Intranasale (in.) has gained popularity as a non-invasive approach to delivering drugs directly to the brain. This approach involves the respiratory or olfactory epithelia 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 pathway 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 in. drug delivery time through the predominant respiratory epithelium.
To facilitate this, a team of researchers, including Professor Chikamasa Yamashita from Tokyo University of Science, Japan, developed a new drug to test its efficiency of absorption by the CNS.
To offer more insight, Professor Yamashita says: “In a previous study, we combined functional sequences (namely, a sequence promoting membrane permeability [CPP] and a sequence promoting endosomal escape [PAS]) to glucagon-like peptide-2 (GLP-2), which is effective against treatment-resistant depression, so that it can be taken up efficiently by neurons. Using this, we sought to construct a nose-brain system mediated by the trigeminal nerve in the respiratory epithelium. »
By studying the absorption of this new PAS-CPP-GLP-2 by the CNS, the team noted that its antidepressant effects via in. administration remained on par with intracerebroventricular (icv.) administration in identical doses. Therefore, Professor Yamashita and colleagues elucidated a nose-to-brain transfer mechanism to explain why intranasally administered GLP-2 derivatives exhibit drug effects at the same dose as intranasally administered GLP-2 derivatives. intracerebroventricular. The team’s findings were documented in a study posted online September 30, 2022 in Volume 351 of the Controlled Release Diary.
The team made icv. et in. administration of PAS-CPP-GLP-2 to mice. The amount of drug transferred to the whole brain was quantified by enzyme immunoassay (ELISA).
Surprisingly, ELISA revealed that much less PAS-CPP-GLP-2 administered intranasally reached the brain than PAS-CPP-GLP-2 administered intracerebroventricularly. However, both icv. et in. administration showed efficacy at the same dose. This is attributed to the fact that icv. administration introduces drugs to the place of origin of the CSF (ventricle), causing them to diffuse into the CSF and spread through the brain. Since CSF is present in spaces outside of brain capillaries, the team saw that much of PAS-CPP-GLP-2 was likely to remain here without being transported to its working sites of action. On the other hand, nasally administered GLP-2 derivatives were rapidly absorbed by the trigeminal nerve of the respiratory epithelium and effectively reached the site of action during neuron transit.
Professor Yamashita explains: “This suggests that the peptide delivered to the site of action by icv. the administration is present in large quantity in the brain but only in very small quantity, because it remains in the perivascular space. On the other hand, PAS-CPP-GLP-2 administered intranasally, unlike icv. administration, can be transferred to the site of action without passing through the CSF or the perivascular space. »
These results prompted the team to identify the central route of administration of the drug after in. administration. This pathway involved the main sensory trigeminal nucleus, followed by the trigeminal lemniscus of the trigeminal nerve, and led to the drug working sites. Finally, the migration of PAS-CPP-GLP-2 via nerve transit was found to underlie its pharmacological activity despite its low levels in the brain after in. administration.
Professor Yamashita explains: “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 the peptides to the site of action with the same efficiency as icv. administration. »
Talking about future applications of the team’s findings, Professor Yamashita concludes: “Current data suggest the possibility of extending the use of this system from the treatment of depression to the administration of drugs in patients with the disease. of Alzheimer’s. It should therefore be applied to neurodegenerative diseases. with high unmet medical demand. »
Source of the story:
Materials provided by Tokyo University of Science. Note: Content may be edited for style and length.