Cortical spreading depression activates and upregulates MMP-9

Area of Science:

• Neuroscience
• Neurophysiology
• Vascular Biology

Background:

• Cortical spreading depression (CSD) is a wave of neuronal depolarization linked to stroke, head trauma, and migraine.
• CSD's impact on neurovascular regulation and blood-brain barrier (BBB) integrity remains incompletely understood.

Purpose of the Study:

• To investigate the role of CSD in altering BBB permeability.
• To identify the specific molecular mechanisms, particularly matrix metalloproteinases (MMPs), involved in CSD-induced BBB disruption.

Main Methods:

• CSD was induced in rodent models.
• MMP levels and activity were assessed using Western blotting and gelatin zymography.
• BBB integrity was evaluated by measuring plasma protein extravasation and brain edema.
• Pharmacological inhibitors (GM6001) and genetic models (MMP-9 null mice) were employed.

Main Results:

• CSD significantly increased MMP-9 levels and gelatinolytic activity in the cortex, peaking at 24 hours.
• CSD led to the downregulation of BBB integrity proteins (laminin, endothelial barrier antigen, zona occludens-1).
• Plasma protein leakage and brain edema were observed post-CSD and were attenuated by MMP inhibition or in MMP-9 null mice.

Conclusions:

• CSD triggers a cascade that compromises BBB integrity through an MMP-9-dependent mechanism.
• MMP activation is a critical factor in CSD-induced neurovascular dysfunction.
• Targeting MMPs may offer therapeutic strategies for conditions associated with CSD.