Effect of Cerebrospinal Fluid Circulation on Nose-to-Brain Direct Delivery and Distribution of Caffeine in Rats
Effect of Cerebrospinal Fluid Circulation on Nose-to-Brain Direct Delivery and Distribution of Caffeine in Rats
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DOI：
10.1021/acs.molpharmaceut.0c00495
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发表时间：
2020-11-02
影响因子：
4.9
通讯作者：
Sugano, Kiyohiko
中科院分区：
文献类型：
--
作者：
Inoue, Daisuke;Furubayashi, Tomoyuki;Sugano, Kiyohiko
药物经鼻直接给药作为治疗中枢神经系统疾病的一种有效策略已引起广泛关注。鼻内给药后，药物分子可直接从鼻递送至脑。然而，这种直接输送到大脑的详细机制尚未阐明。在本研究中，研究了脑流体循环（胶质淋巴系统）的激活对从鼻直接递送至脑的功效的影响。由于胶质淋巴系统被某些麻醉方案激活，因此在大鼠中比较了麻醉和清醒条件下脑递送和药代动力学的差异。在氨基甲酸乙酯麻醉下，促进了从鼻到脑的直接递送，而通过血脑屏障从体循环的脑摄取减少。此外，在麻醉状态下，注入蛛网膜下腔脑脊液（CSF）的咖啡因的脑摄取和纹状体内注射后咖啡因的脑外清除均增强。对于鼻内给药，咖啡因直接从鼻转运至CSF，然后通过CSF循环递送至脑实质。本研究的结果表明，麻醉可以促进从鼻到脑的直接递送。这些发现表明，大脑中的液体循环可有助于药物从鼻直接递送至大脑后更广泛的大脑分布。
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.