Modulation of the Blood-Brain Barrier by Sigma-1R Activation.

Area of Science:

• Neuroscience
• Cell Biology
• Pharmacology

Background:

• Sigma non-opioid intracellular receptor 1 (Sigma-1R) is an intracellular chaperone protein.
• Sigma-1R is abundant in the brain and implicated in various physiological and disease states.
• The precise role of Sigma-1R at the blood-brain barrier (BBB) remains incompletely understood.

Purpose of the Study:

• To investigate the effect of Sigma-1R activation on blood-brain barrier (BBB) integrity.
• To explore the mechanisms underlying Sigma-1R's influence on BBB permeability in vitro and in vivo.

Main Methods:

• In vitro studies using rat brain microvascular endothelial cells (RBMVEC) exposed to Sigma-1R agonist PRE-084.
• In vivo assessment of BBB permeability in rats using Evans Blue and sodium fluorescein extravasation.
• Electric cell-substrate impedance sensing (ECIS) for measuring RBMVEC monolayer electrical resistance.
• Immunocytochemistry to analyze tight/adherens junctions and actin cytoskeleton.
• In vivo brain microcirculation visualization using a miniature integrated fluorescence microscope (miniscope).

Main Results:

• Sigma-1R activation by PRE-084 increased mitochondrial calcium and reactive oxygen species (ROS) in RBMVEC.
• PRE-084 treatment decreased RBMVEC monolayer electrical resistance, indicating BBB disruption.
• In vivo studies confirmed PRE-084 dose-dependently increased BBB permeability, evidenced by enhanced extravasation of tracers.
• Sigma-1R antagonists (BD 1047, NE 100) attenuated the effects of PRE-084.
• PRE-084 disrupted tight/adherens junctions and the actin cytoskeleton.

Conclusions:

• Sigma-1R activation promotes oxidative stress within brain endothelial cells.
• Activation of Sigma-1R leads to increased blood-brain barrier permeability.
• Targeting Sigma-1R may offer therapeutic strategies for conditions involving BBB dysfunction.