Gastrodin ameliorates cognitive impairment induced by a high-salt diet combined with chronic cerebral hypoperfusion by regulating cerebral blood flow and preserving BBB-related structural integrity

ETHNOPHARMACOLOGICAL RELEVANCE: Gastrodia elata Blume (G. elata) is a traditional Chinese medicinal herb documented in the Compendium of Materia Medica and has been widely used for dizziness, convulsive disorders, vertigo, and neurological symptoms. Gastrodin (GAS), the principal bioactive constituent of G. elata, is known to exhibit anti-inflammatory, antioxidant, and neuroprotective properties. Nevertheless, whether GAS is beneficial for vascular cognitive impairment associated with dietary risk factors remains unclear. Clarifying this issue may help explain the pharmacological basis of the traditional neurological use of G. elata. AIM OF THE STUDY: This study investigated whether GAS could alleviate cognitive dysfunction aggravated by a high-salt diet (HSD) in chronic cerebral hypoperfusion (CCH) mice, and explored its possible involvement in cerebral blood flow (CBF) regulation, blood-brain barrier (BBB)-related structural preservation, and amyloidogenic processing. MATERIALS AND METHODS: A mouse model of CCH combined with dietary risk was generated using bilateral common carotid artery stenosis (BCAS) and HSD exposure. Cognitive performance was assessed by the novel object recognition test, Y-maze test, and open field test. CBF was monitored using laser speckle imaging. Hippocampal transcriptomic sequencing was conducted to identify GAS-regulated pathways. Nissl staining, immunohistochemistry, Western blotting, and transmission electron microscopy were used to examine neuronal injury, BBB structure, and related protein expression. Serum Aβ and inflammatory cytokines were quantified by ELISA. RESULTS: HSD exposure further worsened BCAS-induced cerebral hypoperfusion and cognitive deficits. GAS administration restored CBF, improved behavioral performance, and showed a tendency toward partial improvement of hippocampal morphology. Transcriptomic analysis indicated that GAS-responsive differentially expressed genes were enriched in pathways associated with extracellular matrix interaction, tight junctions, vascular function, and PI3K-Akt signaling. Further experiments showed that GAS increased ZO-1, Occludin, and eNOS expression, preserved BBB-related ultrastructural features, restored Akt/mTOR pathway-associated phosphorylation, and attenuated BACE1/APP-, sAPPβ-, Aβ-, and serum TNF-α-related changes. CONCLUSION: GAS ameliorates cognitive impairment induced by HSD exposure combined with BCAS, and this effect is associated with improved CBF, restoration of Akt/mTOR pathway-associated phosphorylation, eNOS-related endothelial regulation, preservation of BBB-related structural integrity, and attenuation of amyloidogenic processing-related and serum inflammatory marker changes. These results provide experimental support for the potential role of GAS in treating vascular cognitive impairment associated with dietary risk factors.