Trigeminal Nerve Study Details New Method for Anti-Depressant Administration

Intranasal (in.) medications have been receiving increasing interest due to their ability to non-invasively deliver drugs straight to the brain. Respiratory and olfactory epithelia reside inside the nasal mucosa, and drugs can act on this system to travel straight to the central nervous system. However, not all administration acts the same – transport from the respiratory epithelium via the trigeminal nerve is slower than transport from the olfactory epithelium via the olfactory bulb or cerebrospinal fluid. As a result, researchers from the Tokyo University of Science, Japan, investigated how they can improve intranasal drug delivery time through the respiratory epithelium.

The team, led by Professor Chikamasa Yamashita, developed a novel drug to test CNS uptake efficacy with intranasal administration. "In a previous study, we combined functional sequences (namely, a membrane permeability-promoting sequence [CPP] and an endosomal escape-promoting sequence [PAS]) to glucagon-like peptide-2 (GLP-2), which is effective against treatment-resistant depression, so that it can be efficiently taken up by neurons," says Prof. Yamashita. "Using this, we aimed to construct a nose-to-brain system mediated by the trigeminal nerve in the respiratory epithelium."

While studying the effects of PAS-CPP-GLP-2 on the central nervous system, the team observed anti-depressant effects like those observed with intracerebroventricular (icv.) administration at identical doses. As a result, Yamashita and colleagues wanted to explore why intranasally administered GLP-2 derivatives show drug effects at the same dose as intracerebroventricularly administered GLP-2 derivatives.

Their findings, published in the Journal of Controlled Release, begin with the team performing both in. and icv. administration of PAS-CPP-GLP-2 into mice. They denoted how much drug transfer occurred to the whole brain via an enzyme-linked immunosorbent assay (ELISA). The results from the ELISA revealed that a much smaller quantity of intranasally administered PAS-CPP-GLP-2 reached the brain compared to the intracerebroventricularly administered PAS-CPP-GLP-2. However, both icv. and in. administration displayed similar efficacy at the same dose. 

The team deduced that this could be because icv. administration introduces drugs straight to CSF within ventricles, causing them to diffuse into CSF and the rest of the brain more effectively. Since CSF is present outside capillaries in the brain, the scientists noted that a large portion of PAS-CPP-GLP-2 was likely to stay here without being transported to the proper working sites of action. Nasally administered GLP-2 derivates, however, were rapidly taken up by the respiratory epithelium's trigeminal nerve and subsequently reached the site of action necessary while transiting neurons.

"This suggests that the peptide delivered to 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," explains Prof. Yamashita. "On the other hand, intranasally administered PAS-CPP-GLP-2, unlike icv. administration, may be transferred to the site of action without passing through the CSF or perivascular space."

These findings prompted the team to map the central transfer drug delivery route post-in. administration. This route involves the principal sensory trigeminal nucleus and trigeminal lemniscus of the trigeminal nerve before leading straight to the drug's working sites. The team also discovered that the migration of PAS-CPP-GLP-2 via nerve transit was the reason behind its slow pharmacological activity, despite low levels in the brain after in. administration.

"This is the world's first drug delivery system that allows intranasally administered peptides to be delivered to the central nervous system via nerve cells, delivering peptides to the site of action with the same efficiency as icv. administration," states Prof. Yamashita.