Oxytocin derivative improves cognitive impairment in Alzheimer’s disease

Summary: An oxytocin derivative delivered intranasally helped improve cognitive function and reduce cognitive impairment in mouse models of Alzheimer’s disease.

Source: Tokyo University of Science

The cognitive decline and memory loss observed in Alzheimer’s disease (AD) are attributed to the accumulation of β-amyloid (Aβ) protein, which impairs neural function in the brain.

Experimentation has shown that oxytocin, a peptide hormone primarily responsible for parturition, bonding and lactation, also regulates cognitive behavior in the central nervous system (CNS) of rodents.

This discovery, along with the identification of oxytocin receptors in CNS neurons, has spurred interest in the potential role of oxytocin in reversing memory loss linked to cognitive disorders like Alzheimer’s disease. of Alzheimer’s.

However, peptides like oxytocin are characterized by low permeability of the blood-brain barrier and therefore can only be efficiently delivered to the brain by intracerebroventricular (ICV) administration. ICV, however, is an invasive technique that is impractical to perform clinically.

Administration of peptides to the CNS intranasally (IN) is a viable clinical option. Professor Chikamasa Yamashita of Tokyo University of Science has recently patented a method to increase the efficiency of peptide delivery to the brain, by introducing cell-penetrating peptides (CPPs) and a penetration (PAS) through structural modifications.

Previous work had confirmed that CPPs and PAS benefit from the route of administration from the nose to the brain. Now, a group of researchers, led by Prof. Akiyoshi Saitoh and Prof. Jun-Ichiro Oka, have taken advantage of this approach to prepare an oxytocin derivative: PAS-CPPs-oxytocin.

Their findings were published online in Neuropsychopharmacology reports September 19, 2022.

“We have already shown that oxytocin reverses amyloid 𝛽 peptide (25-35) (A𝛽25-35)-induced impairment of synaptic plasticity in rodents. We wanted to see if PAS-CPPs-oxytocin could be more efficiently delivered to the mouse brain for clinical application, and if it improved cognitive functional behavior in mice,” says Professor Oka.

The group first developed an A𝛽25-35 peptide-induced amnesia model by providing A𝛽25-35 to mouse brain using ICV delivery. During the study, the spatial working and spatial reference memories of these mice were assessed using the Y-maze and Morris water maze (MWM) tests.

After confirming that the memory is affected in A𝛽25-35-impaired mice, PAS-CPPs-oxytocin and native oxytocin were administered via the IN and ICV routes, respectively, to see if learning and memory improved in the treated mice.

Finally, the distribution of IN-administered oxytocin derivative in brain tissue was profiled by imaging a fluorescently labeled oxytocin derivative.

The results of this study were quite promising. Labeled PAS-CPPs-oxytocin showed distribution throughout mouse brain after IN administration.

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Administration of peptides to the CNS intranasally (IN) is a viable clinical option. Image is in public domain

While ICV administration of native oxytocin improved test scores in the Y-maze and MWM tests, IN-administered PAS-CPPs-oxytocin produced memory-enhancing effects in the maze test in Y.

Welcoming the team’s discovery, Professor Oka says: “My team is the first to show that the oxytocin derivative can improve A𝛽25-35memory impairments induced in mice. This suggests that oxytocin may help reduce the cognitive decline we see in Alzheimer’s disease.

Why are these results clinically useful? Professor Oka explains the wider implications of their work: “The oxytocin derivative enters the brain more efficiently. Additionally, since IN administration is a non-invasive procedure, this modified version of the hormone could potentially be a clinically viable treatment for Alzheimer’s disease.

Funding: The study received funding from JSPS KAKENHI (Grant No.: 15K07974 to JI.O.); the Mochida Memorial Foundation for Medical and Pharmaceutical Research (2015 to SS-H.); the Program supported by MEXT for the Foundation for Strategic Research in Private Universities (2014-2018 at J.-IO); and the Grant for JSPS Fellows (Grant No: JP-21J20036 to JT).

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About this Alzheimer’s disease research news

Author: Hiroshi Matsuda
Source: Tokyo University of Science
Contact: Hiroshi Matsuda – Tokyo University of Science
Image: Image is in public domain

Original research: Free access.
“Intracerebroventricular administration of oxytocin and intranasal administration of the oxytocin derivative ameliorate β-amyloid peptide-induced memory impairment (25–35) in mice” by Chikamasa Yamashita et al. Neuropsychopharmacology reports


Intracerebroventricular administration of oxytocin and intranasal administration of the oxytocin derivative improve memory impairment induced by β-amyloid peptide (25–35) in mice


We have previously reported that oxytocin, a peptide hormone, can reverse the β-amyloid peptide (25–35) (Aβ25–35)-induces alterations in synaptic plasticity of the murine hippocampus. In this study, we investigated the effects of oxytocin on Aβ25–35– induced alteration of cognitive behavior in mice in order to study the potential of oxytocin as a clinical treatment tool for Alzheimer’s disease (AD).


The Y-maze and Morris water labyrinth (MWM) tests were carried out. Since intracerebroventricular (ICV) delivery is both invasive and impractical, we additionally used intranasal (IN) delivery to the brain. To this end, we prepared an oxytocin derivative containing cell-penetrating peptides and a penetration-accelerating sequence, which was then used in our IN delivery experiments.


We showed here that ICV administration of oxytocin in mice exerted memory-enhancing effects on Aβ25–35-amnesia induced in the Y-maze and MWM tests. IN administration of the oxytocin derivative showed memory-enhancing effects in the Y-maze test. Additionally, we gained evidence that the fluorescein isothiocyanate-labeled oxytocin derivative was distributed throughout the mouse brain after IN administration.


Our results suggest that the oxytocin derivative is effective for its delivery of IN to the brain and may be particularly useful in the clinical treatment of cognitive disorders, such as those that characterize AD.

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