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Methamphetamine-induced nitric oxide promotes vesicular transport in blood-brain barrier endothelial cells

Tânia Martins1, Thomas Burgoyne, Bridget-Ann Kenny

  • 1Cell Biology, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.

Neuropharmacology
|September 11, 2012
PubMed

Insights

Methamphetamine (METH) disrupts the blood-brain barrier (BBB) by increasing vesicular transport in brain endothelial cells, not by damaging cell junctions. Nitric oxide mediates this METH-induced BBB dysfunction.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pharmacology

Background:

  • Methamphetamine (METH) neurotoxicity is linked to blood-brain barrier (BBB) dysfunction.
  • Understanding the precise mechanisms of METH-induced BBB compromise is crucial for developing therapeutic strategies.

Purpose of the Study:

  • To investigate the effects of METH on the barrier properties of cultured rat primary brain microvascular endothelial cells (BMVECs).
  • To elucidate the role of nitric oxide (NO) in METH-induced BBB disruption.

Main Methods:

  • Cultured rat primary BMVECs were treated with varying concentrations of METH.
  • Transendothelial electrical resistance (TEER) and transendothelial flux of tracers were measured.
  • Ultrastructural analysis of endothelial junctions and protein distribution was performed.
  • Lymphocyte migration across the endothelial barrier was assessed.
  • The role of endothelial nitric oxide synthase (eNOS) was investigated using inhibitors.

Main Results:

  • METH doubled transendothelial flux of tracers, independent of tracer size, without altering TEER or junctional integrity.
  • METH enhanced horseradish peroxidase uptake into vesicular structures, indicating increased transcytosis.
  • METH increased transendothelial lymphocyte migration, compromising the barrier against cells.
  • These effects were observed at low micromolar METH concentrations and were mediated by nitric oxide via eNOS activation.

Conclusions:

  • METH disrupts the BBB primarily through enhanced fluid-phase transcytosis, not by damaging inter-endothelial junctions.
  • Nitric oxide is a key mediator of METH-induced BBB permeability and lymphocyte migration.
  • This study reveals a novel mechanism of drug-induced BBB dysfunction involving transcytosis and NO signaling.

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