title: Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3β in P301L tau transgenic mice.
abstract: Deferoxamine (DFO), a metal chelator, has been previously reported to slow the loss of spatial memory in a mouse model of amyloid accumulation when delivered intranasally (IN). In this study, we determined whether IN DFO also has beneficial effects in the P301L mouse, which accumulates hyperphosphorylated tau. Mice were intranasally treated three times per week with either 10% DFO (2.4 mg) or saline for 5 months, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with Western blot and ELISA. Wild-type (WT) mice statistically outperformed transgenic (TG) saline mice in the radial arm water maze, while performance of TG-DFO mice was not different than WT mice, suggesting improved performance in the radial arm water maze. Other behavioral changes were not evident. Beneficial changes in brain biochemistry were evident in DFO-treated mice for several proteins. The TG mice had significantly less pGSK3β and HIF-1α, with more interleukin-1β and total protein oxidation than wild-type controls, and for each protein, DFO treatment significantly reduced these differences. There was not a significant decrease in phosphorylated tau in brain tissue of DFO-treated mice at the sites we measured. These data suggest that IN DFO is a potential treatment not only for Alzheimer's disease, but also for other neurodegenerative diseases and psychiatric disorders in which GSK3β and HIF-1α play a prominent role.
authors.affiliation: Alzheimer's Research Center, HealthPartners Research Foundation at Regions Hospital, St. Paul, MN 55101, USA. jared.m.fine@healthpartners.com
authors.forename: J M
authors.initials: JM
authors.lastname: Fine
authors.forename: A M
authors.initials: AM
authors.lastname: Baillargeon
authors.forename: D B
authors.initials: DB
authors.lastname: Renner
authors.forename: N S
authors.initials: NS
authors.lastname: Hoerster
authors.forename: J
authors.initials: J
authors.lastname: Tokarev
authors.forename: S
authors.initials: S
authors.lastname: Colton
authors.forename: A
authors.initials: A
authors.lastname: Pelleg
authors.forename: A
authors.initials: A
authors.lastname: Andrews
authors.forename: K A
authors.initials: KA
authors.lastname: Sparley
authors.forename: K M
authors.initials: KM
authors.lastname: Krogh
authors.forename: W H
authors.initials: WH
authors.lastname: Frey
authors.forename: L R
authors.initials: LR
authors.lastname: Hanson
mesh_terms: D000281:Administration, Intranasal / Q000379:methods; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003676:Deferoxamine / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists* / Q000502:physiology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D017262:Siderophores / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016875:tau Proteins / Q000235:genetics*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017262:Siderophores; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D003676:Deferoxamine