Intracerebroventricular administration of oxytocin and intranasal administration of the oxytocin derivative improve ß-amyloid peptide (25-35)-induced memory impairment in mice.

AIM: We previously reported that oxytocin, a peptide hormone, can reverse the ß-amyloid peptide (25-35) (Aß25-35 )-induced impairments of the murine hippocampal synaptic plasticity. In this study, we examined the effects of oxytocin on the Aß25-35 -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). METHODS: 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. RESULTS: We herein showed that the ICV administration of oxytocin in mice exerted memory-improving effects on the Aß25-35 -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. CONCLUSION: 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.

Oxytocin reverses Aß-induced impairment of hippocampal synaptic plasticity in mice.

AIM: Oxytocin, a peptide hormone synthesized in the hypothalamic paraventricular nucleus, has been reported to participate in the regulation of learning and memory performance. However, no report has demonstrated the effect of oxytocin on the amyloid-beta (Aß)-induced impairment of synaptic plasticity. In this study, we examined the effects of oxytocin on the Aß-induced impairment of synaptic plasticity in mice. METHODS: To investigate the effect of oxytocin on synaptic plasticity, we prepared acute hippocampal slices for extracellular recording and assessed long-term potentiation (LTP) with perfusion of the Aß active fragment (Aß25-35) in the absence and presence of oxytocin. RESULTS: We found that oxytocin reversed the impairment of LTP induced by Aß25-35 perfusion in the mouse hippocampus. These effects were blocked by pretreatment with the selective oxytocin receptor antagonist L-368,899. Furthermore, the treatment with the ERK inhibitor U0126 and selective Ca2+-permeable AMPA receptor antagonist NASPM completely antagonized the effects of oxytocin. CONCLUSION: This is the first report to demonstrate that oxytocin could reverse the effects of Aß on hippocampal LTP in mice. We propose that ERK phosphorylation and Ca2+-permeable AMPA receptors are involved in this effect of oxytocin.

Intranasal administration of neuromedin U derivatives containing cell-penetrating peptides and a penetration-accelerating sequence induced memory improvements in mice.

Neuromedin U (NMU) is a neuropeptide that is expressed and secreted in the brain and gut. We previously demonstrated that the intracerebroventricular (i.c.v.) administration of NMU inhibited inflammation-mediated memory impairment in mice. In order to utilize NMU as a clinical treatment tool for inflammation-mediated amnesia, we herein focused on non-invasive intranasal delivery because the i.c.v. administration route is invasive and impractical. In the present study, we prepared two NMU derivatives containing cell-penetrating peptides (CPPs), octaarginine (R8), and each penetration-accelerating sequence, namely FFLIPKG (PASR8-NMU) and FFFFG (F4R8-NMU), for intranasal (i.n.) administration. In the Y-maze test, the i.c.v. administration of lipopolysaccharide (LPS) (10µg/mouse) significantly decreased spontaneous alternation behavior, and this was prevented by the prior administration of PASR8-NMU or F4R8-NMU (5.6µg/mouse, i.n.). Moreover, the administration of PASR8-NMU or F4R8-NMU (5.6µg/mouse, i.n.) just before the Y-maze test also improved LPS-induced memory impairment. Indocyanine green (ICG)-labeled PASR8-NMU (i.n.) was significantly observed in the hippocampus and paraventricular hypothalamic nucleus 30min after its i.n. administration. PASR8-NMU, but not F4R8-NMU guaranteed the stability of the administration liquid for 24h. These results suggest that PASR8-NMU is effective for i.n. delivery to the brain, and may be useful in the clinical treatment of inflammation-mediated amnesia.