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Intranasally administered neuromedin U derivatives prevented LPS-induced amnesia.Intranasally administered neuromedin U derivatives ameliorated LPS-induced amnesia.Derivatives contained two different sequences exhibited similar anti-amnesic effects.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) (10 μg/mouse) significantly decreased spontaneous alternation behavior, and this was prevented by the prior administration of PASR8-NMU or F4R8-NMU (5.6 μg/mouse, i.n.). Moreover, the administration of PASR8-NMU or F4R8-NMU (5.6 μg/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 30 min after its i.n. administration. PASR8-NMU, but not F4R8-NMU guaranteed the stability of the administration liquid for 24 h. 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.