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The matrix metalloproteinase inhibitor marimastat inhibits seizures in a model of kainic acid-induced status epilepticus

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cris.lastimport.scopus2024-02-12T19:55:31Z
dc.abstract.enAn intra-hippocampus injection of kainic acid serves as a model of status epilepticus and the subsequent development of temporal lobe epilepsy. Matrix metalloproteinase-9 (MMP-9) is an enzyme that controls remodeling of the extracellular milieu under physiological and pathological conditions. In response to brain insult, MMP-9 contributes to pathological synaptic plasticity that may play a role in the progression of an epileptic condition. Marimastat is a metalloproteinase inhibitor that was tested in clinical trials of cancer. The present study assessed whether marimastat can impair the development of epilepsy. The inhibitory efficacy of marimastat was initially tested in neuronal cultures in vitro. As a marker substrate, we used nectin-3. Next, we investigated the blood–brain barrier penetration of marimastat using mass spectrometry and evaluated the therapeutic potential of marimastat against seizure outcomes. We found that marimastat inhibited the cleavage of nectin-3 in hippocampal neuronal cell cultures. Marimastat penetrated the blood–brain barrier and exerted an inhibitory effect on metalloproteinase activity in the brain. Finally, marimastat decreased some seizure parameters, such as seizure score and number, but did not directly affect status epilepticus. The long-term effects of marimastat were evident up to 6 weeks after kainic acid administration, in which marimastat still inhibited seizure duration.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorSTEFANIUK, MARZENA
dc.contributor.authorPijet-Binkiewicz, Barbara
dc.contributor.authorRejmak, Emilia
dc.contributor.authorKhomiak, Danylo
dc.contributor.authorKACZMAREK, LESZEK
dc.contributor.authorPikul, Stanisław
dc.contributor.authorKonopka, Anna
dc.contributor.authorBulska, Ewa
dc.date.accessioned2024-01-26T10:27:38Z
dc.date.available2024-01-26T10:27:38Z
dc.date.copyright2020-12-20
dc.date.issued2020
dc.description.accesstimeAT_PUBLICATION
dc.description.financePublikacja bezkosztowa
dc.description.number1
dc.description.versionFINAL_PUBLISHED
dc.description.volume10
dc.identifier.doi10.1038/S41598-020-78341-Y
dc.identifier.issn2045-2322
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/122665
dc.identifier.weblinkhttp://www.nature.com/articles/s41598-020-78341-y.pdf
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofScientific Reports
dc.relation.pagesart. no. 21314
dc.rightsCC-BY
dc.sciencecloudnosend
dc.titleThe matrix metalloproteinase inhibitor marimastat inhibits seizures in a model of kainic acid-induced status epilepticus
dc.typeJournalArticle
dspace.entity.typePublication