Exploring the nasal-brain pathway for nasal administration to the brain: delivering antidepressants via the trigeminal nerve

Intranasal administration has received increasing attention
as a method of non-invasive delivery of drugs directly to the brain.
This method evades the blood-brain barrier and delivers drugs directly to the brain, which reach the central nervous system (CNS)
through either the respiratory epithelium or the olfactory epithelium of the nasal mucosa.
The drug delivery pathway from respiratory epithelial cells to the central nervous system via the trigeminal nerve is thought to be very slow, much slower than transport from olfactory epithelial cells via olfactory bulb (OB) or cerebrospinal fluid (CSF
).
。 However, the olfactory epithelium makes up a very small proportion of the human nasal mucosa compared to rodents – the ratio of olfactory epithelial cells to respiratory epithelial cells in rodents is 50:50, but only 2:98 has been reported in humans, which forces clinical applications to develop a nasal-to-brain drug delivery technique that can be administered from the respiratory epithelium in a short period of time through the trigeminal nerve – to avoid many capillaries in the respiratory epithelial intercellular space, the drug must be taken up by the respiratory epithelial cells themselves and transferred to the trigeminal nerve
。

To achieve this, a team of researchers, including Professor Chikamasa Yamashita of Tokyo University of Science in Japan, developed a novel drug to test the absorption
effect of the central nervous system on it.
They previously found that the neuropeptide glucagon-like peptide-2 (GLP-2) exerts antidepressant effects not only in depressed model mice, but also in refractory depressed model mice administered through intraventricular administration, so it is expected to become a new antidepressant
.
GLP-2 is a 33-amino acid peptide derived from glucagongen and produced
in the gut and CNS.
To achieve efficient uptake by respiratory epithelial cells and the trigeminal nerve, they created GLP-2 derivatives with the functional sequence PAS-CPP and investigated the pathway by which PAS-CPP-GLP-2 is transferred to the CNS via the trigeminal nerve pathway
after injection.

The researchers treated the mouse model with intranasal administration and intra-brain administration, and used enzyme-linked immunosorbent assay (ELISA) to quantify the whole brain drug transport
.
Surprisingly, although ELISA showed much less transport to the brain with intranasal administration than the intraventricular administration, both modes of administration showed efficacy
at the same dose.

The researchers found that intraventricular administration introduces drugs into the origin of the cerebrospinal fluid (ventricles), causing them to diffuse into the cerebrospinal fluid and spread
throughout the brain.
Because cerebrospinal fluid resides in the space outside the capillaries of the brain, the team found that a large portion of PAS-CPP-GLP-2 may stay here without being transported to its site
of action.
On the other hand, GLP-2 derivatives administered nasally are rapidly uptaken by the trigeminal nerve of the respiratory epithelium and efficiently reach the site of action when transmitting neurons
.
In this way, Professor Yamashita and his colleagues elucidated a mechanism of nasal-brain metastasis to explain why intranasally administered GLP-2 derivatives exhibit drug effects
at the same doses as intraventricular GLP-2 derivatives.

Professor Yamashita explains: "This suggests that the dose delivered to the site of action via ICV in the brain is very small, as many drugs stay in the perivascular space
.
On the other hand, nasal administration does not pass through cerebrospinal fluid or perivascular spaces, and although it is present in lower quantities in the brain, its pharmacological activity is transmitted by nerves
.

"This is the world's first drug delivery system for intranasal drug delivery through nerve cells to deliver drugs to the central nervous system, delivering peptides to the site of action with the same efficiency as intracerebral administration
.
"

"The current data suggest that the system has the potential to expand from treating depression to providing medication
to Alzheimer's patients.
Therefore, it is expected to be applied to neurodegenerative diseases
with high but unmet medical needs.
”