Summary: An intranasally delivered oxytocin derivative helped improve cognitive function and reduced 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) is attributed to the accumulation of β-amyloid protein (Aβ), 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 rodent central nervous system (CNS).
This finding, along with the identification of oxytocin receptors in CNS neurons, has spurred interest in the potential role of oxytocin in reversing memory loss tied to cognitive disorders like AD.
However, peptides like oxytocin are characterized by weak blood-brain barrier permeability, and so can only by efficiently delivered to the brain via intracerebroventricular (ICV) administration. ICV, however, is an invasive technique which is impractical to implement clinically.
Delivering peptides to the CNS via intranasal (IN) administration is a viable clinical option. Prof. Chikamasa Yamashita at 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, leveraged this approach to prepare an oxytocin derivative: PAS-CPPs-oxytocin.
Their findings were published online in Neuropsychopharmacology Reports on 19 September 2022.
“We have previously 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 delivered more efficiently to the mouse brain for clinical application, and if it improved cognitive functional behavior in mice,” states Prof. Oka.
The group first developed an A𝛽25-35 peptide-induced amnesia model by supplying A𝛽25-35 to the mouse brain using ICV delivery. During 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 memory was affected in A𝛽25-35-impaired 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 brain tissue was profiled by imaging of a fluorescent-tagged oxytocin derivative.
The results of this study were quite promising. The tagged PAS-CPPs-oxytocin showed distribution throughout the mouse brain following its IN administration.
While the ICV administration of native oxytocin improved test outcomes in both the Y-maze and MWM tests, the IN administered PAS-CPPs-oxytocin yielded memory improving effects in the Y-maze test.
Hailing the team’s discovery, Prof. Oka says, “My team is the first to show that the oxytocin derivative can improve 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. 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.”
Funding: The study received funding from 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.).
Intracerebroventricular administration of oxytocin and intranasal administration of the oxytocin derivative improve β-amyloid peptide (25–35)-induced memory impairment in mice
We previously reported that oxytocin, a peptide hormone, can reverse the β-amyloid peptide (25–35) (Aβ25–35)-induced impairments of the murine hippocampal synaptic plasticity. In this study, we examined the effects of oxytocin on the Aβ25–35-induced impairment of cognitive behavior in murine in order to investigate the potential of oxytocin as a clinical treatment tool for Alzheimer’s disease (AD).
The Y-maze and Morris water maze (MWM) tests were performed. Since the intracerebroventricular (ICV) administration is both invasive and impractical, we further utilized intranasal (IN) delivery to the brain. For this purpose, we prepared an oxytocin derivative containing cell-penetrating peptides and a penetration accelerating sequence, which was subsequently used in our IN administration experiments.
We herein showed that the ICV administration of oxytocin in mice exerted memory-improving effects on the Aβ25–35-induced amnesia in both the Y-maze and MWM tests. The IN administration of the oxytocin derivative exhibited memory-improving effects in the Y-maze test. Moreover, we acquired evidence that the fluorescein isothiocyanate-labeled oxytocin derivative was distributed throughout the mouse brain following its IN administration.
Our results suggest that the oxytocin derivative is effective for its IN delivery to the brain and may be particularly useful in the clinical treatment of cognitive impairment, such as that characterizing AD.