慢性脑低灌注（chronic cerebral hypoperfusion, CCH）是中枢神经系统常见的病理生理过程，通常导致进行性持久性神经和认知功能障碍，其中包括较为严重的血管性痴呆(vascular dementia, VaD)，其预后效果较差，死亡率高于大多数痴呆类型，故急需在认知障碍出现早期进行有效干预。

昆仑雪菊(Coreopsis tinctoria Nutt., CT)为菊科金鸡菊属植物，传统上具有清热解毒、活血化淤和祛湿功效。近年来，提取自CT的化合物在认知障碍和神经保护方面表现良好，且基于课题组前期对CT总黄酮具有神经保护特性的发现，为进一步挖掘CT的药用价值、探究其中含量最高的黄酮类化合物异奥卡宁-7-O-β-D-葡萄糖苷(flavanomarein, FM)对CCH后认知障碍的影响，本文展开以下研究：

（1）基于课题组前期研究，构建小鼠双侧颈动脉狭窄(bilateral carotid artery stenosis, BCAS)模型，探究FM对CCH的神经保护作用。小鼠行为学、脑血流及相关的病理检查（LFB染色、Nissl染色等）评估发现，FM改善了记忆相关行为，恢复了部分脑血流，减轻了白质损伤和神经元死亡。

（2）通过对小鼠海马转录组学进行分析，对FM可能的作用途径进行预测并通过实验证实。发现FM可抑制下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal, HPA)轴的过度激活，降低血清皮质酮(corticosterone, CORT)水平，并抑制海马促皮质激素释放激素(corticotropin-releasing hormone, CRH)的过度表达。FM增强了vGluT-1、PSD95和SYP的表达，显著降低了谷氨酸能神经元Parthanatos，并调节下游PARP-1、PAR和AIF。

（3）通过对小鼠肠道内容物进行宏基因组及代谢组学分析。结果表明，FM调节了组胺分泌细菌Haemophilus influenza和Paeniclostridium sordellii，改变了血清组胺水平。

本文通过以上研究表明，FM可通过减轻神经元死亡来改善认知障碍，而神经元死亡受肠道微生物群衍生的组胺代谢和HPA轴过度激活的调节。这为植物药通过肠脑轴和神经内分泌系统调节认知功能障碍的作用提供了新的见解。

Chronic cerebral hypoperfusion (CCH) is a prevalent pathological and physiological process affecting the central nervous system, often resulting in progressive and persistent neurological and cognitive dysfunction. In severe cases, it can lead to vascular dementia (VaD), a condition associated with poor prognosis and a higher mortality rate compared to most other types of dementia. Consequently, there is an urgent need for effective early interventions to mitigate cognitive decline.

Coreopsis tinctoria Nutt. (CT), a plant belonging to the genus Coreopsis in the Asteraceae family, has been traditionally recognized for its medicinal properties, including heat-clearing and detoxification, promoting blood circulation and resolving blood stasis, as well as eliminating dampness. In recent years, bioactive compounds extracted from CT have demonstrated promising neuroprotective and cognitive-enhancing effects. Building upon prior research by our group, which established the neuroprotective properties of total flavonoids from Coreopsis tinctoria (CT), this study aims to further investigate the pharmacological potential of CT, particularly the effects of flavanomarein (FM), its most abundant flavonoid compound, on cognitive impairment induced by chronic cerebral hypoperfusion (CCH). The following investigations were conducted:

(1) A bilateral carotid artery stenosis (BCAS) model was established in mice to assess the neuroprotective effects of FM on CCH. Behavioral assessments, cerebral blood flow measurements, and histopathological analyses (e.g., Luxol Fast Blue (LFB) staining, Nissl staining) indicated that FM ameliorated memory-related deficits, partially restored cerebral blood flow, and mitigated white matter damage and neuronal loss.

(2) Transcriptomic analysis of the hippocampus was performed to elucidate the potential molecular mechanisms underlying FM’s effects, followed by experimental validation. Results revealed that FM inhibited excessive activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to a reduction in serum corticosterone (CORT) levels and suppression of hippocampal corticotropin-releasing hormone (CRH) overexpression. Additionally, FM upregulated the expression of vGluT-1, PSD95, and SYP, significantly reduced glutamatergic neuronal, and modulated downstream effectors such as PARP-1, PAR, and AIF.

(3) Metagenomic and metabolomic analyses of mouse intestinal contents revealed that FM modulated histamine-secreting bacteria, including Haemophilus influenzae and Paeniclostridium sordellii, thereby altering serum histamine levels.

Collectively, these findings indicate that FM exerts neuroprotective effects by attenuating neuronal loss, a process modulated through gut microbiota-derived histamine metabolism and HPA axis regulation. This study provides novel insights into the therapeutic potential of phytomedicine in addressing cognitive dysfunction via the gut-brain axis and neuroendocrine system modulation.