Methamphetamine-induced occludin endocytosis is mediated by the Arp2/3 complex-regulated actin rearrangement

Area of Science:

• Neuroscience
• Cell Biology
• Pharmacology

Background:

• Methamphetamine (METH) abuse causes neurotoxicity and neuroinflammation, impairing the blood-brain barrier (BBB).
• METH disrupts tight junction proteins, like occludin, affecting BBB integrity.
• Actin cytoskeletal dynamics play a role in regulating tight junction protein localization.

Purpose of the Study:

• To investigate the role of actin cytoskeletal rearrangement in METH-induced occludin redistribution.
• To determine if modulating actin nucleation can prevent METH-induced BBB disruption.

Main Methods:

• Exposing brain endothelial cells to METH and observing occludin localization.
• Analyzing the activation of the actin-related protein 2/3 (Arp2/3) complex and coronin-1b phosphorylation.
• Using CK-666, an Arp2/3 inhibitor, to block actin nucleation in vitro and in vivo.
• Assessing BBB permeability and occludin levels in METH-injected mice treated with CK-666.

Main Results:

• METH exposure caused occludin to shift from plasma membranes to endosomes in brain endothelial cells.
• METH treatment activated the Arp2/3 complex and increased coronin-1b phosphorylation, promoting actin nucleation.
• Inhibiting actin nucleation with CK-666 prevented METH-induced occludin internalization and monocyte migration.
• CK-666 treatment reduced occludin loss and BBB permeability in METH-injected mice.

Conclusions:

• Actin cytoskeletal dynamics are a key factor in METH-induced BBB dysfunction.
• Targeting actin nucleation pathways may offer a therapeutic strategy to protect the BBB from METH toxicity.