Neurotoxicity Study with Titanium Dioxide Nanoparticles on Rat

2022 ◽  
Vol 905 ◽  
pp. 288-293
Author(s):  
Jun Chen ◽  
Chun Di Zhou
Keyword(s):  
Titanium Dioxide ◽  
Brain Tissue ◽  
Blood Brain Barrier ◽  
Titanium Dioxide Nanoparticles ◽  
Dose Effect ◽  
Brain Barrier ◽  
Blood Brain ◽  
Rat Astrocytes

Numerous studies have shown titanium dioxide nanoparticles (TiO2 NPs) could present a risk or potential risk to humans and other living organisms in certain conditions via inhalation and skin contact. Dermal exposure has limited adverse effects and the possible risks for exogenous inhaled nanoparticles migrating to the brain through the olfactory nerve is still under research. To study the in vivo and in vitro neurotoxicity of brain tissue in rats induced by TiO2 NPs. For in vitro study, rat astrocytes were exposed to TiO2 NPs with three different diameters (10, 50 and 200 nm) at five concentrations levels. Cellular morphology and sulfur rhodamine B (SRB) were carried out to evaluate the viability of particle-treated cells after 72 hours exposure. For in vivo study, suspensions of test material above mentioned were injected into tracheas of Wistar rats at dose of 0.1, 1.0 and 10.0 mg·kg-1 in three groups, respectively. After 72 hours of exposure, the concentration of TiO2 NPs in brain tissue and the levels of IL-1β, TNF-α and IL-10 in brain homogenate were measured, while the cell morphology induced by TiO2 NPs was observed by light microscopy and transmission electron microscopy. TiO2 NPs can significantly affect the growth and morphology of rat astrocytes and inhibit the proliferation of astrocytes, which was positively related to dose-effect and size-dependent response. Pathological observations indicated that TiO2 NPs could penetrate the blood-brain barrier, leading to blood-brain barrier damage in rats, brain tissue necrosis, mitochondrial swelling and apoptosis while the non-nanoscale TiO2 particles showed no significant toxicity in the central nervous system cells.

Size- and shape-dependent effects of titanium dioxide nanoparticles on the permeabilization of the blood–brain barrier

2017 ◽  
Vol 5 (48) ◽  
pp. 9558-9570 ◽  
Author(s):  
Xin Liu ◽  
Baiyan Sui ◽  
Jiao Sun
Keyword(s):  
Titanium Dioxide ◽  
Blood Brain Barrier ◽  
Titanium Dioxide Nanoparticles ◽  
Brain Barrier ◽  
Size And Shape ◽  
Blood Brain

Spherical TiO2-NPs permeabilize the BBB most efficiently by inducing cytoskeletal re-organization, and the neurotoxicity of TiO2-NPs appears minimal.

Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenation

2005 ◽  
Vol 289 (5) ◽  
pp. H2012-H2019 ◽  
Author(s):  
Melissa A. Fleegal ◽  
Sharon Hom ◽  
Lindsay K. Borg ◽  
Thomas P. Davis
Keyword(s):  
Blood Brain Barrier ◽  
Paracellular Permeability ◽  
Cell Permeability ◽  
Brain Barrier ◽  
Cerebral Microvessels ◽  
Permeability Changes ◽  
Blood Brain ◽  
Brain Microvessel

The blood-brain barrier (BBB) is a metabolic and physiological barrier important for maintaining brain homeostasis. The aim of this study was to determine the role of PKC activation in BBB paracellular permeability changes induced by hypoxia and posthypoxic reoxygenation using in vitro and in vivo BBB models. In rat brain microvessel endothelial cells (RMECs) exposed to hypoxia (1% O2-99% N2; 24 h), a significant increase in total PKC activity was observed, and this was reduced by posthypoxic reoxygenation (95% room air-5% CO2) for 2 h. The expression of PKC-βII, PKC-γ, PKC-η, PKC-μ, and PKC-λ also increased following hypoxia (1% O2-99% N2; 24 h), and these protein levels remained elevated following posthypoxic reoxygenation (95% room air-5% CO2; 2 h). Increases in the expression of PKC-ε and PKC-ζ were also observed following posthypoxic reoxygenation (95% room air-5% CO2; 2 h). Moreover, inhibition of PKC with chelerythrine chloride (10 μM) attenuated the hypoxia-induced increases in [14C]sucrose permeability. Similar to what was observed in RMECs, total PKC activity was also stimulated in cerebral microvessels isolated from rats exposed to hypoxia (6% O2-94% N2; 1 h) and posthypoxic reoxygenation (room air; 10 min). In contrast, hypoxia (6% O2-94% N2; 1 h) and posthypoxic reoxygenation (room air; 10 min) significantly increased the expression levels of only PKC-γ and PKC-θ in the in vivo hypoxia model. These data demonstrate that hypoxia-induced BBB paracellular permeability changes occur via a PKC-dependent mechanism, possibly by differentially regulating the protein expression of the 11 PKC isozymes.

Refining In Vitro Neurotoxicity Testing — The Development of Blood–Brain Barrier Models

2003 ◽  
Vol 31 (3) ◽  
pp. 273-276 ◽  
Author(s):  
Hanna Tähti ◽  
Heidi Nevala ◽  
Tarja Toimela
Keyword(s):  
Blood Brain Barrier ◽  
Cell Lines ◽  
Three Dimensional ◽  
Brain Barrier ◽  
Culture Methods ◽  
Blood Brain ◽  
Capillary Endothelial Cells ◽  
In Vitro Bbb Model

The purpose of this paper is to review the current state of development of advanced in vitro blood–brain barrier (BBB) models. The BBB is a special capillary bed that separates the blood from the central nervous system (CNS) parenchyma. Astrocytes maintain the integrity of the BBB, and, without astrocytic contacts, isolated brain capillary endothelial cells in culture lose their barrier characteristics. Therefore, when developing in vitro BBB models, it is important to add astrocytic factors into the culture system. Recently, novel filter techniques and co-culture methods have made it possible to develop models which resemble the in vivo functions of the BBB in an effective way. With a BBB model, kinetic factors can be added into the in vitro batteries used for evaluating the neurotoxic potential of chemicals. The in vitro BBB model also represents a useful tool for the in vitro prediction of the BBB permeability of drugs, and offers the possibility to scan a large number of drugs for their potential to enter the CNS. Cultured monolayers of brain endothelial cell lines or selected epithelial cell lines, combined with astrocyte and neuron cultures, form a novel three-dimensional technique for the screening of neurotoxic compounds.

scholarly journals Proof-of-Concept Study of Drug Brain Permeability Between in Vivo Human Brain and an in Vitro iPSCs-Human Blood-Brain Barrier Model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gwenaëlle Le Roux ◽  
Rafika Jarray ◽  
Anne-Cécile Guyot ◽  
Serena Pavoni ◽  
Narciso Costa ◽  
...  
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Apparent Permeability ◽  
Clinical Drug Development ◽  
Blood Brain

Abstract The development of effective central nervous system (CNS) drugs has been hampered by the lack of robust strategies to mimic the blood-brain barrier (BBB) and cerebrovascular impairments in vitro. Recent technological advancements in BBB modeling using induced pluripotent stem cells (iPSCs) allowed to overcome some of these obstacles, nonetheless the pertinence for their use in drug permeation study remains to be established. This mandatory information requires a cross comparison of in vitro and in vivo pharmacokinetic data in the same species to avoid failure in late clinical drug development. Here, we measured the BBB permeabilities of 8 clinical positron emission tomography (PET) radioligands with known pharmacokinetic parameters in human brain in vivo with a newly developed in vitro iPSC-based human BBB (iPSC-hBBB) model. Our findings showed a good correlation between in vitro and in vivo drug brain permeability (R2 = 0.83; P = 0.008) which contrasted with the limited correlation between in vitro apparent permeability for a set of 18 CNS/non-CNS compounds using the in vitro iPSCs-hBBB model and drug physicochemical properties. Our data suggest that the iPSC-hBBB model can be integrated in a flow scheme of CNS drug screening and potentially used to study species differences in BBB permeation.

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