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 5

The effects of IPR-179 on seizure development in the rapid-kindling rat model.

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The effects of IPR-179 on seizure development in the rapid-kindling rat ...
Percentages of behavioral scores according to Racine’s scale in rats treated with vehicle (A, n = 8), IPR-179 (B, n = 8), or minocycline (C, n = 10) during the test and retest phase. Mixed effects ordinal regression revealed a difference in the interaction between treatment and stimulus number was observed for IPR-179 compared with vehicle (P < 0.05). During kindling, IPR-179–treated rats (B) showed less severe behavioral seizures (stimulation 5, 8–10, 14, 23, 26, 29, 31–34; P < 0.05) compared with vehicle-treated animals (A). Less severe behavioral seizures were seen in minocycline-treated rats (C) compared with vehicle-treated rats (A) (stimulation 5 and 9; P < 0.05). In the absence of the drug, IPR-179–treated rats showed less severe behavioral scores during stimulation 1, 2, and 3 (B) compared with vehicle-treated rats (A), while minocycline-treated rats only showed less severe behavioral scores during stimulation 5 (C). IPR-179–treated rats had a tendency toward more stage 1 and fewer stage 2 and stage 5 seizures compared with vehicle-treated rats (D). During the kindling retest, there was a tendency toward more stage 1 and fewer stage 5 seizures in IPR-treated rats versus vehicle-treated rats (D). IPR-179–treated rats showed a higher relative expression of nectin-3 ratio of full protein over SPF (E). Data shown represent mean + SEMs. *P < 0.05; **P < 0.01, Mann-Whitney U test (A–C and E), 2-way RM ANOVA followed by Dunnett’s post hoc test (D).