Methamphetamine induces autophagy as a pro-survival response against apoptotic endothelial cell death through the Kappa opioid receptor

J. Ma, J. Wan, J. Meng, S. Banerjee, S. Ramakrishnan, S. Roy

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83 Scopus citations


Methamphetamine (METH) is a psychostimulant with high abuse potential and severe neurotoxicity. Recent studies in animal models have indicated that METH can impair the blood-brain barrier (BBB), suggesting that some of the neurotoxic effects resulting from METH abuse could be due to barrier disruption. We report here that while chronic exposure to METH disrupts barrier function of primary human brain microvascular endothelial cells (HBMECs) and human umbilical vein endothelial cells (HUVECs), an early pro-survival response is observed following acute exposure by induction of autophagic mechanisms. Acute METH exposure induces an early increase in Beclin1 and LC3 recruitment. This is mediated through inactivation of the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70S6K pathway, and upregulation of the ERK1/2. Blockade of Kappa opioid receptor (KOR), and treatment with autophagic inhibitors accelerated METH-induced apoptosis, suggesting that the early autophagic response is a survival mechanism for endothelial cells and is mediated through the kappa opioid receptor. Our studies indicate that kappa opioid receptor can be therapeutically exploited for attenuating METH-induced BBB dysfunction.

Original languageEnglish (US)
Article numbere1099
JournalCell Death and Disease
Issue number3
StatePublished - Mar 2014

Bibliographical note

Funding Information:
Acknowledgements. This work was supported by National Institutes of Health grants RO1 DA 12104, RO1 DA 022935, RO1 DA031202, K05DA033881, P50 DA 011806 and 1R01DA034582 (SR). We are grateful to Ms Fang Zhou for the assistance of TEM. TEM was carried out in the Characterization Facility, University of Minnesota and a member of the NSF-funded Materials Research Facilities Network ( via the MRSEC program.


  • Autophagy
  • Cell death
  • Kappa opioid receptor
  • Methamphetamine


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