Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3β in P301L tau transgenic mice

被引:69
作者
Fine, J. M. [1 ]
Baillargeon, A. M. [1 ]
Renner, D. B. [1 ]
Hoerster, N. S. [1 ]
Tokarev, J. [1 ]
Colton, S. [1 ]
Pelleg, A. [1 ]
Andrews, A. [1 ]
Sparley, K. A. [1 ]
Krogh, K. M. [1 ]
Frey, W. H. [1 ,2 ]
Hanson, L. R. [1 ]
机构
[1] Reg Hosp, HealthPartners Res Fdn, Alzheimers Res Ctr, St Paul, MN 55101 USA
[2] Univ Minnesota, Dept Pharmaceut, Minneapolis, MN 55455 USA
关键词
Deferoxamine; Intranasal; Tau; Transgenic; HIF-1; alpha; pGSK3; beta; AMYLOID-BETA PEPTIDE; INDUCIBLE FACTOR-I; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; COGNITIVE PERFORMANCE; HYPOXIA; DESFERRIOXAMINE; CATENIN; RAT; MECHANISMS;
D O I
10.1007/s00221-012-3101-0
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 pGSK3 beta and HIF-1 alpha, with more interleukin-1 beta 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 GSK3 beta and HIF-1 alpha play a prominent role.
引用
收藏
页码:381 / 390
页数:10
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