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Molecular NeurobiologyVolume 53, Issue 1, 1 January 2016, Pages 408-422

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

  • aAddiction Biology Group, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre, 823, Porto, 4150-180, Portugal
  • bSchool of Allied Health Sciences, Polytechnic Institute of Porto (ESTSP-IPP), Porto, Portugal
  • cFaculdade de Medicina, Universidade do Porto (FMUP), Porto, Portugal
  • dInstitute de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
  • eInstitute of Biomedical Research on Light and Image (IBILI), University of Coimbra, Coimbra, Portugal

Abstract

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 METH-triggered 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. © 2014, Springer Science+Business Media New York.

Author keywords

Acetyl-L-carnitineBlood-brain-barrierIntegrin-linked kinaseMatrix-metalloproteinase-9MethamphetamineTight junctions

Indexed keywords

EMTREE drug terms:claudin 5F actingelatinase Bintegrin linked kinaselevacecarninemethamphetamineacetylcarnitineactinclaudin 5gelatinase Bintegrin-linked kinasemethamphetamineoccludinprotein serine threonine kinaseprotein ZO1
EMTREE medical terms:animal cellanimal tissueArticleblood brain barriercell damagecell structurecontrolled studycytoplasmcytotoxicitydrug targetingendothelium cellenzyme activationenzyme activityimmortalized cell linemouseneuroprotectionnonhumanprotein expressionprotein localizationtight junctionactin filamentanimalbiological modelcell deathcell linecell survivaldrug effectsendothelium cellenzymologygene silencingmetabolismpathology
MeSH:AcetylcarnitineActin CytoskeletonActinsAnimalsCell DeathCell LineCell SurvivalClaudin-5Endothelial CellsGene SilencingMatrix Metalloproteinase 9MethamphetamineMiceModels, BiologicalOccludinProtein-Serine-Threonine KinasesZonula Occludens-1 Protein

Chemicals and CAS Registry Numbers:

F actin, 39409-31-9; gelatinase B, 146480-36-6; levacecarnine, 3040-38-8, 5080-50-2; methamphetamine, 28297-73-6, 51-57-0, 537-46-2, 7632-10-2; acetylcarnitine, 14992-62-2; occludin, 176304-61-3; protein serine threonine kinase;

Acetylcarnitine; Actins; Claudin-5; integrin-linked kinase; Matrix Metalloproteinase 9; Methamphetamine; Occludin; Protein-Serine-Threonine Kinases; Zonula Occludens-1 Protein

Manufacturers:

Drug manufacturer:

Sigma Tau, Italy

Funding details

Funding sponsor Funding number Acronym
Programa Operacional Temático Factores de CompetitividadeCOMPETE
Programa Operacional Temático Factores de Competitividade
FCT PTDC/SAU-OSM/100630/2008
College of Environmental Science and Forestry, State University of New York

  • 1

    This research project was funded by Programa Operacional Factores de Competitividade (COMPETE) and by National funds through FCT?Funda??o para a Ciencia e Tecnologia, reference FCOMP-01-0124-FEDER-011320 (FCT PTDC/SAU-OSM/100630/2008). Joana Bravo received a research grant under this project. Teresa Summavielle was supported by Programa Ci?ncia?Programa Operacional Potencial Humano (POPH)-Promotion of Scientific Employment, ESF and MCTES and program Investigador FCT, POPH and Fundo Social Europeu. We thank Glial Cell Biology Group as a whole and specially Dr Joana Paes Faria and Dr Jo?o Relvas for providing the lentivirus for shRNA-mediated silencing of ILK. We thank Dr F?tima Pina (INEB, University of Porto) for statistic advice in the analyses of the actin data. We thank Dr Maria Jos? Oliveira (INEB, University of Porto) for her kind support regarding the zymography methodology. We also thank Dr Paula Sampaio and Paula Magalh?es (IBMC Technical Services) for assistance with image analyses and cell culture facilities.

  • ISSN: 08937648
  • CODEN: MONBE
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1007/s12035-014-8973-5
  • PubMed ID: 25465237
  • Document Type: Article
  • Publisher: Humana Press Inc.

  Summavielle, T.; Addiction Biology Group, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre, 823, Porto, Portugal;
© Copyright 2018 Elsevier B.V., All rights reserved.

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