Osthole/borneol thermosensitive gel via intranasal administration enhances intracerebral bioavailability to improve cognitive impairment in APP/PS1 transgenic mice.
Osthole/borneol thermosensitive gel via intranasal administration enhances intracerebral bioavailability to improve cognitive impairment in APP/PS1 transgenic mice.
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DOI：
10.3389/fphar.2023.1224856
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发表时间：
2023
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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阿尔茨海默病（AD）对全球老年人口构成重大威胁。中药（TCM）已广泛应用于AD的治疗。蛇床子素是一种在许多中药配方中被列为“皇”的生物活性成分，已被证明可以有效缓解 AD 症状。然而，其在脑内的生物利用度较低，限制了其临床应用。本研究旨在基于经典的“皇帝-大臣-辅佐-使者”模型，以冰片为“使者”，提高蛇床子素脑内生物利用度，探讨蛇床子素对AD的增强药理作用。结果表明，适合鼻内给药的原位热敏凝胶基质与蛇床子素和冰片混合，由20%的P407、7%的P188和6%的PEG300组成。与口服相比，鼻内给予蛇床子素/冰片后，脑脊液中蛇床子素的浓度几乎增加了十倍。机制表明，冰片作为“信使”，通过抑制ZO-1和occludin的表达，打开细胞间隙，松弛鼻粘膜的紧密连接，从而加快鼻子到大脑的路径，引导蛇床子素作为“皇帝”到达大脑中的目标。与单独使用蛇床子素相比，冰片辅助蛇床子素在抑制 caspase-3 表达、增加 Bcl-2/Bax 比值、改善 T-SOD 和过氧化氢酶表达、降低丙二醛水平、抑制神经元凋亡以及通过抑制 BACE1 表达降低 Aβ 水平以减轻认知障碍方面的效率显着提高。总体而言，我们的研究表明，通过鼻内给予蛇床子素/冰片，蛇床子素的脑内生物利用度显着提高，并为中药治疗 AD 提供了更广泛的应用，具有更高的脑内生物利用度。
Alzheimer’s disease (AD) poses a significant threat to the global elderly population. Traditional Chinese medicine (TCM) has been widely utilized in the treatment of AD. Osthole, a bioactive ingredient classified as an “emperor” in many TCM formulas, has been demonstrated to effectively alleviate AD symptoms. However, its low bioavailability in the brain has limited its clinical application. This study aimed to increase the intracerebral bioavailability of osthole by using borneol as a “courier,” based on the classical “Emperor–Minister–Assistant–Courier” model, and to investigate the enhanced pharmacological performance of osthole on AD. Results indicated that a suitable in situ thermosensitive gel matrix for intranasal administration mixed with osthole and borneol consists of P407 at 20%, P188 at 7%, and PEG300 at 6%. The concentration of osthole in the cerebrospinal fluid increased almost tenfold after intranasal administration of osthole/borneol compared to oral administration. Mechanisms showed that borneol as a “courier” opened up intercellular space and loosened the tight junctions of the nasal mucosa by suppressing ZO-1 and occludin expression, thereby expediting the nose-to-brain route and guiding osthole as “emperor” to its target in the brain. Osthole assisted by borneol demonstrated significantly improved efficiency in suppressing cleaved caspase-3 expression, increasing the Bcl-2/Bax ratio, improving T-SOD and catalase expression, reducing malondialdehyde levels, inhibiting neuron apoptosis, and decreasing Aβ levels by inhibiting BACE1 expression to alleviate cognitive impairment in APP/PS1 mice compared to osthole alone. Overall, our study demonstrated that the intracerebral bioavailability of osthole profoundly improved with intranasal administration of osthole/borneol and provided a wider application of TCM for AD treatment with higher intracerebral bioavailability.
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