An oxytocin derivative improves cognitive impairment in Alzheimer’s disease

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

Source: Tokyo University of Science

Cognitive decline and memory loss seen in Alzheimer’s disease (AD) is attributed to the accumulation of β-amyloid protein (Aβ), which damages neural functions in the brain.

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

This discovery, together with the identification of oxytocin receptors in CNS neurons, has fueled interest in the potential role of oxytocin in reversing memory loss associated with cognitive disorders such as AD.

However, peptides such as oxytocin are characterized by poor permeability of the blood-brain barrier, so they can only be effectively delivered to the brain via intracerebroventricular (ICV) administration. ICV, however, is an invasive technique that is clinically impractical to perform.

Peptide delivery to the CNS via intranasal (IN) administration is a viable clinical option. Prof. Chikamasa Yamashita of Tokyo University of Science recently patented a method to increase the efficiency of peptide delivery to the brain by introducing cell-penetrating peptides (CPPs) and penetration-accelerating sequences (PASs) through structural modifications.

Previous work has confirmed that both CPP and PAS benefit from nose-to-brain transmission. Now a group of researchers, led by prof. Akiyoshi Saitoh and prof. Jun-Ichiro Oka, used this approach to prepare oxytocin derivatives: PAS-CPPs-oxytocin.

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

“We have previously shown that oxytocin reverses amyloid 𝛽 peptide (25-35) (A𝛽_{25-35 (display, other).})-induced impairment of synaptic plasticity in rodents. We wanted to see if PAS-CPPs-oxytocin can be more efficiently delivered to the mouse brain for clinical use and if it can improve cognitive functional behavior in mice,” says prof. Eye.

The group first developed A𝛽_{25-35 (display, other).} model of peptide-induced amnesia by delivery of A𝛽_{25-35 (display, other).} mouse brain using ICV delivery. During the study, the spatial working memory and spatial reference memory of these mice were assessed using the Y-maze and Morris water maze (MWM) tests.

After confirming that memory is affected in A𝛽_{25-35 (display, other).}-injured mice, PAS-CPPs-oxytocin and native oxytocin were administered using the IN and ICV routes, respectively, to see if learning and memory improved in the treated mice.

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

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

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

Welcoming the team’s discovery, prof. Oka says, “My team is the first to show that an oxytocin derivative can enhance A𝛽_{25-35 (display, other).}-induced memory impairment in mice. This suggests that oxytocin may help reduce the cognitive decline we see in Alzheimer’s disease.”

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

Financing: The study was funded by JSPS KAKENHI (grant no.: 15K07974 to JI.O.); Mochida Memorial Foundation for Medical and Pharmaceutical Research (2015 to SS-H.); Program supported by MEXT for the Foundation for Strategic Research in Private Universities (2014-2018 for J.-IO); and Grant-in-Aid for JSPS Scholars (Grant No.: JP-21J20036 to JT).

About this Alzheimer’s research news

Author: Hiroshi Matsuda
Source: Tokyo University of Science
Contact: Hiroshi Matsuda – Tokyo University of Science
Picture: The image is in the public domain

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

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Abstract

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

Goal

We previously reported that oxytocin, a peptide hormone, can reverse β-amyloid peptide (25-35) (Aβ_{25–35 (view, professional).})-induced impairment of synaptic plasticity in the mouse hippocampus. In this study, we examined the effects of oxytocin on Aβ_{25–35 (view, professional).}-induced cognitive behavioral impairment in mice to investigate the potential of oxytocin as a clinical tool for the treatment of Alzheimer’s disease (AD).

Methods

Y-maze and Morris water maze (MWM) tests were performed. Because intracerebroventricular (ICV) administration is 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 later used in our IN administration experiments.

the results

Here we show that ICV administration of oxytocin in mice has an Aβ-enhancing memory effect_{25–35 (display, other).}-induced amnesia in the Y-maze and MWM test. IN administration of oxytocin derivatives showed memory improvement effects in the Y-maze test. Moreover, we collected evidence that a fluorescein isothiocyanate-labeled oxytocin derivative was distributed in the mouse brain after IN administration.

Conclusion

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