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

Abstract

AbstractAn 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.