Qizhi Tongluo capsule improves vascular dementia in rats via integrated metabolomics and molecular mechanism research.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: QiZhi Tongluo (QZTL) capsule is a Traditional Chinese Medicine(TCM) designed to treat cerebral apoplexy sequelae. TCM considers vascular dementia (VD) as a syndrome secondary to stroke, with memory disorders as the primary manifestation. Therefore, it falls under the category of "stroke" and "dementia" in TCM. Clinical trials have demonstrated significant potential for the QZTL capsule in the treatment of ischemic stroke, as well as in enhancing cognitive function among VD patients. Nevertheless, it mechanism remains unclear. AIM OF THE STUDY: The research focused on elucidating the therapeutic effects and underlying metabolomic mechanism of QZTL capsules in a rat model of VD. MATERIALS AND METHODS: The VD rat model was established by permanent bilateral common carotid artery occlusion (2-VO). We observed the effects of QZTL capsules on cognitive function, neuronal damage, and serum metabolite profiles in VD rats. Non-targeted metabolomic analysis was used to analyze the regulatory effects of QZTL capsules on serum metabolites. Enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and Western Blot were used to investigate the potential mechanisms of the QZTL capsule on VD. RESULTS: The Morris water maze (MWM) test demonstrated that spatial learning and memory impairments resulting from 2-VO were significantly improved by QZTL treatment. Results from hematoxylin and eosin (H&E) staining revealed that QZTL capsule reduced neuronal injury in the CA1 region of the hippocampus. Untargeted serum metabolomics based on UHPLC-Q-TOF-MS revealed 33 differential metabolites in VD model rats, mainly associated with glycerophospholipids, amino acids, and primary bile acids metabolism. These metabolic disturbance were significantly reversed by QZTL treatment, with the high-dose group showing the most pronounced effect. We found that the mechanism underlying QZTL's efficacy involved suppressing neuroinflammation (NF-κB, MMP-9, TNF-α, IL-1β), alleviating oxidative stress (Nrf2, HO-1, SOD, MDA, NOX2), inhibiting apoptosis (Bcl-2, Bax, Caspase-3), and improving vascular function/neurotransmitter balance (VEGF, HIF-1α, ET, CGRP, 5-HT, NO, NOS). CONCLUSIONS: The findings indicate that the therapeutic effect of QZTL capsules on vascular dementia is achieved through multi-targeted regulation of metabolic disorders, which in turn mitigates oxidative stress, neuroinflammation, and apoptosis, offering experimental evidence to support its clinical use.