Xie Ruiye, Liu Zhen, Zheng Jingjing, Tan Qiwen, Wu Haitao, Liang Yong
Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
Department of Chemistry & the MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China.
Drug Deliv Transl Res. 2025 Sep 19. doi: 10.1007/s13346-025-01975-w.
Alzheimer's disease (AD) is a neurodegenerative disorder strongly associated with aging, and Dauricine (DAU) has demonstrated significant neuropharmacological properties for AD treatment. However, its bioavailability is significantly limited when administered orally, leaving the mechanisms underlying its effects on AD largely unexplored. In this study, a DAU-loaded thermosensitive gel was formulated for delivery via the nasal-nerve route, and its potential to enhance the bioavailability of DAU in rat plasma and cerebrospinal fluid (CSF) was assessed through a pharmacokinetic study. The anti-Alzheimer's disease (AD) mechanism of DAU was investigated using network pharmacology approaches, molecular docking, and dynamics simulations, complemented by in vivo experimental validation. DAU can be effectively incorporated into a thermosensitive gel and administered to the brain within 30 min via intranasal delivery. Following nasal administration, the pharmacokinetic parameters of DAU in cerebrospinal fluid and plasma were significantly elevated compared to oral administration (P < 0.01), indicating a substantial improvement in bioavailability at equivalent doses. Behavioral studies demonstrated that DAU (dose of 1 mg/kg and 2 mg/kg in gel) enhanced cognitive function in intracerebroventricular-streptozotocin (ICV-STZ) rats and decelerated aging processes by reversing oxidative stress and mitigating neuronal apoptosis. Additionally, DAU contributed to lowering blood glucose levels, increasing insulin-like growth factor 1 (IGF-1) content, and reducing insulin resistance. Network pharmacological analysis, molecular docking, molecular dynamics simulations, and in vivo experiments collectively suggested that DAU exerted significant therapeutic effects on Alzheimer's disease by inhibiting the PI3K/AKT/mTOR pathway. Our study demonstrates a significant enhancement in the bioavailability of DAU in the brain via nasal-nerve delivery route and also this research is the first to report that DAU ameliorates cognitive impairment in ICV-STZ rats through the PI3K/AKT/mTOR pathway. Our findings contribute to the scientific understanding of DAU's potential in Alzheimer's disease treatment and offer a novel experimental foundation for the development of anti-Alzheimer's drugs.
阿尔茨海默病（AD）是一种与衰老密切相关的神经退行性疾病，蝙蝠葛碱（DAU）已显示出对AD治疗具有显著的神经药理学特性。然而，口服给药时其生物利用度显著受限，其对AD作用的潜在机制在很大程度上尚未得到探索。在本研究中，制备了一种负载DAU的热敏凝胶，用于通过鼻神经途径给药，并通过药代动力学研究评估其提高大鼠血浆和脑脊液（CSF）中DAU生物利用度的潜力。使用网络药理学方法、分子对接和动力学模拟研究了DAU的抗阿尔茨海默病（AD）机制，并通过体内实验验证进行补充。DAU可有效掺入热敏凝胶中，并通过鼻内给药在30分钟内进入大脑。鼻内给药后，与口服给药相比，脑脊液和血浆中DAU的药代动力学参数显著升高（P < 0.01），表明在等效剂量下生物利用度有显著提高。行为学研究表明，DAU（凝胶中剂量为1mg/kg和2mg/kg）可增强脑室内注射链脲佐菌素（ICV-STZ）大鼠的认知功能，并通过逆转氧化应激和减轻神经元凋亡来延缓衰老过程。此外，DAU有助于降低血糖水平、增加胰岛素样生长因子1（IGF-1）含量并降低胰岛素抵抗。网络药理学分析、分子对接、分子动力学模拟和体内实验共同表明，DAU通过抑制PI3K/AKT/mTOR途径对阿尔茨海默病发挥显著治疗作用。我们的研究表明，通过鼻神经给药途径，DAU在大脑中的生物利用度显著提高，并且本研究首次报道DAU通过PI3K/AKT/mTOR途径改善ICV-STZ大鼠的认知障碍。我们的研究结果有助于科学理解DAU在阿尔茨海默病治疗中的潜力，并为抗阿尔茨海默病药物的开发提供了新的实验基础。
