Alzheimer’s disease (AD), characterized by an accumulation of -amyloid protein (Aβ) in brain tissue, is a major cause of dementia. Researchers at Tokyo University of Science previously reported on the oxytocin-induced reversal of impaired synaptic plasticity caused by amyloid -peptide (25-35) (Aβ25-35). They now show that an oxytocin derivative with modifications to improve brain perfusion is Aβ. can reverse25-35-induced cognitive impairment in mice.
The cognitive decline and memory loss seen in Alzheimer’s disease (AD) is attributed to the accumulation of -amyloid protein (Aβ), which impairs neural function in the brain. Experiments have shown that oxytocin, a peptide hormone primarily responsible for childbirth, bonding and lactation, also regulates cognitive behavior in the central nervous system (CNS) of rodents. This finding, along with the identification of oxytocin receptors in CNS neurons, has sparked interest in oxytocin’s possible role in reversing memory loss associated with cognitive impairments such as AD.
However, peptides such as oxytocin are characterized by poor blood-brain barrier permeability and thus can only be efficiently delivered to the brain via intracerebroventricular (ICV) administration. However, ICV is an invasive technique that is impractical to implement clinically.
Delivery of peptides to the CNS via intranasal (IN) administration is a viable clinical option. Prof. dr. 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 a penetration accelerating sequence (PAS) through structural modifications. Previous work had confirmed that both CPPs and the PAS benefit the nose-to-brain delivery pathway. Now a group of researchers, led by Prof. Akiyoshi Saitoh and Prof. Jun-Ichiro Oka, has used this approach to prepare an oxytocin derivative: PAS-CPPs-oxytocin. Their findings were published online September 19, 2022 in Neuropsychopharmacology Reports.
“We have previously shown that oxytocin reverses amyloid -peptide (25-35) (A𝛽25-35)-induced impairment of synaptic plasticity in rodents. We wanted to see whether PAS-CPPs-oxytocin could be delivered more efficiently to the mouse brain for clinical application, and whether it would improve cognitive functional behavior in mice,” says Prof. Oka.
The group first developed an A&β25-35 peptide-induced amnesia model by Aβ. to deliver25-35 to the mouse brain using ICV delivery. Over the course of the study, the spatial working and spatial reference memories of these mice were evaluated using the Y-maze and Morris water maze (MWM) tests. After confirming that the memory was impaired in Aβ25-35disabled mice were administered PAS-CPPs oxytocin and native oxytocin via the IN and ICV pathways, respectively, to see if learning and memory improved in the treated mice. Finally, the distribution of the IN-administered oxytocin derivative in brain tissue was profiled by imaging a fluorescently-labeled oxytocin derivative.
The results of this study were promising! The labeled PAS-CPPs oxytocin showed distribution throughout the mouse brain after IN administration. While the ICV administration of native oxytocin improved test results in both the Y-maze and MWM tests, the IN administered PAS-CPPs oxytocin yielded memory-enhancing effects in the Y-maze test. Prof. dr. Oka greets the team’s discovery and says, “My team is the first to show that the oxytocin derivative reduces the 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. dr. Oka explains the broader implications of their work: “The oxytocin derivative enters the brain more efficiently. In addition, since IN delivery is a non-invasive procedure, this modified version of the hormone could potentially provide a clinically viable treatment for Alzheimer’s disease.” to be. “