Effect of Cerebrospinal Fluid Circulation on Nose-to-Brain Direct Delivery and Distribution of Caffeine in Rats


The nasal route has gained attention as it is a direct non-invasive way to transport drugs to the brain which cannot be transferred via the oral route. To date, olfactory and trigeminal nerves have been shown to be safe and effective pathways to deliver therapeutic agents to brain. For instance, nucleic acids have been investigated as a potential treatment for Parkinson’s disease, mucopolysaccharidosis, and mechanical allodynia following traumatic brain injury, whereas peptides have been used to treat Alzheimer’s disease, autism spectrum disorder, and narcolepsy. The olfactory nerve extends over the upper portion of the nasal cavity as it travels from the olfactory bulb to the nasal cavity through the cribriform plate. The olfactory nerve distribution terminal is located in the olfactory region, which is the top section of the nasal cavity under the epithelium. The cribriform plate is placed above the olfactory bulb. The olfactory nerve exits the olfactory bulb and enters the nasal cavity through the ethmoidal hole. As a result, drugs administered through the nose may go to the brain via the olfactory pathway, which joins the cerebrospinal fluid with the perineural portion of the olfactory nerve (CSF).

The olfactory pathway, which travels through the perineural space of the olfactory nerve, is a favorable route through which medications are delivered. Because the olfactory and trigeminal nerves’ perineural spaces are filled with CSF, a medication injected into the nasal cavity may pass through the mucosal membrane and enter the CSF. The medication might then be circulated and delivered to the brain. According to previous studies, the glymphatic system (circulation and interexchange of CSF and ISF) may have an influence on the property of brain delivery and the pharmacokinetics of drug in the brain after intranasal (IN) administration. The effect of glymphatic system activation on brain delivery efficiency and the pharmacokinetics of the drug in the brain after nasal application were explored in this work to better understand the precise mechanism of nasal drug delivery to the brain. Since the glymphatic system is thought to be active during restful sleep or under general anaesthesia, the differences in brain delivery and pharmacokinetics in rats under anaesthetic and conscious situations were examined.

In a new study published in Molecular Pharmaceutics Japanese scientists led by Dr. Daisuke Inoue investigated how anaesthesia affected nasal medication delivery to the brain by stimulating CSF circulation. According to the glymphatic system’s facts, it is feasible that drug delivery to the brain via the nose will become more efficient and practical. The findings of their investigation can help in developing a novel nasal delivery system for brain drug delivery. Greater glymphatic inflow has been associated with higher electroencephalogram (EEG) delta power in earlier investigations. Rats were put to sleep using a variety of anaesthetic protocols in order to promote the glymphatic circulation. Rats that have been general-anesthetized are frequently used as models for how people fall asleep naturally on the glymphatic study. Following direct injection into the cisternal CSF, the concentration profiles of caffeine in the brain parenchyma were examined in order to confirm the caffeine’s real transit from the CSF to the brain parenchyma. When under anaesthesia, caffeine was swiftly transferred from the CSF to the brain, and extracerebral elimination of caffeine was accelerated. The glymphatic system was stimulated by anaesthesia, which enhanced the brain’s fluid flow. The rapid exchange of caffeine in the CSF with the brain extracellular fluid enhanced both caffeine absorption and clearance from the brain. The findings of this study demonstrate that direct brain supply is enhanced during anaesthesia, which may be connected to the active glymphatic system. Intranasal administration of a therapeutic drug to patients before sleep enables for efficient drug delivery to the brain during sleep because direct drug distribution from nose to brain is enabled concurrently with the commencement of sleep. As a result, it has been shown that, in clinical practise, the nasal drug delivery system can be a useful treatment approach for disorders of the central nervous system when using formulations with a longer nasal residence duration.

According to the authors, the current study demonstrated that while direct drug transport from the nose to the brain was improved under anaesthesia, transfer from the systemic circulation to the brain through the BBB was lowered. These results indicate that nasal caffeine delivery to the brain after intra nasal administration was improved by the anaesthetic circumstances’ stimulation of the glymphatic system.

Effect of Cerebrospinal Fluid Circulation on Nose-to-Brain Direct Delivery and Distribution of Caffeine in Rats - Medicine Innovates

About the author

Daisuke Inoue, Ph.D.

Department of Medical Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, University of Toyama, Japan

E-mail: [email protected]

Dr. Daisuke Inoue is an assistant professor at University of Toyama in Japan since 2022. He received his PhD degree from Okayama University, Japan, in 2013. He began his work in 2009, and he was an assistant professor at Shujitsu University (-2019) and Ritsumeikan University (-2021). His current research interests include nose-to-brain drug delivery, intranasal drug application for therapeutics of CNS diseases, intranasal formulation development, pharmacokinetic study on intranasal drug absorption model.


Inoue D, Furubayashi T, Tanaka A, Sakane T, Sugano K. Effect of Cerebrospinal Fluid Circulation on Nose-to-Brain Direct Delivery and Distribution of Caffeine in Rats. Molecular Pharmaceutics. 2020 Sep 21;17(11):4067-76.

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