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The cranial part of the parasympathetic division plays a crucial role in regulating the visceral functions of the head and specific structures in the neck, thoracic, and abdominopelvic cavities. Preganglionic fibers of the parasympathetic division exit the brain through cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus), delivering parasympathetic output to the respective visceral structures.
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The sympathetic chain ganglia, also known as the sympathetic trunk ganglia or paravertebral ganglia, are a series of ganglia located bilaterally on either side of the spinal column. These ganglia serve as relay stations for the sympathetic nervous system. Preganglionic neurons originating in the spinal cord project their axons to the sympathetic chain ganglia. Within the ganglia, these preganglionic fibers synapse with postganglionic neurons.
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Serotonin, a crucial neurotransmitter synthesized by enterochromaffin cells, plays a cardinal role in regulating gastrointestinal (GI) motility. With over 90% of the body's total serotonin in the GI tract, its influence on digestive processes is profound. Serotonin is swiftly released upon various stimuli, such as food boluses or certain drugs, triggering intrinsic sensory neurons in the myenteric plexus and extrinsic vagal and spinal sensory neurons. This leads to the activation of the...
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Sensory impulses related to touch, pressure, vibration, and proprioception from various body parts, such as the limbs, trunk, neck, and posterior head, travel to the cerebral cortex through the posterior column-medial lemniscus pathway. The pathway’s name derives from the two white-matter tracts that convey the impulses: the spinal cord's posterior column and the brainstem's medial lemniscus. First-order sensory neurons extend their axons into the spinal cord, forming the...
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GLP-1 derivatives with functional sequences transit and migrate through trigeminal neurons.

Tomomi Akita1, Mizuki Shimamura1, Ayano Tezuka1

  • 1Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.

European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V
|January 7, 2024
PubMed
Summary

A novel Glucagon-like peptide-1 (GLP-1) derivative, PAS-CPP-GLP-1, was developed for intranasal delivery to the brain. This enhanced GLP-1 improved memory and learning in mice, offering a promising new avenue for dementia treatment.

Keywords:
Cell-penetrating peptideGlucagon-like peptide-1Intracellular dynamicsLearning and memoryNose-to-brain systemPenetration accelerating sequence

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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.