The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects
| Autor: | Elodie Chabrol, Roger Prades, Anatoly Korotkov, Oleg Senkov, Shaobo Jia, Johannes C. Baayen, Jan A. Gorter, Diede W. M. Broekaart, Alexander Dityatev, Wytse J. Wadman, Sander Idema, Jasper J. Anink, Alexandra Bertran, Erwin A. van Vliet, Eleonora Aronica, Albert J. Becker, James D. Mills, Jesús Seco, Anika Bongaarts, Teresa Tarragó |
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| Přispěvatelé: | Neurology, Neurosurgery, Amsterdam Neuroscience - Systems & Network Neuroscience, Pathology, Graduate School, APH - Aging & Later Life, APH - Mental Health, ANS - Cellular & Molecular Mechanisms, Cellular and Computational Neuroscience (SILS, FNWI) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Matrix metalloproteinase inhibitor enzymology [Brain] Hippocampus Matrix metalloproteinase Pharmacology Epileptogenesis Rats Sprague-Dawley chemistry.chemical_compound Epilepsy Mice 0302 clinical medicine Status Epilepticus pathology [Brain] Medicine drug therapy [Status Epilepticus] Cognitive decline Brain General Medicine Extracellular matrix metabolism [Matrix Metalloproteinase 9] Matrix Metalloproteinase 9 030220 oncology & carcinogenesis pathology [Status Epilepticus] Matrix Metalloproteinase 2 Female medicine.symptom Research Article Kainic acid enzymology [Status Epilepticus] pathology [Epilepsy Temporal Lobe] pharmacology [Matrix Metalloproteinase Inhibitors] Status epilepticus Therapeutics Matrix Metalloproteinase Inhibitors 03 medical and health sciences Seizures Animals Humans ddc:610 drug therapy [Epilepsy Temporal Lobe] enzymology [Epilepsy Temporal Lobe] business.industry medicine.disease metabolism [Matrix Metalloproteinase 2] Rats 030104 developmental biology chemistry Epilepsy Temporal Lobe nervous system business Neuroscience |
| Zdroj: | Journal of Clinical Investigation, 131(1):e138332. The American Society for Clinical Investigation Broekaart, D W M, Bertran, A, Jia, S, Korotkov, A, Senkov, O, Bongaarts, A, Mills, J D, Anink, J J, Seco, J, Baayen, J C, Idema, S, Chabrol, E, Becker, A J, Wadman, W J, Tarragó, T, Gorter, J A, Aronica, E, Prades, R, Dityatev, A & van Vliet, E A 2021, ' The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects ', Journal of Clinical Investigation, vol. 131, no. 1, e138332 . https://doi.org/10.1172/JCI138332 J Clin Invest The journal of clinical investigation 131(1), e138332 (2021). doi:10.1172/JCI138332 Journal of clinical investigation, 131(1):e138332. The American Society for Clinical Investigation The journal of clinical investigation, 131(1):e138332. The American Society for Clinical Investigation |
| ISSN: | 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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