Japanese scientists show how intranasally delivered oxytocin derivative could be used to treat Alzheimer’s disease — ScienceDaily

Alzheimer’s disease (AD), characterized by the accumulation of β-amyloid protein (Aβ) in brain tissue, is a leading cause of dementia. Researchers at Tokyo University of Science previously reported the oxytocin-induced reversal of impaired synaptic plasticity induced by amyloid β peptide (25-35) (Aβ25-35). They now show that an oxytocin derivative with modifications to improve cerebral perfusion can reverse Aβ25-35-induced cognitive impairment in mice.

Cognitive decline and memory loss seen in Alzheimer’s disease (AD) are attributed to the accumulation of β-amyloid protein (Aβ), which impairs neuronal function in the brain. Experiments show that oxytocin, a peptide hormone primarily responsible for birth, 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, stimulated 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 and therefore can only be effectively delivered to the brain by intracerebroventricular (ICV) administration. However, ICV is an invasive technique that is impractical for clinical application.

CNS delivery of peptides 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 sequence (PAS) through structural modifications. Previous work confirmed that both CPP and PAS benefit the nose-to-brain delivery route. Now, a group of researchers led by Prof. Akiyoshi Saitoh and Prof. Jun-Ichiro Oka used this approach to prepare an oxytocin derivative: PAS-CPPs-oxytocin. Their findings were published online in Neuropsychopharmacology Reports on September 19, 2022.

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

The group first developed A&β25-35 peptide-induced amnesia model by delivery of Aβ25-35 to the mouse brain using ICV delivery. During the study, the spatial working and spatial reference memory of these mice were assessed using Y-maze and Morris water maze (MWM) tests. After confirming that the memory is affected in Ar25-35impaired 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 fluorescently labeled oxytocin derivative.

The results of this study were quite promising! Labeled PAS-CPPs-oxytocin shows distribution in the mouse brain after its IN administration. While ICV administration of native oxytocin improved test performance in both the Y-maze and MWM tests, IN administered PAS-CPPs-oxytocin produced memory-enhancing effects in the Y-maze test. Welcoming the team’s discovery, Prof. Oka said: “My team is the first to show that an oxytocin derivative can improve A𝛽25-35-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, because IN delivery is a non-invasive procedure, this modified version of the hormone could potentially be a clinically viable treatment for Alzheimer’s disease. “

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Materials provided by Tokyo University of Science. Note: Content may be edited for style and length.

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