The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

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 acr...

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Bibliographic Details
Published in:Journal of cerebral blood flow and metabolism 2015-08, Vol.35 (8), p.1260-1271
Main Authors: Coelho-Santos, Vanessa, Leitão, Ricardo A, Cardoso, Filipa L, Palmela, Inês, Rito, Manuel, Barbosa, Marcos, Brito, Maria A, Fontes-Ribeiro, Carlos A, Silva, Ana P
Format: Article
Language:English
Subjects:
Animals
Astrocytes - metabolism
Astrocytes - pathology
Biological Transport - drug effects
Blood-Brain Barrier - metabolism
Blood-Brain Barrier - pathology
Central Nervous System Stimulants - adverse effects
Central Nervous System Stimulants - pharmacology
Endothelial Cells - metabolism
Endothelial Cells - pathology
Methamphetamine - adverse effects
Methamphetamine - pharmacology
NF-kappa B - metabolism
Original
Rats
Rats, Wistar
Signal Transduction - drug effects
Tumor Necrosis Factor-alpha - metabolism
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Summary: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-α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-κB) 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-α/NF-κB 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-α and subsequent activation of NF-κB pathway culminating in barrier dysfunction.
ISSN:0271-678X
1559-7016
DOI:10.1038/jcbfm.2015.59