Matrix Metalloproteinase-Mediated Blood-Brain Barrier Dysfunction in Epilepsy

Abstract

The blood-brain barrier is dysfunctional in epilepsy, thereby contributing to seizure genesis and resistance to antiseizure drugs. Previously, several groups reported that seizures increase brain glutamate levels, which leads to barrier dysfunction. One critical component of barrier dysfunction is brain capillary leakage. Based on our preliminary data, we hypothesized that glutamate released during seizures mediates an increase in matrix-metalloproteinase (MMP) expression and activity levels, thereby contributing to barrier leakage. To test this hypothesis, we exposed isolated brain capillaries from male Sprague Dawley rats to glutamate and used an/ approach of isolated brain capillaries from female Wistar rats that experienced status epilepticus as an acute seizure model. We found that exposing isolated rat brain capillaries to glutamate increased MMP-2 and MMP-9 protein and activity levels, and decreased tight junction protein levels, which resulted in barrier leakage. We confirmed these findings in rats after status epilepticus and in brain capillaries from male mice lacking cytosolic phospholipase A Together, our data support the hypothesis that glutamate released during seizures signals an increase in MMP-2 and MMP-9 protein expression and activity levels, resulting in blood-brain barrier leakage. The mechanism leading to seizure-mediated blood-brain barrier dysfunction in epilepsy is poorly understood. In the present study, we focused on defining this mechanism in the brain capillary endothelium. We demonstrate that seizures trigger a pathway that involves glutamate signaling through cytosolic phospholipase A, which increases MMP levels and decreases tight junction protein expression levels, resulting in barrier leakage. These findings may provide potential therapeutic avenues within the blood-brain barrier to limit barrier dysfunction in epilepsy and decrease seizure burden.

Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy

“…Note that Glu may also cause an increase in MMP expression and activity level as reported by a recent study 41 . PNNs and CSPGs play crucial roles in protecting neurons from oxidative stress 33 and glutamate excitotoxicity 42 and combined actions of glioma-released proteases and Glu might explain the selective vulnerability of PV neurons over principle neurons in the PTC.…”

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

“…For example, seizure-induced increases in brain glutamate levels may lead to barrier dysfunction [21,36]. A recent study suggests that glutamate released during seizures increases the expression and activity levels of matrix metalloproteinases (MMP-2 and MMP-9) at the BBB, contributing to barrier dysfunction [37]. MMPs likely affect barrier integrity by digesting and remodeling the extracellular matrix surrounding brain capillaries and by degrading tight junction proteins that seal the endothelium [38,39].…”

Vascular Abnormalities and the Role of Vascular Endothelial Growth Factor in the Epileptic Brain

“…In particular, the prominent upregulation of MMP-9, one of the MMP family members that is expressed in brain capillaries, was observed. In the brains of pilocarpine-induced SE rats, the increased release of glutamate by neurons increased MMP levels, leading to BBB dysfunction (Rempe et al, 2018). VEGF is another molecule associated with BBB dysfunction in the brain (Croll et al, 2004;Rigau et al, 2007).…”