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

An 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.

Design and synthesis of selective and blood-brain barrier-permeable hydroxamate-based gelatinase inhibitors.

Matrix metalloproteinases (MMPs), a family of zinc-containing endopeptidases involved in the degradation of the extracellular matrix, make a major contribution to the progression of a vast number of diseases, such cancer or epilepsy. Although several MMP inhibitors (MMPi) have been developed to date for the treatment of cancer, they have all failed in clinical trials due to lack of efficacy and, most importantly, the presence of severe side effects. The latter can be explained by their lack of selectivity of these inhibitors. In this regard, MMPs' family members have a high structural homology, which challenge the development of selective inhibitors for a specific MMP. Here, we have used in silico calculations and in vitro data to design MMPi that selectively target gelatinases (MMP-2 and MMP-9) and have the capacity to cross the blood-brain barrier. Following this approach, we obtained compound 40 that shows high proteolytic stability and low cytotoxicity. This compound may be of particular interest for the treatment of central nervous diseases such epilepsy or Alzheimer's disease, where gelatinase activity is increased. Our data show the specificity of compound 40 for recombinant MMP-9 and MMP-2 and endogenous MMP-9 from rat hippocampal cell cultures, and reveals its permeability across the blood-brain barrier in vivo.

Matrix metalloproteinase 9 and epileptogenesis - the crucial role of the enzyme and strategies to prevent the disease development.

Epileptogenesis is the process responsible for converting normal brain into an epileptic. It may be triggered by an event such as brain injury or status epilepticus (SE). The main mechanisms responsible include neuroinflammation and blood-brain barrier (BBB) disruption, pathologic neuronal networks' reorganisation and aberrant synaptic plasticity. Accumulating amount of evidence from animal models and epileptic patients strongly suggest that matrix metalloproteinase 9 (MMP-9) is potentially one of the key executors of the processes of epileptogenesis. MMP-9 by affecting synaptic plasticity is suggested to enable epileptic remodelling of the brain circuitry. MMP-9's dependent cleavage of BBB followed by inflammatory cell infiltration into the brain contributes to the neuroinflamation component of epileptogenesis. The goal of this review was to analyse all possible ways MMP-9 may be involved in epileptogenesis and consider MMP-9 inhibition as potential therapeutic strategy.