The cognitive and memory decline observed in Alzheimer’s disease (AD) is caused by the accumulation of β-amyloid protein (Aβ), which leads to neural impairment. Previous studies have shown that oxytocin – a peptide hormone responsible for parturition, bonding, and lactation – could also regulate cognitive performance and behavior in the central nervous system of rodents.
However, while research suggests that oxytocin could play an important role in reversing memory loss caused by cognitive disorders such as AD, until recently this hormone could only be efficiently delivered to the brain through intracerebroventricular (ICV) administration – an invasive technique that is impractical to implement clinically.
Now, a team of researchers from the Tokyo University of Science has explored the possibility of delivering oxytocin to the central nervous system via intranasal (IN) administration, a considerably less invasive method. The experts devised a technique 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, and leveraged this approach to prepare an oxytocin derivative, PAS-CPPs-oxytocin.
“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,” reported study senior author Jun-ichiro Oka, an expert in Neuropharmacology at Tokyo University.
After developing an A𝛽25-35 peptide-induced amnesia model by supplying A𝛽25-35 to the mouse brain via ICV delivery, the scientists assessed the spatial working and spatial reference memories of mice by using the Y-maze and Morris water maze (MWM) tests. After confirming that memory was affected in A𝛽25-35-impaired mice, the researchers administered PAS-CPPs-oxytocin and native oxytocin via an IN and an ICV route, respectively, in order to clarify whether learning and memory improved in the treated mice. Finally, they profiled the distribution of the IN-administered derivative in brain tissues by imaging of a fluorescent-tagged oxytocin derivative.
The tagged PAS-CPPs-oxytocin showed efficient distribution throughout the brain after its IN administration, and, while the ICV administration of native oxytocin improved test outcomes in both the Y-maze and MWM tests, the IN administration of PAS-CPPs-oxytocin led to better outcomes in the Y-maze test.
“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. 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,” Professor Oka concluded.
The study is published in the journal Neuropsychopharmacology Reports.
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