GLP-1 derivatives with functional sequences transit and migrate through trigeminal neurons

Area of Science:

• Neuroscience
• Pharmacology
• Biotechnology

Background:

• Dementia prevalence is rising with an aging population, creating a significant unmet medical need.
• Glucagon-like peptide-1 (GLP-1) shows potential for improving cognitive function, but effective brain delivery remains a challenge.
• Intranasal administration offers a non-invasive route for direct drug delivery to the brain.

Purpose of the Study:

• To develop and evaluate a modified GLP-1 (PAS-CPP-GLP-1) for enhanced intranasal brain delivery.
• To investigate the in vitro and in vivo efficacy of PAS-CPP-GLP-1 for improving learning and memory.

Main Methods:

• Creation of a GLP-1 derivative by incorporating cell-penetrating peptides (CPP) and penetration accelerating sequences (PAS).
• In vitro assessment of cellular uptake, endosomal escape, and cell exit mechanisms.
• In vivo evaluation of PAS-CPP-GLP-1 brain translocation via trigeminal nerve pathways in mice.
• Assessment of cognitive function improvement in mice following intranasal administration.

Main Results:

• PAS-CPP-GLP-1 demonstrated enhanced cellular uptake via macropinocytosis, facilitated by CPP.
• PAS-CPP-GLP-1 efficiently escaped endosomes due to PAS, enabling cell exit.
• The derivative successfully translocated through trigeminal nerve cells to adjacent neurons.
• Intranasal administration of PAS-CPP-GLP-1 significantly improved learning and memory in mice within 20 minutes.

Conclusions:

• The combination of CPP and PAS is crucial for efficient intranasal delivery of GLP-1 to the brain.
• PAS-CPP-GLP-1 represents a promising therapeutic strategy for dementia and cognitive disorders.
• This approach facilitates direct nose-to-brain drug transfer, bypassing systemic circulation.