TY - JOUR
T1 - The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects
AU - Broekaart, Diede W.M.
AU - Bertran, Alexandra
AU - Jia, Shaobo
AU - Korotkov, Anatoly
AU - Senkov, Oleg
AU - Bongaarts, Anika
AU - Mills, James D.
AU - Anink, Jasper J.
AU - Seco, Jesús
AU - Baayen, Johannes C.
AU - Idema, Sander
AU - Chabrol, Elodie
AU - Becker, Albert J.
AU - Wadman, Wytse J.
AU - Tarragó, Teresa
AU - Gorter, Jan A.
AU - Aronica, Eleonora
AU - Prades, Roger
AU - Dityatev, Alexander
AU - van Vliet, Erwin A.
N1 - Funding Information: We thank Leszek Kaczmarek (Nencki Institute, Warsaw, Poland) for the information about MMP9 activity assays and Matthew Walker (UCL Institute of Neurology, University College London, Queen Square, London, United Kingdom) for critically reading the manuscript. The research leading to these results has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska Curie grant agreement no. 642881 (ECMED; to A Bertran, SJ, AK, EC, EA, and AD), the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602102 (EPITAR-GET; to EAVV, JAG, and EA), and the Dutch Epilepsy Foundation, project number 16-05 (to DWMB and EAVV). Publisher Copyright: © 2021, American Society for Clinical Investigation. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/4
Y1 - 2021/1/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85098867940&partnerID=8YFLogxK
UR - https://pure.uva.nl/ws/files/54205291/JCI138332.sd.pdf
U2 - https://doi.org/10.1172/JCI138332
DO - https://doi.org/10.1172/JCI138332
M3 - Article
C2 - 33141761
SN - 0021-9738
VL - 131
JO - Journal of clinical investigation
JF - Journal of clinical investigation
IS - 1
M1 - e138332
ER -