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

• Published in: Experimental brain research 2012-06, Vol.219 (3), p.381-390
• Main Authors: Fine, J. M., Baillargeon, A. M., Renner, D. B., Hoerster, N. S., Tokarev, J., Colton, S., Pelleg, A., Andrews, A., Sparley, K. A., Krogh, K. M., Frey, W. H., Hanson, L. R.
• Format: Article
• Language: English
• Subjects: Administration, Intranasal - methods; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid; Animal models; Animals; Biochemical analysis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Chelating agents; Chromium; Complications and side effects; Data processing; Deferoxamine; Deferoxamine - pharmacology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA binding proteins; Dosage and administration; Drug therapy; Enzyme-linked immunosorbent assay; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Hypoxia-inducible factor 1 alpha; Hypoxia-Inducible Factor 1, alpha Subunit - agonists; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Interleukin 1; Maze Learning - drug effects; Maze Learning - physiology; Medical sciences; Memory Disorders - drug therapy; Memory Disorders - genetics; Memory Disorders - physiopathology; Mental disorders; Metals; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurodegenerative diseases; Neurology; Neurosciences; Oxidation; Phosphorylation - drug effects; Phosphorylation - physiology; Physiological aspects; Research Article; Siderophores - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; spatial memory; Tau protein; tau Proteins - genetics; Transgenic mice; Western blotting
• ISSN: 0014-4819; 1432-1106
• DOI: 10.1007/s00221-012-3101-0

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.