Understanding the Role of the Leaky Blood-brain Barrier in Epilepsy

Leaky Blood-Brain Barrier

Glutamate elevation following seizure results in increased MMP activation and decreased TJ, which cause BBB leakage, potentially contributing to ASD. Inhibiting the glutamate/MMP pathway may prevent leaky BBB-mediated drug resistant epilepsy.

Wednesday, December 4, 2019

Approximately one-third of people with epilepsy suffer from refractory (or drug-resistant) epilepsy that is not controlled by anti-seizure drugs (ASDs). The recurrence of these uncontrolled seizures has a significant impact on their quality of life. However, why their seizures resist treatment remains poorly understood.

Leaks in the Blood-brain Barrier

  • One contributing factor to seizure medication resistance is thought to be the leakiness of the blood-brain barrier (BBB).
  • The BBB is a semi-permeable membrane, meaning some things can pass through this layer but others can’t. The membrane that consists of cellular and extracellular (outside the cells) matrix (ECM) components that work to protect the brain. The protection occurs by regulating the movement of molecules, ions, and immune cells between the blood and the central nervous system (CNS).
  • Normally, the BBB protects the brain from toxins, pathogens, and injury. The protection comes from proteins between cells called tight junctions (TJs) that selectively restrict the passage of certain compounds. Therefore, the BBB is often an obstacle that needs to be bypassed for drug delivery.
  • BBB leakage, which is associated with an increase in the chemical messenger glutamate, has been suggested in the process of developing epilepsy.
  • Leaky BBB is thought to affect ASD resistance due to the influx of serum proteins that can bind to drugs and reduce their effectiveness in the brain.
  • Therefore, better understanding the cause of seizure-induced BBB leakage in epilepsy could be important for developing targeted treatment for people with epilepsy and for increasing effectiveness of ASDs.

Study Summary and Findings

In a study published in The Journal of Neuroscience, scientists tried to find how seizures trigger BBB leakage to better understand the start of BBB leaks and how it may contribute to anti-seizure drug resistance.

Tools Used

  • All procedures were performed using national and institutional guidelines to ensure humane treatment of animals.
  • Enzymes critical for ECM and tissue remodeling called matrix metalloproteinase (specifically, MMP-2 and MMP-9), as well as TJ proteins, were measured in:
    • Brain capillaries isolated from rats that experienced seizures
    • Capillaries isolated from normal rats that were exposed to glutamate, with and without the presence of MMP inhibitors
  • Finally, the relationship between BBB leakiness (measured by outflow of fluorescent dye over time), glutamate signaling, and MMP activity) was evaluated by chemical and genetic inhibition of the glutamate pathway.

Findings

  • BBB leakage was 18-times higher in rats having prolonged seizures compared to untreated/non-seizure rats.
  • Elevated levels of active MMP-2 and MMP-9 and reduced levels of TJ proteins were found in the brain capillaries of rats that experienced seizures.
  • Similarly, capillaries isolated from non-seizure rats exposed to high concentrations of glutamate exhibited significantly decreased expression of TJ proteins, elevated expression of MMPs, and increased BBB leakage.
  • Inhibition of MMP activity prevented the ability of glutamate to induce BBB leakage.
  • Inhibition of glutamate receptor signaling abolished MMP-mediated BBB capillary leakage.

Conclusions

  • This work established a possible mechanism by which seizures trigger enzyme-induced BBB leakage that could contribute to drug resistance and epilepsy progression.
  • Inhibition of the glutamate pathway could potentially be a treatment target and reduce seizure burden.
  • More research is needed to evaluate the feasibility and consequences of targeting this pathway. However, this study has important implications for the development and evaluation of more effective drug treatments for epilepsy and other leaky BBB-associated neurological disorders.

Reference

Rempe RG, et al., Matrix Metalloproteinase-Mediated Blood-Brain Barrier Dysfunction in Epilepsy. J Neurosci. 2018 May2;38(18):4301-4315.

Authored by: Michele Waters PhD on 12/2019
Reviewed by: Sloka Iyengar PhD, PMP | Elaine Wirrell MD on 12/2019

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