Molecular Mechanisms of Synaptic Plasticity Impairment in Chronic Cerebral Hypoperfusion-Induced Vascular Cognitive Impairment and Advances in Traditional Chinese Medicine Interventions

Abstract

Chronic cerebral hypoperfusion (CCH) is considered one of the major driving factors underlying vascular cognitive impairment (VCI), and CCH-induced impairment of synaptic plasticity constitutes an important pathological basis for cognitive decline. This review summarizes the molecular mechanisms underlying CCH-induced synaptic plasticity impairment and recent advances in traditional Chinese medicine (TCM) interventions. Current evidence suggests that CCH can suppress the BDNF/TrkB/CREB signaling axis, disrupt the PI3K/Akt/mTOR pathway, remodel the glutamatergic receptor system, and disturb calcium homeostasis, thereby initiating a vicious cycle in which neuroinflammation and synaptic dysfunction mutually reinforce each other. These pathological changes ultimately contribute to dendritic spine loss and impaired hippocampal long-term potentiation (LTP). Regarding TCM interventions, various herbal formulas and bioactive compounds have been shown to regulate these pathways through multiple targets, exerting synergistic neuroprotective effects by activating neurotrophic signaling, restoring synaptic protein synthesis, rebalancing central excitatory signaling, and remodeling the neurovascular microenvironment. Nevertheless, current research is still limited by insufficient clinical translation, inadequate target validation, heterogeneity among experimental models, and sex bias. Future studies should integrate biomarker-driven clinical trials, druggability assessment of therapeutic targets, and animal models that more closely reflect clinical conditions to facilitate precision TCM interventions for VCI.