Abstract
There is no doubt that various nanoparticles (NPs) can enter the brain from the nasal cavity. It is assumed that NPs can penetrate from blood into the central nervous system (CNS) only by breaking the blood–brain barrier (BBB). The accumulation of NPs in CNS can provoke many neurological diseases; therefore, the understanding of its mechanisms is of both academic and practical interest. Although hitting from the surface of the lungs into the bloodstream, NPs can accumulate in various mucous membranes, including the nasal mucosa. Thus, we cannot rule out the ability of NPs to be transported from the bloodstream to the brain through the olfactory uptake. To test this hypothesis, we used paramagnetic NPs of manganese oxide (Mn3O4-NPs), whose accumulation patterns in the mouse brain were recorded using T1-weighted magnetic resonance imaging. The effect of intranasal application of endocytosis and axonal transport inhibitors on the brain accumulation patterns of intranasally or intravenously injected Mn3O4-NPs was evaluated. A comparative analysis of the results showed that the transport of Mn3O4-NPs from the nasal cavity to the brain is more efficient than their local permeation through BBB into CNS from the bloodstream, for example with the accumulation of Mn3O4NPs in the dentate gyrus of the hippocampus, and through the capture and transport of NPs from the blood by olfactory epithelium cells. Also, experiments with the administration of chlorpromazine, a specific inhibitor of clathrin-dependent endocytosis, and methyl-β-cyclodextrin, inhibitor of the lipid rafts involved in the capture of substances by endothelium cells, showed differences in the mechanisms of NP uptake from the nasal cavity and from the bloodstream. In this study, we show a significant contribution of axonal transport to NP accumulation patterns in the brain, both from the nasal cavity and from the vascular bed. This explains the accumulation of different sorts of submicron particles (neurotropic viruses, insoluble xenobiotics, etc.), unable to pass BBB, in the brain. The results will add to the understanding of the pathogenesis of various neurodegenerative diseases and help studying the side effects of therapeutics administered intravenously.
Highlights
People, like other mammalians, are constantly exposed to solid aerosols, which may include a great many of xenobiotics
The level of magnetic resonance imaging (MRI) signal in olfactory epithelium (OE) and olfactory bulbs (OB) was higher when Mn3O4-NPs was injected into the nasal cavity than in the retroorbital sinus, and manganese accumulation in the dentate gyrus of the hippocampus (DG) was higher after intravenous administration of Mn3O4-NPs
The propagation of Mn3O4-NPs after intranasal or intravenous injection was limited mainly by the structure of the olfactory system. This raises the question of the role of the olfactory epithelium in the penetration of nanoparticles into the brain from both the nasal cavity and the vascular bed
Summary
Like other mammalians, are constantly exposed to solid aerosols, which may include a great many of xenobiotics. Sedimentation of submicron and nanosized aerosols on the surface of the upper and lower respiratory tracts is followed by their penetration into blood and migration into internal organs, including the brain. The main route of penetration into the central nervous system of mammals is their transport from the nasal cavity to the brain. These include: herpes virus (HSV-1, HSV-2), (Kennedy, Chaudhuri, 2002), influenza A virus (Tanaka et al, 2003), bornaviruses (Sauder, Staeheli, 2003), rhabdoviruses, including rabies virus (Astic et al, 1993), parainfluenza (Mori et al, 2004), and prions (Zanusso et al, 2003). The basis of the olfactory transport of viruses and nanoparticles (Mistry et al, 2009) from the nasal cavity to the brain, is the uptake of the particles by the endings of the olfactory nerves, followed by movement inside the axons and passage through synaptic transmissions (Mori et al, 2005)
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