PAS-CPP-modified GLP-2 achieved nose-to-brain delivery with antidepressant effects within 20 minutes of intranasal administration at the same dose effective via direct brain injection, while intravenous delivery was ineffective.
20 minutesonset of antidepressant effect from intranasal PAS-CPP-GLP-2, matching direct brain injection efficacy
What the researchers found
PAS-CPP-GLP-2 showed antidepressant-like effects within 20 min of intranasal administration at the same dose effective by i.c.v. injection, while i.v. delivery was ineffective. The modification prevented degradation and enabled transcellular nose-to-brain transport.
Why it matters
Depression affects hundreds of millions of people, and treatment-resistant depression has few options. A nasal spray delivering an effective brain peptide within minutes could transform treatment — especially since GLP-2 works in treatment-resistant models where conventional antidepressants fail.
The numbers in context
CPPs significantly enhanced nasal GLP-2 brain delivery; antidepressant effects in both depression and treatment-resistant depression models.
How the study worked
In vitro: cellular uptake mechanism (macropinocytosis via CPP), endosomal escape (via PAS), and transcellular transport studies. In vivo: depression model mice tested with intranasal, intravenous, and intracerebroventricular PAS-CPP-GLP-2 administration.
Who was studied
Depression and treatment-resistant depression model mice
What this study cannot tell us
Mouse depression model — behavioral tests are proxies for human depression. Dose-response optimization and long-term efficacy not established. PAS-CPP modification adds manufacturing complexity. Safety profile of repeated intranasal delivery needs evaluation.
How to read the evidence
Innovative proof-of-concept with compelling evidence of nose-to-brain delivery (intranasal effective, IV ineffective). Mouse depression model is standard but limited in predicting human outcomes.
When this study was published
Published in 2021. Nose-to-brain peptide delivery for psychiatric conditions is an emerging field.
The bigger picture
Nose-to-brain delivery is one of the most promising routes for CNS drug delivery, bypassing the blood-brain barrier. This proof-of-concept with GLP-2 demonstrates that CPP/PAS modification can make neuropeptides clinically viable as nasal therapies for brain disorders.
Questions still open
- Can PAS-CPP-GLP-2 nasal spray be advanced to human clinical trials for depression?
- Would this nose-to-brain delivery approach work for other neuropeptides?
- How does the antidepressant effect compare to rapid-acting treatments like ketamine?
Common questions
How does a nasal spray deliver drugs to the brain?
What is treatment-resistant depression?
Read the original research
Usefulness of cell-penetrating peptides and penetration accelerating sequence for nose-to-brain delivery of glucagon-like peptide-2.
Journal of controlled release : official journal of the Controlled Release Society, 335, 575-583
Citation
Akita, Tomomi; Kimura, Ryosuke; Akaguma, Saki; Nagai, Mio; Nakao, Yusuke; Tsugane, Mamiko; Suzuki, Hiroaki; Oka, Jun-Ichiro; Yamashita, Chikamasa. (2021). Usefulness of cell-penetrating peptides and penetration accelerating sequence for nose-to-brain delivery of glucagon-like peptide-2.. Journal of controlled release : official journal of the Controlled Release Society, 335, 575-583. https://doi.org/10.1016/j.jconrel.2021.06.007