The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction. Issue 8 (August 2015)

• Record Type: Journal Article
• 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
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 35:Issue 8(2015)
• Page Start: 1260
• Page End: 1271
• Publication Date: 2015-08
• Subjects: astrocytes -- blood–brain barrier -- methamphetamine -- nuclear factor-kappa B -- tumor necrosis factor-alpha; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1038/jcbfm.2015.59
• Languages: English
• ISSNs: 0271-678X

Abstract

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- κ 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- α /NF- κ 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- α and subsequent activation of NF- κ B pathway culminating in barrier dysfunction.