Laquinimod enhances central nervous system barrier functions.

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS).
• Laquinimod is an investigational drug for MS, but its mechanism of action is not fully understood.
• Current research focuses on understanding how laquinimod affects immune cell infiltration and CNS damage.

Purpose of the Study:

• To elucidate the mechanism of action of laquinimod in experimental autoimmune encephalomyelitis (EAE), an animal model of MS.
• To investigate the impact of laquinimod on T cell trafficking and blood-brain barrier (BBB) integrity.

Main Methods:

• Tracking fluorescently-labeled encephalitogenic T cells in EAE models.
• Assessing T cell activation, differentiation, and migration.
• Analyzing the expression of tight junction proteins and adhesion molecules in brain endothelial cells.
• Measuring transendothelial electrical resistance (TEER) of brain endothelial cell monolayers.

Main Results:

• Laquinimod significantly reduced the invasion of pathogenic effector T cells into the CNS.
• Laquinimod treatment upregulated tight junction proteins (p120, ZO-1) in brain endothelial cells, increasing BBB integrity.
• Expression of ALCAM, CCL2, and IP-10 was suppressed, reducing T cell migration across the BBB.
• T cell activation and differentiation in lymphoid organs were minimally affected.

Conclusions:

• Laquinimod's therapeutic effect in MS models is primarily mediated by enhancing BBB function.
• The drug tightens the BBB, limiting inflammatory T cell infiltration into the CNS and reducing tissue damage.
• This mechanism suggests laquinimod as a promising therapeutic agent for MS by preserving BBB integrity.