Neuroscience and Behavioral Physiology

, Volume 40, Issue 7, pp 737–743 | Cite as

Prevention of Neurodegenerative Damage to the Brain in Rats in Experimental Alzheimer’s Disease by Adaptation to Hypoxia

  • E. B. Manukhina
  • A. V. Goryacheva
  • I. V. Barskov
  • I. V. Viktorov
  • A. A. Guseva
  • M. G. Pshennikova
  • I. P. Khomenko
  • S. Yu. Mashina
  • D. A. Pokidyshev
  • I. Yu. Malyshev
Article

We report here studies addressing the possibility of preventing neurodegenerative changes in the brain using adaptation to periodic hypoxia in rats with experimental Alzheimer’s disease induced by administration of the neurotoxic peptide fragment of β-amyloid (Ab) into the basal magnocellular nucleus. Adaptation to periodic hypoxia was performed in a barochamber (4000 m, 4 h per day, 14 days). The following results were obtained 15 days after administration of Ab. 1. Adaptation to periodic hypoxia significantly blocked Ab-induced memory degradation in rats, as assessed by testing a conditioned passive avoidance reflex. 2. Adaptation to periodic hypoxia significantly restricted increases in oxidative stress, measured spectrophotometrically in the hippocampus in terms of the content of thiobarbituric acid-reactive secondary lipid peroxidation products. 3. Adaptation to periodic hypoxia completely prevented the overproduction of NO in the brains of rats with experimental Alzheimer’s disease, as measured in terms of increases in tissue levels of stable NO metabolites, i.e., nitrites and nitrates. 4. The cerebral cortex of rats given Ab injections after adaptation to periodic hypoxia did not contain neurons with pathomorphological changes or dead neurons (Nissl staining), which were typical in animals with experimental Alzheimer’s disease. Thus, adaptation to periodic hypoxia effectively prevented oxidative and nitrosative stress, protecting against neurodegenerative changes and protecting cognitive functions in experimental Alzheimer’s disease.

Key words

beta-amyloid Alzheimer’s disease nitric oxide oxidative stress brain neurons adaptation to hypoxia 

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References

  1. 1.
    S. O. Bachurin, “Medical chemistry of the targeted search for agents for the treatment and prevention of neurodegenerative diseases using Alzheimer’s disease as an example,” in: Neurodegenerative Diseases and Aging [in Russian], I. A. Zavalishin, N. N. Yakhno, and S. I. Gavrilova (eds.), Moscow (2001), pp. 399–454.Google Scholar
  2. 2.
    A. F. Vanin, “Dinitrosyl complexes of iron and S-nitrosothiols – two possible forms of stabilization and transport of nitric oxide in biological systems,” Biokhimiya, 63, No. 7, 924–938 (1998).Google Scholar
  3. 3.
    S. A. Elchaninova, N. A. Korenyak, I. V. Smagina, L. E. Pinegin, and B. Ya. Varshavskii, “Discontinuous hypoxia in the treatment of chronic cerebral ischemia,” Zh. Nevrol. Psikhiat. im. S. S. Korsakova, 102, 29–32 (2002).Google Scholar
  4. 4.
    A. L. Krushinskii, V. P. Reutov, V. S. Kuzenkov, E. G. Sorokina, V. B. Koshelev, O. E. Fadyukova, L. M. Baider, Z. V. Kuropteva, T. T. Zhumabaeva, L. Kh. Komissarova, T. V. Ryasina, N. S. Kositsyn, and V. G. Pinelis, “Nitric oxide is involved in the mechanisms of short-term adaptation to hypoxia and protective actions during the development of stress lesions in Krushinskii-Molodkina rats,” Izv. Ros. Akad. Nauk. Ser. Biol., 34, No. 3, 329–335 (2007).Google Scholar
  5. 5.
    V. I. Kulinskii, L. N. Minakina, and T. V. Gavrilina, “Neuroprotective effects of hypoxic preconditioning: the phenomenon and its mechanisms,” Byull. Eksperim. Biol. Med., 133, No. 2, 237–239 (2002).Google Scholar
  6. 6.
    E. B. Manukhina, F. Viegant,V. I. Torshin, A. V. Goryacheva, I. P. Khomenko, S. V. Kruglov, S. Yu. Mashina, D. A. Pokidyshev, E. V. Popova, M. G. Pshennikova, M. A. Vlasova, O. M. Zelenina, and I. Yu. Malyshev, “Potential non-medication-based approaches to Alzheimer’s disease,” Izv. Ros. Akad. Nauk. Ser. Biol., 31, No. 4, 382–395 (2004).Google Scholar
  7. 7.
    E. B. Manukhina and I. Yu. Malyshev, “The stress-limiting nitric oxide system,” Ros. Fiziol. Zh. im. I. M. Sechenova, 86, No. 10, 1283–1292 (2000).Google Scholar
  8. 8.
    E. B. Manukhina, B. V. Smirin, I. Yu. Malyshev, Zh-K. Stokle, B. Muller, A. P. Solodkov, V. I. Shebeko, and A. F. Vanin, “Deposition of nitric oxide in the cardiovascular system,” Izv. Akad. Nauk. Ser. Biol., 29, No. 5, 585–596 (2002).Google Scholar
  9. 9.
    S. Yu. Mashina,V. V. Aleksandrov, A. V. Goryacheva, M. A. Vlasova, A. F. Vanin, I. Yu. Malyshev, and E. B. Manukhina, “Adaptation to hypoxia prevents impairments of cerebral circulation in neurodegenerative damage: the role of nitric oxide,” Byull. Eksperim. Biol. Med., 142, No. 8, 132–135 (2006).Google Scholar
  10. 10.
    F. Z. Meerson, Adaptation Medicine: Mechanisms and Protective Effects of Adaptation, Hypoxia Medical Ltd., Moscow (1993).Google Scholar
  11. 11.
    F. Z. Meerson, V. G. Pinelis, V. B. Kosheleva, L. Yu. Golubeva, T. V. Ryasina, N. Arsen’eva, A. L. Krushinskii, and T. P. Storozhevykh, “Adaptation to periodic hypoxia restricts subdural hemorrhage in epileptiform convulsions in rats,” Byull. Eksperim. Biol. Med., 116, 572–574 (1993).Google Scholar
  12. 12.
    M. G. Pshennikova, E. V. Popkova, D. A. Pokidyshev, I. P. Khomenko, O. M. Zelenina, S. V. Kruglov, E. B. Manukhina, M. V. Shimkovich, A. V. Goryaeva, and I. Yu. Malyshev, “Effects of adaptation to hypoxia on resistance to neurodegenerative brain damage in rats of different genetic strains,” Vestn. Ros. Akad. Med. Nauk., No. 2, 50–55 (2007).Google Scholar
  13. 13.
    M. G. Pshennikova, E. V. Popkova, I. P. Khomenko, E. B. Manukhina, A. V. Goryacheva, S. Yu. Mashina, D. A. Pokidyshev, and I. Yu. Malyshev, “Comparison of resistance to neurodegenerative brain damage in august rats and the Wistar population,” Byull. Eksperim. Biol. Med., 139, No. 5, 540–542 (2005).CrossRefGoogle Scholar
  14. 14.
    J. I. Addae, F. F. Youssef, and T. W. Stone, “Neuroprotective role of learning in dementia: a biological explanation,” J. Alzheimer’s Dis., 5, 91–104 (2003).Google Scholar
  15. 15.
    R. L. Berghmans, “Anti-Alzheimer drugs: ethical aspects of research and practice,” Tijdschr. Gerontol. Geriatr., 31, 100–106 (2000).PubMedGoogle Scholar
  16. 16.
    M. Bernaudin, A. S. Nedelec, D. Divoux, E. T. MacKenzie, E. Petit, and P. Schumann-Bard, “Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain,” J. Cereb. Blood Flow Metab., 22, 393–403 (2002).CrossRefPubMedGoogle Scholar
  17. 17.
    D. Boyd-Kimball, R. Sultana, H. F. Poon, B. C. Lunn, F. Casamenti, G. Pepeu, J. B. Klein, and D. A. Butterfield, “Proteomic identification of proteins specifically oxidized by intracerebral injection of amyloid beta-peptide (1–42) into rat brain: implications for Alzheimer’s disease,” Neurosci., 132, 313–324 (2005).CrossRefGoogle Scholar
  18. 18.
    H. Braak, U. Rüb, C. Schultz, and K. Del Tredici, “Vulnerability of cortical neurons to Alzheimer’s and Parkinson’s diseases,” J. Alzheimer’s Dis., 9, No. 3, Supplement, 35–44 (2006).Google Scholar
  19. 19.
    D. A. Butterfield, “Amyloid beta-peptide (1–42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review,” Free Radic. Res., 36, 1307–1313 (2002).CrossRefPubMedGoogle Scholar
  20. 20.
    V. Calabrese, E. Guagliano, M. Sapienza, C. Mancuso, D. A. Butterfield, and A. M. Stella, “Redox regulation of cellular stress response in neurodegenerative disorders,” Ital. J. Biochem., 55, 263–282 (2006).PubMedGoogle Scholar
  21. 21.
    V. Calabrese, T. E. Bates, and A. M. Stella, “NO synthase and NOdependent signal pathways in brain aging and neurodegenerative disorders: the role of oxidant/antioxidant balance,” Neurochem. Res., 25, 1315–1341 (2000).CrossRefPubMedGoogle Scholar
  22. 22.
    C. A. Davies, D. M. Mann, P. Q. Sumpter, and P. O. Yates, “A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease,” J. Neurol. Sci., 78, 151–164 (1987).CrossRefPubMedGoogle Scholar
  23. 23.
    S. T. De Kosky and S. W. Scheff, “Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity,” Ann. Neurol., 27, 457–464 (1990).CrossRefGoogle Scholar
  24. 24.
    H. Fai Poon, V. Calabrese, G. Scapagnini, and D. A. Butterfield, “Free radicals: Key to brain aging and heme oxygenase as a cellular response to oxidative stress,” J. Gerontol. Series A: Biol. Sci. Med. Sci., 59, M478–M493 (2004).Google Scholar
  25. 25.
    M. R. Farlow, M. L. Miller, and V. Pejovic, “Treatment options in Alzheimer’s disease: maximizing benefit, managing expectations,” Dement. Geriatr. Cogn. Disord., 25, 408–422, (2008).CrossRefPubMedGoogle Scholar
  26. 26.
    R. A. Floyd, “Antioxidants, oxidative stress, and degenerative neurological disorders,” Proc. Soc. Exp. Biol. Med., 222, 236–245 (1999).CrossRefPubMedGoogle Scholar
  27. 27.
    N. V. Gulyaeva, M. V. Stepanichev, M. V. Onufriev, I. V. Sergeev, O. S. Mitrokhina, Yu. V. Moiseeva, and E. N. Tkatchouk, “Interval hypoxia training prevents oxidative stress in striatum and locomotor disturbances in a rat model of parkinsonism,” in: Progress in Alzheimer’s and Parkinson’s Diseases, A. Fisher, I. Hahn, and M. Yoshida (eds.), Plenum Press (1998), pp. 717–723.Google Scholar
  28. 28.
    M. E. Jung, J. W. Simpkins, A. M. Wilson, H. F. Downey, and R. T. Mallet, “Intermittent hypoxia conditioning prevents behavioral deficit and brain oxidative stress in ethanol withdrawn rats,” J. Appl. Physiol. [Epub ahead of print, May 22, 2008].Google Scholar
  29. 29.
    U. Keil, A. Bonert, C. A. Marques, I. Scherping, J. Weyerman, J. B. Strosznajder, F. Müller-Spahn, C. Haass, C. Czech, L. Pradier, W. E. Müller, and A. Eckert, “Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis,” J. Biol. Chem., 279, 50310–50320 (2004).CrossRefPubMedGoogle Scholar
  30. 30.
    D. S. Kim, J. Y. Kim, and Y. S. Han, “Alzheimer’s disease drug discovery from herbs: neuroprotectivity from beta-amyloid (1–42) insult,” J. Atern. Complement. Med., 13, 333–340 (2007).CrossRefGoogle Scholar
  31. 31.
    A. M. Lin, C. F. Chen, and L. T. Ho, “Neuroprotective effect of intermittent hypoxia on iron-induced oxidative injury in rat brain,” Exp. Neurol., 176, 328–335 (2002).CrossRefPubMedGoogle Scholar
  32. 32.
    N. Mahendra and S. Arkin, “Effects of four years of exercise, language, and social interventions on Alzheimer discourse,” J. Commun. Disord., 36, 395–422 (2003).CrossRefPubMedGoogle Scholar
  33. 33.
    T. Malinski, “Nitric oxide and nitroxidative stress in Alzheimer’s disease,” J. Alzheimer’s Dis., 11, 207–218 (2007).Google Scholar
  34. 34.
    S. I. Marklund, N. G. Westman, E. Lundgren, and G. Roos, “Copperand zinc-containing superoxide dismutase, manganese-containing superoxide dismutase, catalase, and glutathione peroxidase in normal and neoplastic human cell lines and normal human tissues,” Cancer Res., 42, 1955–1961 (1982).PubMedGoogle Scholar
  35. 35.
    P. I. Moreira, M. S. Santos, C. R. Oliveira, J. C. Shenk, A. Nunomura, M. A. Smith, X. Zhu, and G. Perry, “Alzheimer disease and the role of free radicals in the pathogenesis of the disease,” CNS Neurol. Disord. Targets, 7, 3–10 (2008).CrossRefGoogle Scholar
  36. 36.
    J. A. Neubauer, “Physiological and pathophysiological responses to intermittent hypoxia,” J. Appl. Hypoxia, 90, 1593–1599 (2001).Google Scholar
  37. 37.
    H. Ohkawa, N. Ohishi, and K. Yagi, “Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction,” Anal. Biochem., 95, 351–358 (1979).CrossRefPubMedGoogle Scholar
  38. 38.
    G. M. Pasinetti, Z. Zhao, W. Qin, L. Ho, Y. Shrishailam, D. Macgrogan, W. Ressmann, N. Humala, X. Liu, C. Romero, B. Stetka, L. Chen, H. Ksiezak-Reding, and J. Wang, “Caloric intake and Alzheimer’s disease. Experimental approaches and therapeutic implications,” Interdiscip. Top. Gerontol., 35, 159–175 (2007).PubMedGoogle Scholar
  39. 39.
    K. N. Prasad, W. C. Cole, and K. C. Prasad, “Risk factors for Alzheimer’s disease: role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment,” J. Am. Coll. Nutr., 21, 506–522 (2002).PubMedGoogle Scholar
  40. 40.
    D. J. Selkoe, “Alzheimer’s disease is a synaptic failure,” Science, 298, 789–791 (2002).CrossRefPubMedGoogle Scholar
  41. 41.
    G. L. Semenza, “O2-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1,” J. Appl. Physiol., 96, 1173–1177 (2004).CrossRefPubMedGoogle Scholar
  42. 42.
    T. Soucek, R. Cumming, R. Dargusch, P. Maher, and D. Schubert, “The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide,” Neuron, 39, 43–56 (2003).CrossRefPubMedGoogle Scholar
  43. 43.
    P. J. Whitehouse, D. L. Price, A. W. Clark, J. T. Coyle, and M. R. De- Long, “Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis,” Ann. Neurol., 10, 122–126 (1981).CrossRefPubMedGoogle Scholar
  44. 44.
    M. M. Zaleska, K. Nagy, and R. A. Floyd, “Iron-induced lipid peroxidation and inhibition of dopamine synthesis in striatum synaptosomes,” Neurochemistry, 14, 597–605 (1989).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2010

Authors and Affiliations

  • E. B. Manukhina
    • 1
  • A. V. Goryacheva
    • 1
  • I. V. Barskov
    • 2
  • I. V. Viktorov
    • 2
  • A. A. Guseva
  • M. G. Pshennikova
    • 1
  • I. P. Khomenko
    • 1
  • S. Yu. Mashina
    • 1
  • D. A. Pokidyshev
    • 1
  • I. Yu. Malyshev
    • 1
  1. 1.State Research Institute of General Pathology and PathophysiologyRussian Academy of Medical SciencesMoscowRussia
  2. 2.Faculty of BiologyLomonosov Moscow State UniversityMoscowRussia

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