
慢性脑缺血（CCI）可导致血管性认知障碍，但治疗选择有限。认知-运动双重任务（CEDT）作为一种潜在的康复干预措施，可以减轻认知障碍。然而，相关机制尚不清楚。本研究采用雄性 SD 大鼠 2 血管闭塞（2-VO）建立 CCI 模型。大鼠接受认知、运动或 CEDT 干预 21 天。采用 Morris 水迷宫（MWM）测试评估认知能力。TUNEL 染色检测神经元凋亡。免疫荧光、RT-qPCR 和 Western blot 检测 EphrinA3、EphA4、p-PI3K 和 p-Akt 的蛋白或 mRNA 水平。结果表明，CEDT 可改善 MWM 测试中的表现，逆转 CCI 大鼠中 EphrinA3 和 EphA4 的表达增加以及 p-PI3K 和 p-Akt 的表达减少，优于运动和认知干预。在体外，用氧葡萄糖剥夺（OGD）挑战星形胶质细胞和神经元细胞模拟脑缺血。免疫荧光检测显示，OGD 刺激后 EphrinA3 过表达细胞中 MAP-2、p-PI3K 和 p-Akt 的水平降低。最后，shRNA 敲低 EphrinA3 可显著促进 CEDT 治疗后 CCI 大鼠认知功能的恢复和 PI3K/Akt 的激活。总之，本研究表明 CEDT 通过调节 EphrinA3/EphA4/PI3K/Akt 信号轴促进 CCI 后认知功能的恢复。
