期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 35, 期 8, 页码 1260-1271出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2015.59
关键词
astrocytes; blood-brain barrier; methamphetamine; nuclear factor-kappa B; tumor necrosis factor-alpha
资金
- Foundation for Science and Technology (FCT Portugal) [PTDC/SAU-FCF/098685/2008]
- FEDER fund
- FCT Portugal [SFRH/BD/84408/2012, SFRH/BD/85556/2012]
- QREN
- COMPETE fund
- Fundação para a Ciência e a Tecnologia [SFRH/BD/84408/2012, SFRH/BD/85556/2012, PTDC/SAU-FCF/098685/2008] Funding Source: FCT
Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood-brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF-alpha), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-kappa B) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF-alpha/NF-kappa B pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF-alpha and subsequent activation of NF-kappa B pathway culminating in barrier dysfunction.
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