title: Effect of an Enhanced Nose-to-Brain Delivery of Insulin on Mild and Progressive Memory Loss in the Senescence-Accelerated Mouse.
abstract: Insulin is now considered to be a new drug candidate for treating dementias, such as Alzheimer's disease, whose pathologies are linked to insulin resistance in the brain. Our recent work has clarified that a noncovalent strategy involving cell-penetrating peptides (CPPs) can increase the direct transport of insulin from the nasal cavity into the brain parenchyma. The present study aimed to determine whether the brain insulin level increased by intranasal coadministration of insulin with the CPP penetratin has potential for treating dementia. The pharmacological actions of insulin were investigated at different stages of memory impairment using a senescence-accelerated mouse-prone 8 (SAMP8) model. The results of spatial learning tests suggested that chronic intranasal administration of insulin with l-penetratin to SAMP8 slowed the progression of memory loss in the early stage of memory impairment. However, contrary to expectations, this strategy using penetratin was ineffective in recovering the severe cognitive dysfunction in the progressive stage, which involves brain accumulation of amyloid β (Aβ). Immunohistological examination of hippocampal regions of samples from SAMP8 in the progressive stage suggested that accelerated nose-to-brain insulin delivery had a partial neuroprotective function but unexpectedly increased Aβ plaque deposition in the hippocampus. These findings suggest that the efficient nose-to-brain delivery of insulin combined with noncovalent CPP strategy has different effects on dementia during the mild and progressive stages of cognitive dysfunction.
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University , 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Kamei
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University , 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Misa
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University , 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Hayoung
authors.initials: H
authors.lastname: Choi
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University , 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Okada
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University , 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University , 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Itokazu
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University , 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Mariko
authors.identifier: 0000-0001-6796-5163
authors.initials: M
authors.lastname: Takeda-Morishita
mesh_terms: D000281:Administration, Intranasal / Q000379:methods; D000375:Aging / Q000187:drug effects*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000008:administration & dosage; D057846:Cell-Penetrating Peptides / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000378:metabolism; D003704:Dementia / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism*; D007328:Insulin / Q000008:administration & dosage*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D009297:Nasal Mucosa / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D007328:Insulin; C414409:penetratin
keywords: Alzheimer’s disease; amyloid β; cell-penetrating peptide; cognitive dysfunction; insulin; nose-to-brain delivery