Molecular Pharmaceutics Laboratory, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, Japan.
Department of Pharmaceutics, School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan.
Mol Pharm. 2020 Nov 2;17(11):4067-4076. doi: 10.1021/acs.molpharmaceut.0c00495. Epub 2020 Sep 30.
Direct drug delivery from nose to brain has drawn much attention as an effective strategy for the treatment of central nervous system diseases. After intranasal administration, drug molecules can be directly delivered from the nose to the brain. However, the detailed mechanism for this direct delivery to the brain has not been elucidated. In the present study, the effect of the activation of the cerebral fluid circulation (the glymphatic system) on the efficacy of direct delivery from nose to brain was investigated. Because the glymphatic system is activated by some anesthetic regimens, the differences in brain delivery and the pharmacokinetics under anesthetic and conscious conditions were compared in rats. Under urethane anesthesia, direct delivery from the nose to the brain was facilitated, whereas the brain uptake from the systemic circulation via the blood-brain barrier was decreased. In addition, both the brain uptake of caffeine injected into the subarachnoid cerebrospinal fluid (CSF) and the extracerebral clearance of caffeine after intrastriatal injection were enhanced under anesthesia. For intranasal administration, caffeine was transported directly from the nose to the CSF and then delivered into the brain parenchyma by the CSF circulation. The results obtained in the present study clarified that the direct delivery from nose to brain could be facilitated by anesthesia. These findings suggest that fluid circulation in the brain can contribute to a wider cerebral distribution of the drug after direct delivery from nose to brain.
药物经鼻腔直接递送至脑部作为一种治疗中枢神经系统疾病的有效策略引起了广泛关注。鼻内给药后，药物分子可以直接从鼻腔递送至脑部。然而，这种直接递送至脑部的详细机制尚未阐明。在本研究中，研究了脑内液循环（神经胶质淋巴系统）的激活对经鼻直接递送至脑部效果的影响。由于一些麻醉方案可激活神经胶质淋巴系统，因此比较了麻醉和清醒状态下药物从鼻腔递送至脑部的差异和药代动力学。在氨基甲酸乙酯麻醉下，经鼻直接递送至脑部的效果得到增强，而通过血脑屏障从全身循环向脑部的摄取则减少。此外，蛛网膜下腔脑脊髓液（CSF）中注射咖啡因后的脑摄取以及纹状体注射后咖啡因的脑外清除率在麻醉下均增强。对于经鼻给药，咖啡因直接从鼻腔转运至 CSF，然后通过 CSF 循环递送至脑实质。本研究的结果阐明了麻醉可促进经鼻直接递送至脑部。这些发现表明，脑内液循环可促进经鼻直接递送至脑部后药物在脑部的更广泛分布。
