Tissue-Type Plasminogen Activator and Tenecteplase-Mediated Increase in Blood Brain Barrier Permeability Involves...

Area of Science:

• Neuroscience
• Pharmacology
• Immunology

Background:

• Tissue-type plasminogen activator (t-PA) is a primary treatment for acute ischemic stroke (AIS), but can cause intracerebral hemorrhage and affect blood-brain barrier (BBB) permeability.
• Complement activation, a process also occurring in AIS, can increase BBB permeability. The role of tenecteplase (TNK-tPA), a t-PA variant, in BBB modulation and complement activation is less understood.

Purpose of the Study:

• To investigate the impact of C5 and C5a-receptor 1 (C5aR1) inhibitors on BBB opening induced by t-PA and TNK-tPA.
• To explore the potential therapeutic role of C5aR1 inhibition in AIS.

Main Methods:

• An in vitro BBB model using co-cultured human brain endothelial cells and astrocytes was employed.
• Cells were stimulated with t-PA or TNK-tPA in the presence of plasminogen and various C5aR1 inhibitors (PMX205, Avacopan) or a C5 inhibitor (Eculizumab).
• BBB permeability was assessed at 5 and 24 hours, and C5/C5aR1 expression was analyzed via immunofluorescence.

Main Results:

• PMX205, a non-competitive C5aR1 antagonist, significantly inhibited t-PA- and TNK-tPA-induced BBB permeability increase at both time points.
• Avacopan (competitive C5aR1 antagonist) and Eculizumab (C5 inhibitor) did not block t-PA-mediated BBB opening.
• Immunofluorescence confirmed intracellular C5 and cell surface/intracellular C5aR1 expression in both endothelial cells and astrocytes.

Conclusions:

• t-PA and TNK-tPA increase BBB permeability through C5aR1 receptor activation, driven by cell-derived C5a.
• Targeting C5aR1 with selective inhibitors presents a promising therapeutic strategy for managing BBB dysfunction in AIS.