Zhu Ziman, Tao Xue, Dai Tengteng, Wu Jilin, Han Conglin, Huang Peiling, Gong Weijun
Beijing Rehabilitation Hospital, Beijing Rehabilitation Medicine Academy, Capital Medical University, Beijing 100144, China.
Department of Research, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, China.
Exp Neurol. 2024 Feb;372:114617. doi: 10.1016/j.expneurol.2023.114617. Epub 2023 Nov 23.
The prevalence of vascular cognitive impairment induced by chronic cerebral ischemia (CCI) is increasing year by year. Cognitive-exercise dual-task intervention has shown beneficial effects on improving cognitive performance in ischemic patients. It is well known that the tyrosine kinase ligand-receptor (Ephrin-Eph) system plays an important role in synaptic transmission and that the cAMP/PKA pathway is associated with cognitive function. However, it is unclear whether they are responsible for the dual-task improving cognitive impairment in CCI.
Bilateral common carotid artery occlusion (BCCAO) in SD rats was used to establish the CCI model. The effects of dual-task and single-task on cognitive function and the expressions of EphrinA3, EphA4, cAMP, and PKA in rats were detected by the novel object recognition (NOR) test, immunofluorescence staining, quantitative real-time polymerase chain reaction (qPCR), and Western blotting (WB), respectively. Overexpression or knockdown of EphrinA3 in astrocytes or rats were constructed by lentivirus infection to verify the effects of EphrinA3/EphA4 on the cAMP/PKA pathway.
After dual-task intervention, the discrimination index of rats increased significantly compared with the rats in the CCI group. The expressions of EphrinA3 and EphA4 were decreased, while the expressions of cAMP and PKA were increased. Furthermore, knockdown of EphrinA3 alleviated the trend of CCI-induced cognitive decline in rats and OGD-stimulated cellular damage. It also increased cAMP/PKA expression in hippocampal neurons.
Cognitive-exercise dual-task can significantly improve the cognitive impairment induced by CCI, and this effect may be better than that of the cognitive or exercise single-task intervention. The improvement may be related to the inhibition of EphrinA3/EphA4, followed by activation of the cAMP/PKA pathway.
慢性脑缺血（CCI）所致血管性认知障碍的患病率逐年上升。认知-运动双任务干预已显示出对改善缺血性患者认知功能的有益作用。众所周知，酪氨酸激酶配体-受体（Ephrin-Eph）系统在突触传递中起重要作用，且cAMP/PKA信号通路与认知功能相关。然而，尚不清楚它们是否是双任务改善CCI认知障碍的原因。
采用双侧颈总动脉闭塞（BCCAO）法建立SD大鼠CCI模型。分别通过新物体识别（NOR）试验、免疫荧光染色、定量实时聚合酶链反应（qPCR）和蛋白质免疫印迹法（WB）检测双任务和单任务对大鼠认知功能以及EphrinA3、EphA4、cAMP和PKA表达水平的影响。通过慢病毒感染构建星形胶质细胞或大鼠中EphrinA3的过表达或敲低模型，以验证EphrinA3/EphA4对cAMP/PKA信号通路的影响。
双任务干预后，与CCI组大鼠相比，干预组大鼠的辨别指数显著增加。EphrinA3和EphA4的表达降低，而cAMP和PKA的表达增加。此外，敲低EphrinA3可减轻CCI诱导的大鼠认知能力下降趋势以及氧糖剥夺（OGD）刺激引起的细胞损伤。它还增加了海马神经元中cAMP/PKA的表达。
认知-运动双任务可显著改善CCI所致的认知障碍，且该效果可能优于认知或运动单任务干预。这种改善可能与抑制EphrinA3/EphA4，随后激活cAMP/PKA信号通路有关。
