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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
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.
Conneely OM. Antiinflammatory activities of lactoferrin. J. Am. Coll. Nutr. 2001;20(5, Suppl):389S-395S.
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.
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.
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.
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.
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.
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.
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.
Johnson EE, Wessling-Resnick M. Iron metabolism and the innate immune response to infection. Microbes Infect. 2012;14(3):207-216.
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.
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.
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
Orsi N. The antimicrobial activity of lactoferrin: current status and perspectives. Biometals. 2004;17(3):189-196.
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.
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.
Suzuki YA, Lopez V, Lönnerdal B. Mammalian lactoferrin receptors: structure and function. Cell. Mol. Life Sci. 2005;62(22):2560-2575.
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.
Tuccari G, Barresi G. Lactoferrin in human tumours: immunohistochemical investigations during more than 25 years. Biometals. 2011;24(5):775-784.
Ward PP, Conneely OM. Lactoferrin: role in iron homeostasis and host defense against microbial infection. Biometals. 2004;17(3):203-208.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Additional information
Translated from Kletochnye Tekhnologii v Biologii i Meditsine, No. 2, pp. 106-113, June, 2019
Rights and permissions
About this article
Cite this article
Kopaeva, Y., Cherepov, A.B., Zarayskaya, I.Y. et al. Transport of Human Lactoferrin into Mouse Brain: Administration Routes and Distribution. Bull Exp Biol Med 167, 561–567 (2019). https://doi.org/10.1007/s10517-019-04572-3
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10517-019-04572-3