Exploring the role of the trigeminal nerves in the delivery of intranasally administered antidepressants

Exploring the role of the trigeminal nerves in the delivery of intranasally administered antidepressants

Intranasal (in.) administration has gained increasing popularity as a non-invasive method of delivering drugs directly to the brain. This approach involves the respiratory or olfactory epithelium of the nasal mucosa through which drugs reach the central nervous system (CNS). Transport from the respiratory epithelium via the trigeminal nerve is considerably slower than transport from the olfactory epithelium via the olfactory bulb (OB) or cerebrospinal fluid (CSF). However, only a small portion of the nasal mucosa in humans is made up of olfactory epithelium, prompting researchers to focus on improving drug delivery time through the predominant respiratory epithelium.

To facilitate this, a team of researchers, including Professor Chikamasa Yamashita of the Tokyo University of Sciences, Japan, developed a novel drug to test its CNS absorption efficiency.

To provide more information, Professor Yamashita states: “In a previous study, we combined functional sequences (i.e. a sequence that promotes membrane permeability [CPP] and an endosomal escape promoter sequence [PAS]) to glucagon-like peptide-2 (GLP-2), which is effective against treatment-resistant depression, so that neurons can take it up efficiently. Using this, we aimed to build a trigeminal nerve-mediated nose-to-brain system in the respiratory epithelium.”

While studying the uptake of this new PAS-CPP-GLP-2 by the CNS, the team noted that its intravenous antidepressant effects were on par with intracerebroventricular (icv) administration at identical doses. Therefore, Professor Yamashita and his colleagues elucidated a nose-to-brain transfer mechanism to explain why intranasally administered GLP-2 derivatives show pharmacological effects at the same dose as GLP-2 derivatives. administered intracerebroventricularly. The team’s findings were documented in a study available online on September 30, 2022 in Volume 351 of the Controlled Release Diary.

The team performed icv. and in the administration of PAS-CPP-GLP-2 in mice. The amount of drug transferred to the whole brain was quantified by enzyme-linked immunosorbent assay (ELISA).

Surprisingly, ELISA revealed that much less intranasally administered PAS-CPP-GLP-2 reached the brain than intracerebroventricularly administered PAS-CPP-GLP-2. However, both icv. and intramuscular administration showed efficacy at the same dose. This is attributed to the fact that icv. administration introduces drugs to the site of CSF origin (ventricle), causing them to diffuse into the CSF and spread throughout the brain. Since CSF is present in the spaces outside the capillaries of the brain, the team found that a large part of PAS-CPP-GLP-2 was likely to remain here without being transported to its work sites. On the other hand, nasally administered GLP-2 derivatives were rapidly absorbed by the trigeminal nerve of the respiratory epithelium and efficiently reached the site of action while transiting neurons.

Prof. Yamashita explains: “This suggests that the peptide reached the site of action by icv. administration is present in large amounts in the brain but only in very small amounts as it remains in the perivascular space. On the other hand, PAS-CPP-GLP-2 administered intranasally, unlike icv. administration, it can be transferred to the site of action without passing through the CSF or the perivascular space.

These results led the team to identify the central transfer drug administration route after administration. This route involved the main trigeminal sensory nucleus, followed by the trigeminal lemniscus of the trigeminal nerve, and led to the drug’s work sites. Finally, the migration of PAS-CPP-GLP-2 through nerve transit was found to be the reason behind its pharmacological activity despite its low levels in the brain upon administration.

Professor Yamashita explains: “This is the world’s first drug delivery system that allows intranasally administered peptides to reach the central nervous system via nerve cells, delivering peptides to the site of action with the same efficiency as icv management.”

Speaking about future applications of the team’s findings, Prof. Yamashita concludes: “Current data suggest the possibility of extending the use of this system from the treatment of depression to drug delivery in patients with Alzheimer’s disease. Therefore, it is expected to be applied to neurodegenerative diseases with a high unmet medical demand.”



DOI: https://doi.org/10.1016/j.jconrel.2022.09.047

About Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest private science research university in Japan, with four campuses in central and suburban Tokyo and in Hokkaido. Established in 1881, the university has continuously contributed to Japan’s scientific development by instilling a love of science in researchers, technicians, and educators.

With the mission of “Creating science and technology for the harmonious development of nature, human beings and society”, TUS has undertaken a wide range of research from basic to applied science. TUS has taken a multidisciplinary approach to research and has conducted intensive studies in some of today’s most vital fields. TUS is a meritocracy where the best of science is recognized and promoted. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia that produces Nobel Prize winners within the field of natural sciences.

Website: https://www.tus.ac.jp/en/mediarelations/

About Professor Chikamasa Yamashita of the Tokyo University of Science

Prof. Chikamasa Yamashita is a Distinguished Professor at the Faculty of Pharmaceutical Sciences, Department of Medicine and Life Sciences, Tokyo University of Science, Japan. Prof. Yamashita has a Ph.D. in the field of Pharmaceutical Sciences from Tokushima University, Japan. With over 30 years of pharmaceutical research experience, Prof. Yamashita is an expert in the field of regenerative medicine and nasal drug delivery systems. He has helped author more than 150 research publications in nationally and internationally accredited journals and currently holds five patents in the field of pharmaceutical research to his credit.

Financing information

This work was supported by research funds from Daiichi Sankyo’s TaNeDS Funding Program.

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