The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects
Diede W.M. Broekaart, … , Alexander Dityatev, Erwin A. van Vliet
Diede W.M. Broekaart, … , Alexander Dityatev, Erwin A. van Vliet
Published November 3, 2020
Citation Information: J Clin Invest. 2021;131(1):e138332. https://doi.org/10.1172/JCI138332.
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Research Article Neuroscience

The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects

Abstract

Matrix metalloproteinases (MMPs) are synthesized by neurons and glia and released into the extracellular space, where they act as modulators of neuroplasticity and neuroinflammatory agents. Development of epilepsy (epileptogenesis) is associated with increased expression of MMPs, and therefore, they may represent potential therapeutic drug targets. Using quantitative PCR (qPCR) and immunohistochemistry, we studied the expression of MMPs and their endogenous inhibitors tissue inhibitors of metalloproteinases (TIMPs) in patients with status epilepticus (SE) or temporal lobe epilepsy (TLE) and in a rat TLE model. Furthermore, we tested the MMP2/9 inhibitor IPR-179 in the rapid-kindling rat model and in the intrahippocampal kainic acid mouse model. In both human and experimental epilepsy, MMP and TIMP expression were persistently dysregulated in the hippocampus compared with in controls. IPR-179 treatment reduced seizure severity in the rapid-kindling model and reduced the number of spontaneous seizures in the kainic acid model (during and up to 7 weeks after delivery) without side effects while improving cognitive behavior. Moreover, our data suggest that IPR-179 prevented an MMP2/9-dependent switch-off normally restraining network excitability during the activity period. Since increased MMP expression is a prominent hallmark of the human epileptogenic brain and the MMP inhibitor IPR-179 exhibits antiseizure and antiepileptogenic effects in rodent epilepsy models and attenuates seizure-induced cognitive decline, it deserves further investigation in clinical trials.

Authors

Diede W.M. Broekaart, Alexandra Bertran, Shaobo Jia, Anatoly Korotkov, Oleg Senkov, Anika Bongaarts, James D. Mills, Jasper J. Anink, Jesús Seco, Johannes C. Baayen, Sander Idema, Elodie Chabrol, Albert J. Becker, Wytse J. Wadman, Teresa Tarragó, Jan A. Gorter, Eleonora Aronica, Roger Prades, Alexander Dityatev, Erwin A. van Vliet

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Figure 2

Expression of MMP9 protein in the DG and CA1 of the human hippocampus.

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Expression of MMP9 protein in the DG and CA1 of the human hippocampus. I...
In controls, MMP9 was weakly expressed in neurons while it was not detected in glial cells (A and B). Higher MMP9 expression was observed in hippocampal neurons and glia of patients who died after SE (C and D) compared with controls. In patients with TLE, expression in both neurons and glia was increased compared with that in controls (E–H). Scale bar: 50 μm. Arrowheads indicate positive cells with glial morphology. Arrows indicate positive neurons. Insets depict double labeling of MMP9 in NeuN-positive cells (neurons) and GFAP-positive cells (astrocytes), but not with CR3/43-positive cells (microglia). Photographs are taken from representative cases of control (n = 8), SE (n = 5), TLE without HS (TLE – no HS) (n = 5), and TLE with HS (TLE – HS) (n = 10) patients.