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. 2021 Jul 18;9(7):837.
doi: 10.3390/biomedicines9070837.

Pitavastatin Ameliorates Lipopolysaccharide-Induced Blood-Brain Barrier Dysfunction

Takashi Fujimoto  1   2   3 , Yoichi Morofuji  1   4 , Andrej Kovac  5 , Michelle A Erickson  2   3 , Mária A Deli  6 , Masami Niwa  7 , William A Banks  2   3
Affiliations

Pitavastatin Ameliorates Lipopolysaccharide-Induced Blood-Brain Barrier Dysfunction

Takashi Fujimoto et al. Biomedicines. .

Abstract

Statins have neuroprotective effects on neurological diseases, including a pleiotropic effect possibly related to blood-brain barrier (BBB) function. In this study, we investigated the effects of pitavastatin (PTV) on lipopolysaccharide (LPS)-induced BBB dysfunction in an in vitro BBB model comprising cocultured primary mouse brain endothelial cells, pericytes, and astrocytes. LPS (1 ng/mL, 24 h) increased the permeability and lowered the transendothelial electrical resistance of the BBB, and the co-administration of PTV prevented these effects. LPS increased the release of interleukin-6, granulocyte colony-stimulating factor, keratinocyte-derived chemokine, monocyte chemotactic protein-1, and regulated on activation, normal T-cell expressed and secreted from the BBB model. PTV inhibited the LPS-induced release of these cytokines. These results suggest that PTV can ameliorate LPS-induced BBB dysfunction, and these effects might be mediated through the inhibition of LPS-induced cytokine production. Clinically, therapeutic approaches using statins combined with novel strategies need to be designed. Our present finding sheds light on the pharmacological significance of statins in the treatment of central nervous system diseases.

Keywords: blood-brain barrier; central nervous system diseases; cytokine; inflammation; lipopolysaccharide; statin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effects of LPS on TEER in an in vitro BBB model. The figure illustrates that the addition of LPS to the luminal chamber of the in vitro BBB model for 24 h decreased TEER in a concentration-dependent manner. ** p < 0.01, *** p < 0.001 vs. control (one-way ANOVA, p-values were calculated from Tukey’s Multiple Comparison Test). The TEER experiment was conducted with technical replicates in triplicate experiments, n = 6 per group.
Figure 2
Figure 2
PTV restores LPS-induced changes in TEER and endothelial permeability in an in vitro BBB model. Cells were incubated with PTV in the presence or absence of LPS (added only to the luminal chamber) for 24 h. * p < 0.05 vs. control; ## p < 0.01, ### p < 0.001 vs. LPS (one-way ANOVA, p-values were calculated from Tukey’s Multiple Comparison Test). The TEER and endothelial permeability test were conducted with two technical replicates in triplicate experiments, n = 6 per group.
Figure 3
Figure 3
LPS increased the release of IL-6, G-CSF, KC, MCP-1, and RANTES from the in vitro BBB model into the luminal chamber. PTV inhibited the LPS-induced release of these cytokines. ** p < 0.01, *** p < 0.001 vs. control; ### p < 0.001 vs. LPS (two-way ANOVA).
Figure 4
Figure 4
LPS increased the release of G-CSF and KC from the in vitro BBB model into the abluminal chamber, and PTV inhibited the LPS-induced release of these cytokines. The addition of LPS to the luminal chamber did not induce significant increases in the secretion of other cytokines in the abluminal chamber. *** p < 0.001 vs. control; ### p < 0.001 vs. LPS (two-way ANOVA).
See this image and copyright information in PMC

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