A study on the effect of JNK inhibitor, SP600125, on the disruption of blood–brain barrier induced by methamphetamine

Urrutia, Andrés; Rubio-Araiz, Ana; Gutiérrez-López, Marı́a Dolores; ElAli, Ayman; Hermann, Dirk M.; O’Shea, Esther; Colado, María Isabel

doi:10.1016/j.nbd.2012.10.006

Cited by 53 publications

(55 citation statements)

References 54 publications

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“…METH-induced permeability at the BBB has been consistently reported both in vivo and in vitro [4,5,11]. In mice models, METH was seen to increase permeability and induce massive leakage of macromolecules across the BBB in the cerebral cortex, hippocampus, and other limbic regions [5,6,9].…”

Section: Introductionmentioning

confidence: 87%

“…Both short-and long-term METH uses lead to long-lasting deleterious effects [1,2]. METH toxicity is typically characterized by disruption of synaptic integrity and decreased monoamine production [3][4][5], concomitant with terminal degeneration and neuronal death [2, Electronic supplementary material The online version of this article (doi:10.1007/s12035-014-8973-5) contains supplementary material, which is available to authorized users. 6].…”

Section: Introductionmentioning

confidence: 99%

“…METH is increasingly recognized to impact also nonneuronal cells, such as microglia, and astrocytes and the blood-brain-barrier (BBB), causing the release of inflammatory mediators and astrogliosis [1,3,7,8]. The concept of METH-induced damage at the level of the BBB has gained relevance over the last few years, justifying the interest in understanding its consequences at the endothelium [4,9,10].…”

Section: Introductionmentioning

confidence: 99%

“…There is also evidence that it can interfere with actin structure and arrangement, which also may lead to compromised TJ function [14,26]. Although the molecular mechanisms underlying BBB disruption under METH exposure are not fully characterized, the activation of matrix metalloproteinases (MMPs), commonly involved in remodeling and degradation of the neurovascular matrix components and therefore associated with BBB leakiness, has been reported [4,6,9,27].…”

Section: Introductionmentioning

confidence: 99%

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Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity

et al. 2014

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Methamphetamine (METH) is a potent psychostimulant highly used worldwide. Recent studies evidenced the involvement of METH in the breakdown of the blood-brain-barrier (BBB) integrity leading to compromised function. The involvement of the matrix metalloproteinases (MMPs) in the degradation of the neurovascular matrix components and tight junctions (TJs) is one of the most recent findings in METH-induced toxicity. As BBB dysfunction is a pathological feature of many neurological conditions, unveiling new protective agents in this field is of major relevance. Acetyl-L-carnitine (ALC) has been described to protect the BBB function in different paradigms, but the mechanisms underling its action remain mostly unknown. Here, the immortalized bEnd.3 cell line was used to evaluate the neuroprotective features of ALC in METH-induced damage. Cells were exposed to ranging concentrations of METH, and the protective effect of ALC 1 mM was assessed 24 h after treatment. F-actin rearrangement, TJ expression and distribution, and MMPs activity were evaluated. Integrin-linked kinase (ILK) knockdown cells were used to assess role of ALC in ILK mediated METHtriggered MMPs' activity. Our results show that METH led to disruption of the actin filaments concomitant with claudin-5 translocation to the cytoplasm. These events were mediated by MMP-9 activation in association with ILK overexpression. Pretreatment with ALC prevented METH-induced activation of MMP-9, preserving claudin-5 location and the structural arrangement of the actin filaments. The present results support the potential of ALC in preserving BBB integrity, highlighting ILK as a new target for the ALC therapeutic use.

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Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity

et al. 2014

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“…However, METH has been increasingly recognized to impact also the blood-brain-barrier (BBB), causing the release of inflammatory mediators and astrogliosis (Gold et al, 2009;Goncalves et al, 2010;Northrop and Yamamoto, 2012;Ramirez et al, 2009). METH-induced permeability at the BBB level has been consistently reported both in vivo and in vitro (Conant et al, 2011;Martins et al, 2011;Urrutia et al, 2013), as a result of tight junction and cytoskeleton disarrangement (Dietrich, 2009;Kousik et al, 2012;Park et al, 2013). In endothelial cells, METH was also shown to trigger nitric oxide (NO)-mediated transcytosis (Martins et al, 2013).…”

Section: Introduction Methamphetamine (Meth) Is a Powerful Psychostimmentioning

confidence: 99%

Methamphetamine promotes α-tubulin deacetylation in endothelial cells: The protective role of acetyl-l-carnitine

2015

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Methamphetamine (METH) is a powerful psychostimulant drug used worldwide for its reinforcing properties. In addition to the classic long-lasting monoaminergic-disrupting effects extensively described in the literature, METH has been consistently reported to increase blood brain barrier (BBB) permeability, both in vivo and in vitro, as a result of tight junction and cytoskeleton disarrangement. Microtubules play a critical role in cell stability, which relies on post-translational modifications such as a-tubulin acetylation. As there is evidence that psychostimulants drugs modulate the expression of histone deacetylases (HDACs), we hypothesized that in endothelial cells METH-mediation of cytoplasmatic HDAC6 activity could affect tubulin acetylation and further contribute to BBB dysfunction. To validate our hypothesis, we exposed the bEnd.3 endothelial cells to increasing doses of METH and verified that itleads to an extensivea-tubulin deacetylation mediated by HDACs activation. Furthermore, since we recently reported that acetyl-L-carnitine (ALC), a natural occurring compound, prevents BBB structural loss in a context of METH exposure, we reasoned that ALC could also preserve the acetylation of microtubules under METH action. The present results confirm that ALC is able to prevent METH-induced deacetylation providing effective protection on microtubule acetylation. Although further investigation is still needed, HDACs regulation may become a new therapeutic target for ALC.

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Neuroprotection

Green

Colado

2014

Encyclopedia of Psychopharmacology

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A study on the effect of JNK inhibitor, SP600125, on the disruption of blood–brain barrier induced by methamphetamine

Cited by 53 publications

References 54 publications

Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity

Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity

Methamphetamine promotes α-tubulin deacetylation in endothelial cells: The protective role of acetyl-l-carnitine

Neuroprotection

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