Japanese scientists have developed a novel drug delivery framework which could one day be used in the treatment of neurodegenerative diseases such as Alzheimer’s.
Researchers at the Tokyo University of Science in Japan, have developed a novel concept of a nose-to-brain system for the clinical application of neuropeptides.
They developed a derivative of glucagon-like peptide-2 and found that when administered intranasally (through the nose), it is efficiently delivered through the trigeminal nerve to the site of action and exhibits antidepressant-like effects.
This is the first demonstration in the world that intranasally administered neuropeptides reach the brain (hippocampus and hypothalamus) via neurons.
Those behind it say this framework could be applied to drug design for neurodegenerative diseases with high, unmet medical demand like Alzheimer’s disease.
What is intranasal administration?
Intranasal administration has been garnering increasing popularity as a non-invasive approach to deliver drugs directly to the brain. This approach involves the respiratory or olfactory epithelia of the nasal mucosa through which the 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 route 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, propelling researchers to focus on improving intranasal drug delivery time through the predominant respiratory epithelium.
To facilitate this, a team of researchers including Professor Chikamasa Yamashita, developed a novel drug to test its uptake efficacy by the CNS.
“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,” explains Professor Yamashita.
“Using this, we aimed to construct a nose-to-brain system mediated by the trigeminal nerve in the respiratory epithelium.”
What the research shows
While studying the uptake, the team noted that its anti-depressant effects via intranasal (in) administration remained on par with intracerebroventricular (icv) administration at identical doses.
When they performed intracerebroventricular and intranasal administration of PAS-CPP-GLP-2 into mice, the amount of drug transferred to the whole brain was quantified by enzyme-linked immunosorbent assay (ELISA).
The ELISA revealed that a much smaller amount of intranasally administered PAS-CPP-GLP-2 reached the brain than icv administered PAS-CPP-GLP-2. However, both icv and in. administration showed efficacy at the same dose.
Professor Yamashita explains: “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. 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.”
It was then discovered that the migration of PAS-CPP-GLP-2 via nerve transit was the reason behind its pharmacological activity despite its low levels in the brain in administration.
Potential for future treatments
“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,” adds Professor Yamashita.
“Current data suggests the possibility of extending the use of this system from treating depression to delivering drugs in patients with Alzheimer’s disease. It is therefore expected to be applied to neurodegenerative diseases with high, unmet medical demand.”
