New strategy for alerting central nervous system toxicity: Integration of blood-brain barrier toxicity and permeability in neurotoxicity assessment.
The combination of an in vitro BBB model (4d/24w) with a neuronal cell line (SH-SY5Y) provides a convenient approach to explore the importance of BBB permeability in neurotoxicity assessment of compounds. The toxicity of 16 compounds on SH-SY5Y cells was evaluated after 24h incubation with each compound and compared to their toxicity on SH-SY5Y after passage through the BBB model. Nine out of 16 compounds were found toxic after direct exposure at 100muM while only three still induced toxicity on SH-SY5Y cells after BBB transport. The BBB permeability values of each compound revealed that in the case of compounds that did not induce toxicity, the amount that crossed the BBB was not enough to exert a toxic effect on the neuronal cells. Since disrupting the BBB may also cause unwanted effect on brain cells, the BBB toxicity of these compounds have been assessed. Our results prompted the importance of BBB permeability assessment in neurotoxicity evaluation, as it allows a better estimation of the actual concentration at the target site.
Hallier-Vanuxeem
Dorothée
D
Université Lille Nord de France, Laboratoire de Physiopathologie de la Barrière Hémato-encéphalique, EA 2465 - IMPRT 114, Faculté Jean Perrin, Rue Jean Souvraz, S.P. 18, F-62300 Lens, France.
Prieto
Pilar
P
Culot
Maxime
M
Diallo
Heidi
H
Landry
Christophe
C
Tähti
Hanna
H
Cecchelli
Roméo
R
D000826:Animal Testing Alternatives; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D009420:Nervous System / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D015262:Xenobiotics / Q000145:classification / Q000378:metabolism / Q000633:toxicity*
D013778:Tetrazolium Salts; D013844:Thiazoles; D015262:Xenobiotics; C070380:3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium