State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China.
Institute of TCM, Natural Products College of Pharmacy, Jinan University, Guangzhou, 510632, China.
J Ethnopharmacol. 2021 Mar 1;267:113491. doi: 10.1016/j.jep.2020.113491. Epub 2020 Oct 19.
Gardenia jasminoides J. Ellis (Fructus Gardenia) is a traditional Chinese medicine with diverse pharmacological functions, such as anti-inflammation, anti-depression, as well as improvement of cognition and ischemia brain injury. GJ-4 is a natural extract from Gardenia jasminoides J. Ellis (Fructus Gardenia) and has been proved to improve memory impairment in Alzheimer's disease (AD) mouse model in our previous studies.
This study aimed to evaluate the therapeutic effects of GJ-4 on vascular dementia (VD) and explore the potential mechanisms.
In our experiment, a focal cerebral ischemia and reperfusion rat model was successfully developed by the middle cerebral artery occlusion and reperfusion (MCAO/R). GJ-4 (10 mg/kg, 25 mg/kg, 50 mg/kg) and nimodipine (10 mg/kg) were orally administered to rats once a day for consecutive 12 days. Learning and memory behavioral performance was assayed by step-down test and Morris water maze test. The neurological scoring test was performed to evaluate the neurological function of rats. 2,3,5-Triphenyltetrazolium chloride (TTC) staining and Nissl staining were respectively employed to determine the infarct condition and neuronal injury of the brain. Iba1 immunohistochemistry was used to show the activation of microglia. Moreover, the synaptic damage and inflammatory level were detected by Western blot.
GJ-4 could significantly improve memory impairment, cerebral infraction, as well as neurological deficits of VD rats induced by MCAO/R. Further research indicated VD-induced neuronal injury was alleviated by GJ-4. In addition, GJ-4 could protect synapse of VD rats by upregulating synaptophysin (SYP) expression, post synaptic density 95 protein (PSD95) expression, and downregulating N-Methyl-D-Aspartate receptor 1 (NMDAR1) expression. Subsequent investigation of the underlying mechanisms identified that GJ-4 could suppress neuroinflammatory responses, supported by inhibited activation of microglia and reduced expression of inflammatory proteins, which ultimately exerted neuroprotective effects on VD. Further mechanistic study indicated that janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) pathway was inhibited by GJ-4 treatment.
These results suggested that GJ-4 might serve as a potential drug to improve VD. In addition, our study indicated that inhibition of neuroinflammation might be a promising target to treat VD.
栀子（Gardenia jasminoides J. Ellis，果实）是一种具有多种药理功能的中药，如抗炎、抗抑郁以及改善认知和缺血性脑损伤。GJ-4 是栀子（Gardenia jasminoides J. Ellis，果实）的天然提取物，在我们之前的研究中已被证明可改善阿尔茨海默病（AD）小鼠模型的记忆障碍。
本研究旨在评估 GJ-4 对血管性痴呆（VD）的治疗作用，并探讨其潜在机制。
在我们的实验中，通过大脑中动脉闭塞再灌注（MCAO/R）成功建立了局灶性脑缺血再灌注大鼠模型。GJ-4（10mg/kg、25mg/kg、50mg/kg）和尼莫地平（10mg/kg）每天口服一次，连续 12 天。通过跌落试验和 Morris 水迷宫试验测定学习和记忆行为表现。神经评分试验用于评估大鼠的神经功能。2,3,5-三苯基氯化四氮唑（TTC）染色和尼氏染色分别用于确定脑梗死情况和神经元损伤。Iba1 免疫组化用于显示小胶质细胞的激活。此外，通过 Western blot 检测突触损伤和炎症水平。
GJ-4 可显著改善 MCAO/R 诱导的 VD 大鼠的记忆障碍、脑梗死和神经功能缺损。进一步的研究表明，GJ-4 减轻了 VD 诱导的神经元损伤。此外，GJ-4 通过上调突触小泡相关蛋白（SYP）表达、后突触密度 95 蛋白（PSD95）表达和下调 N-甲基-D-天冬氨酸受体 1（NMDAR1）表达来保护 VD 大鼠的突触。对潜在机制的后续研究表明，GJ-4 通过抑制小胶质细胞的激活和减少炎症蛋白的表达来抑制神经炎症反应，从而对 VD 发挥神经保护作用。进一步的机制研究表明，GJ-4 抑制了 Janus 激酶 2（JAK2）/信号转导和转录激活因子 1（STAT1）通路。
这些结果表明，GJ-4 可能是一种改善 VD 的潜在药物。此外，我们的研究表明，抑制神经炎症可能是治疗 VD 的一个有前途的靶点。
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