Modified Dioscorea pills ameliorate cognitive impairment induced by chronic cerebral hypoperfusion via restoring the hippocampal neurovascular unit

Abstract

Chronic cerebral hypoperfusion (CCH) is a major cause of progressive cognitive decline and vascular dementia in older adults. Modified Dioscorea Pills (MDP), a traditional Chinese medicinal formula, has demonstrated clinical efficacy for dementia treatment. However, the effects and molecular mechanisms of MDP on the hippocampal neurovascular unit (NVU) in CCH remain unclear. This study aimed to explore whether MDP alleviates CCH-induced cognitive impairment by protecting and restoring the hippocampal NVU in rats. A rat CCH model was established via bilateral common carotid artery occlusion (BCCAO). Forty SPF-grade male Sprague-Dawley rats were randomly divided into Sham, CCH model and MDP treatment groups. Rats received intragastric administration of normal saline or MDP concentrated decoction for 45 consecutive days. The Morris Water Maze test was used to assess learning and memory functions. Immunohistochemistry was applied to detect the expression of apoptosis-, inflammation-, neuron-, synapse-, glia-, myelin- and endothelial-related proteins, as well as microvessel density (MVD). Western blot was used to quantify Ang-1, Ang-2, Tie2 and VEGF levels. Transmission electron microscopy (TEM) was performed to observe neuronal and synaptic ultrastructure. Pearson correlation analysis was used to evaluate the correlations among NVU-related indicators. MDP significantly improved learning and memory deficits in CCH rats. MDP downregulated NF- κ B p65 expression and the Bax/Bcl-2 ratio, consistent with the attenuation of neuroinflammation and apoptosis-associated signaling, inhibited excessive gliosis, and upregulated neuronal, synaptic and myelin-related protein levels. MDP further activated the Ang/Tie2/VEGF pathway and reduced the abnormally elevated CD34 expression and microvessel density (MVD), indicating that MDP promoted vascular stabilization and remodeling of the excessive immature microvasculature rather than further pathological angiogenesis. TEM confirmed that MDP relieved neuronal nuclear damage and synaptic destruction. Correlation analysis revealed statistically significant associations among multiple components of the hippocampal NVU, whereas inflammation-related markers were negatively associated with NVU integrity. MDP ameliorates CCH-induced cognitive impairment by comprehensively restoring the structure and function of the hippocampal NVU. The mechanisms involve attenuation of neuroinflammation and apoptosis-associated signaling, protection of neurons and synapses, inhibition of pathological gliosis, restoration of oligodendrocyte-lineage integrity, and stabilization and remodeling of the hippocampal microvasculature. This work provides preclinical evidence for the clinical application of MDP in CCH and vascular dementia.