Buyang Huanwu Decoction alleviates vascular cognitive impairment by inhibiting neuroinflammation via regulation of the p53/cGAS/STING pathway.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine (TCM) formulation renowned for its properties in replenishing qi and promoting blood circulation, corresponds closely with the pathophysiological framework of "qi deficiency and blood stasis" observed in vascular cognitive impairment (VCI). Consequently, there is a critical need to validate its therapeutic efficacy and elucidate the pharmacological mechanisms underlying its use in VCI treatment. AIM OF THE STUDY: This investigation aimed to systematically assess the therapeutic effects of BYHWD on VCI and to clarify the molecular mechanisms involved. MATERIALS AND METHODS: The bioactive constituents of BYHWD were characterized via UHPLC-MS/MS. A rat model of VCI was established through two-vessel occlusion (2VO). Experimental groups received oral gavage administration of BYHWD at dosages of 6.4, 12.8, and 25.6 g/kg daily for four weeks, with Ginaton (14.4 mg/kg) employed as a positive control. Cerebral blood flow was assessed using laser speckle imaging. Cognitive performance was evaluated through the Morris water maze (MWM) test. Histopathological changes in brain tissue were assessed by Nissl and LFB staining. To investigate pharmacological mechanisms, ELISA, immunohistochemistry, Western blot, and immunofluorescence analyses were conducted. Additionally, in vitro studies utilized an oxygen-glucose deprivation (OGD) model in BV2 microglial cells, with intervention by the p53 activator Nutlin-3 to further validate mechanistic pathways. RESULTS: Administration of BYHWD markedly enhanced learning and memory functions, increased cerebral perfusion, and mitigated neuronal loss and white matter injury in 2VO rats. Furthermore, BYHWD significantly inhibited microglial activation and decreased the secretion of pro-inflammatory cytokines. Mechanistic investigations demonstrated that BYHWD downregulated the expression of proteins associated with the p53/cGAS/STING signaling pathway in the 2VO model. In vitro, activation of p53 by Nutlin-3 negated the neuroprotective effects of BYHWD on OGD-induced BV2 cells and concurrently intensified inflammatory responses. CONCLUSION: BYHWD ameliorates cognitive deficits and neuropathological damage in 2VO rats primarily through suppression of the p53/cGAS/STING signaling cascade and attenuation of neuroinflammation. This study provides strong pharmacological evidence for the early prevention and clinical treatment of VCI.