Advertisement

Transport of Human Lactoferrin into Mouse Brain: Administration Routes and Distribution

  • Yu. KopaevaEmail author
  • A. B. Cherepov
  • I. Yu. Zarayskaya
  • M. V. Nesterenko
Article
  • 13 Downloads

We studied different ways of transport of human lactoferrin to the brain of C57Bl/6 mice after its administration via different routes, analyzed its distribution in the brain, and determined the phenotype of lactoferrin-containing cells. Colocalization of lactoferrin and markers of various cell types was estimated by fluorescent immunohistochemical analysis. Lactoferrin was detected in mouse brain sections after its intranasal, sublingual, and intraperitoneal administration, but not after conjunctival administration. After intranasal administration, lactoferrin rapidly penetrated into the brain and accumulated in the cytoplasm of vascular endothelial cells in the neocortex, striatum, hippocampus, and thalamus. After application of protein solution onto fixed floating sections, highly specific binding of lactoferrin was found in the nuclei of neurons, astrocytes, and microglia cells, but not in the nuclei of endothelial cells of mouse brain.

Key Words

human lactoferrin neurons astrocytes microglia endothelial cells 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bi C, Wang A, Chu Y, Liu S, Mu H, Liu W, Wu Z, Sun K, Li Y. Intranasal delivery of rotigotine to the brain with lactoferrinmodified PEG-PLGA nanoparticles for Parkinson’s disease treatment. Int. J. Nanomedicine. 2016;11:6547-6559.CrossRefGoogle Scholar
  2. 2.
    Conneely OM. Antiinflammatory activities of lactoferrin. J. Am. Coll. Nutr. 2001;20(5, Suppl):389S-395S.CrossRefGoogle Scholar
  3. 3.
    Elfinger M, Maucksch C, Rudolph C. Characterization of lactoferrin as a targeting ligand for nonviral gene delivery to airway epithelial cells. Biomaterials. 2007;28(23):3448-3455.CrossRefGoogle Scholar
  4. 4.
    Faraji N, Zhang Y, Ray AK. Determination of adsorption isotherm parameters for minor whey proteins by gradient elution preparative liquid chromatography. J. Chromatogr. A. 2015;1412:67-74.CrossRefGoogle Scholar
  5. 5.
    Fillebeen C, Descamps L, Dehouck MP, Fenart L, Benaïssa M, Spik G, Cecchelli R, Pierce A. Receptor-mediated transcytosis of lactoferrin through the blood-brain barrier. J. Biol. Chem. 1999;274(11):7011-7017.CrossRefGoogle Scholar
  6. 6.
    Fischer R, Debbabi H, Blais A, Dubarry M, Rautureau M, Boyaka PN, Tome D. Uptake of ingested bovine lactoferrin and its accumulation in adult mouse tissues. Int. Immunopharmacol. 2007;7(10):1387-1393.CrossRefGoogle Scholar
  7. 7.
    García-Montoya IA, Cendón TS, Arévalo-Gallegos S, Rascón-Cruz Q. Lactoferrin a multiple bioactive protein: an overview. Biochim. Biophys. Acta. 2012;1820(3):226-236.CrossRefGoogle Scholar
  8. 8.
    Hayashi T, To M, Saruta J, Sato C, Yamamoto Y, Kondo Y, Shimizu T, Kamata Y, Tsukinoki K. Salivary lactoferrin is transferred into the brain via the sublingual route. Biosci. Biotechnol. Biochem. 2017;81(7):1300-1304.CrossRefGoogle Scholar
  9. 9.
    Hu K, Li J, Shen Y, Lu W, Gao X, Zhang Q, Jiang X. Lactoferrin-conjugated PEG-PLA nanoparticles with improved brain delivery: in vitro and in vivo evaluations. J. Control. Release. 2009;134(1):55-61.CrossRefGoogle Scholar
  10. 10.
    Johnson EE, Wessling-Resnick M. Iron metabolism and the innate immune response to infection. Microbes Infect. 2012;14(3):207-216.CrossRefGoogle Scholar
  11. 11.
    Kamemori N, Takeuchi T, Sugiyama A, Miyabayashi M, Kitagawa H, Shimizu H, Ando K, Harada E. Trans-endothelial and trans-epithelial transfer of lactoferrin into the brain through BBB and BCSFB in adult rats. J. Vet. Med. Sci. 2008;70(3):313-315.CrossRefGoogle Scholar
  12. 12.
    Kumar V, Hassan M.I, Kashav T, Singh TP, Yadav S. Heparin-binding proteins of human seminal plasma: purification and characterization. Mol. Reprod. Dev. 2008;75(12):1767-1774.CrossRefGoogle Scholar
  13. 13.
    Kumari S, Ahsan SM, Kumar JM, Kondapi AK, Rao NM. Overcoming blood brain barrier with a dual purpose temozolomide loaded lactoferrin nanoparticles for combating glioma (SERP-17-12433). Sci. Rep. 2017;7(1). ID 6602. doi:  https://doi.org/10.1038/s41598-017-06888-4
  14. 14.
    Orsi N. The antimicrobial activity of lactoferrin: current status and perspectives. Biometals. 2004;17(3):189-196.CrossRefGoogle Scholar
  15. 15.
    Qian ZM, Wang Q. Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders. Brain Res. Brain Res. Rev. 1998;27(3):257-267.CrossRefGoogle Scholar
  16. 16.
    Rosa L, Cutone A, Lepanto MS, Scotti MJ, Conte MP, Paesano R, Valenti P. Physico-chemical properties influence the functions and efficacy of commercial bovine lactoferrins. Biometals. 2018;31(3):301-312.CrossRefGoogle Scholar
  17. 17.
    Suzuki YA, Lopez V, Lönnerdal B. Mammalian lactoferrin receptors: structure and function. Cell. Mol. Life Sci. 2005;62(22):2560-2575.CrossRefGoogle Scholar
  18. 18.
    Thorne RG, Lakkaraju A, Rodriguez-Boulan E, Nicholson C. In vivo diffusion of lactoferrin in brain extracellular space is regulated by interactions with heparan sulfate. Proc. Natl Acad. Sci. USA. 2008;105(24):8416-8421.CrossRefGoogle Scholar
  19. 19.
    Tuccari G, Barresi G. Lactoferrin in human tumours: immunohistochemical investigations during more than 25 years. Biometals. 2011;24(5):775-784.CrossRefGoogle Scholar
  20. 20.
    Ward PP, Conneely OM. Lactoferrin: role in iron homeostasis and host defense against microbial infection. Biometals. 2004;17(3):203-208.CrossRefGoogle Scholar
  21. 21.
    Yan X, Xu L, Bi C, Duan D, Chu L, Yu X, Wu Z, Wang A, Sun K. Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects. Int. J. Nanomedicine. 2018;13:273-281.CrossRefGoogle Scholar
  22. 22.
    Zhang Y, Lou F, Wu W, Dong X, Ren J, Shen Q. Determination of bovine lactoferrin in food by HPLC with a heparin affinity column for sample preparation. J. AOAC Int. 2017;100(1):133-138.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yu. Kopaeva
    • 1
    Email author
  • A. B. Cherepov
    • 1
  • I. Yu. Zarayskaya
    • 1
  • M. V. Nesterenko
    • 1
  1. 1.National Research Center Kurchatov Institute, Lactobio CompanyMoscowRussia

Personalised recommendations