Summary: An intranasally delivered oxytocin derivative improved cognitive function and reduced memory impairment in mouse models of Alzheimer’s disease.
Source: Tokyo University of Science
Cognitive decline and memory loss in Alzheimer’s disease (AD) are closely linked to accumulation of β-amyloid protein (Aβ), which disrupts neural function in the brain.
Research has shown that oxytocin — a peptide hormone best known for its roles in childbirth, bonding, and lactation — also influences cognitive behavior in the rodent central nervous system (CNS). The presence of oxytocin receptors on CNS neurons has prompted investigation into whether oxytocin can help reverse memory loss associated with disorders such as AD.
A major obstacle has been the poor permeability of peptide hormones across the blood-brain barrier, which typically requires invasive intracerebroventricular (ICV) administration for effective brain delivery. ICV is not practical for routine clinical use.
Intranasal (IN) delivery offers a non-invasive route to the brain, and Professor Chikamasa Yamashita at Tokyo University of Science developed a strategy to enhance peptide transport along the nose-to-brain pathway. His patented approach combines cell-penetrating peptides (CPPs) with a penetration-accelerating sequence (PAS), modifying peptide structure to improve brain uptake.
Building on these advances, researchers led by Professor Akiyoshi Saitoh and Professor Jun-Ichiro Oka designed an oxytocin derivative incorporating PAS and CPPs, referred to here as PAS-CPPs-oxytocin, and tested whether intranasal delivery of this derivative could reach the brain effectively and improve cognition in mice.
Their findings were published online in Neuropsychopharmacology Reports on 19 September 2022.
“We previously demonstrated that oxytocin can reverse Aβ25–35-induced impairment of synaptic plasticity in rodents,” says Professor Oka. “In this study we evaluated whether a modified oxytocin could be delivered more efficiently to the mouse brain via the intranasal route and whether it could improve learning and memory in an Alzheimer’s-like model.”
To model Aβ-induced memory loss, the team used intracerebroventricular administration of the β-amyloid peptide Aβ25–35 to induce amnesia in mice. They then assessed spatial working and reference memory using the Y-maze and Morris water maze (MWM) behavioral tests.
After confirming memory deficits in Aβ25–35-treated mice, the researchers compared outcomes after administering native oxytocin directly via ICV and PAS-CPPs-oxytocin via the non-invasive intranasal route. They also tracked distribution of the intranasally delivered derivative using a fluorescently tagged version of the molecule to visualize brain penetration.
Results showed that the fluorescently labeled PAS-CPPs-oxytocin distributed broadly throughout the mouse brain after intranasal administration, supporting effective nose-to-brain transport. Behaviorally, ICV administration of native oxytocin improved performance in both the Y-maze and MWM tests, indicating recovery of spatial memory. Intranasal PAS-CPPs-oxytocin produced memory-enhancing effects in the Y-maze test, demonstrating that the modified peptide can exert functional benefits when delivered non-invasively.
Professor Oka emphasizes the significance of these findings: “Our team is the first to show that an oxytocin derivative delivered intranasally can improve Aβ25–35-induced memory impairment in mice. This suggests oxytocin-based approaches may help reduce cognitive decline in Alzheimer’s disease.”
Clinically, the study highlights two important advantages. First, the PAS-CPPs modification increases the peptide’s ability to enter the brain. Second, intranasal delivery is non-invasive and more practical than ICV administration, making it a promising route for potential therapeutic use in cognitive impairment and AD.
Funding: This research was supported by JSPS KAKENHI (Grant No.: 15K07974 to J.-I.O.), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (2015 to S.S.-H.), the MEXT-Supported Program for the Strategic Research Foundation at Private Universities (2014–2018 to J.-I.O.), and the Grant-in-Aid for JSPS Fellows (Grant No.: JP-21J20036 to J.T.).
About this Alzheimer’s disease research news
Author: Hiroshi Matsuda
Source: Tokyo University of Science
Contact: Hiroshi Matsuda – Tokyo University of Science
Image: The image is in the public domain
Original Research: Open access. “Intracerebroventricular administration of oxytocin and intranasal administration of the oxytocin derivative improve β-amyloid peptide (25–35)-induced memory impairment in mice” by Chikamasa Yamashita et al., Neuropsychopharmacology Reports
Abstract
Intracerebroventricular administration of oxytocin and intranasal administration of the oxytocin derivative improve β-amyloid peptide (25–35)-induced memory impairment in mice
Aim
Previous work demonstrated that oxytocin can reverse Aβ25–35-induced impairments of hippocampal synaptic plasticity in mice. This study evaluated whether oxytocin and a structurally modified oxytocin derivative could mitigate Aβ25–35-induced cognitive deficits, and whether intranasal delivery of the derivative provides a viable, non-invasive route to the brain for potential clinical application in Alzheimer’s disease.
Methods
Behavioral assessment employed the Y-maze and Morris water maze (MWM) tests to quantify spatial working and reference memory. Because intracerebroventricular administration is invasive and impractical for clinical use, the team developed an oxytocin derivative incorporating cell-penetrating peptides and a penetration-accelerating sequence, and evaluated its performance after intranasal administration. Distribution of a fluorescently labeled derivative was imaged to confirm nose-to-brain transport.
Results
ICV administration of native oxytocin produced memory-improving effects in both Y-maze and MWM tests in Aβ25–35-treated mice. Intranasal administration of the PAS-CPPs-oxytocin derivative improved performance in the Y-maze, and fluorescent labeling demonstrated wide distribution of the derivative throughout the brain following intranasal delivery.
Conclusion
These findings indicate that structural modification of oxytocin enhances its intranasal delivery to the brain and that the oxytocin derivative can ameliorate Aβ25–35-induced memory impairments. The results support further exploration of intranasal oxytocin-based therapies for cognitive impairment associated with Alzheimer’s disease.