Regulation of Human Brain Microvascular Endothelial Cell Adhesion and Barrier Functions by Memantine

Area of Science:

• Neuroscience
• Pharmacology
• Cell Biology

Background:

• Vascular risk factors and microvascular inflammation are linked to cognitive decline and Alzheimer's disease (AD).
• Endothelial inflammation may drive neurodegeneration in AD.
• Memantine is an NMDA receptor antagonist used for moderate to severe AD, but its anti-inflammatory effects on endothelium are unclear.

Purpose of the Study:

• To investigate the anti-inflammatory effects of memantine on human brain microvascular endothelial cells (HBMVEs) stimulated with tumor necrosis factor-α (TNF-α).
• To explore memantine's impact on endothelial dysfunction and the blood-brain barrier (BBB) model.

Main Methods:

• Utilized an in vitro BBB model with HBMVEs and monocyte THP-1 cells.
• Assessed monocyte attachment and transmigration across the endothelial barrier.
• Measured expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and NF-κB pathway activation (IκBα phosphorylation/degradation).

Main Results:

• Memantine inhibited monocyte adhesion to HBMVEs.
• Memantine protected the in vitro BBB model from TNF-α-induced disruption and reduced monocyte transmigration.
• Memantine prevented TNF-α-induced upregulation of ICAM-1, VCAM-1, and E-selectin.
• Memantine reversed TNF-α-induced NF-κB activation by stabilizing IκBα.

Conclusions:

• Memantine exhibits novel anti-inflammatory effects on brain endothelial cells.
• These findings suggest an endothelial cell-mediated neuroprotective mechanism for memantine.
• Memantine's ability to mitigate endothelial dysfunction and BBB disruption may contribute to its therapeutic benefits in AD.