The Gelatinase Inhibitor ACT-03 Reduces Gliosis in the Rapid Kindling Rat Model of Epilepsy, and Attenuates Inflammation and Loss of Barrier Integrity In Vitro
Diede W. M. Broekaart,
Till S. Zimmer,
Sophie T. Cohen,
Rianne Tessers,
Jasper J. Anink,
Helga E. de Vries,
Jan A. Gorter,
Roger Prades,
Eleonora Aronica,
Erwin A. van Vliet
Affiliations
Diede W. M. Broekaart
Amsterdam UMC, Location University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Till S. Zimmer
Amsterdam UMC, Location University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Sophie T. Cohen
Amsterdam UMC, Location University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Rianne Tessers
Amsterdam UMC, Location University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Jasper J. Anink
Amsterdam UMC, Location University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Helga E. de Vries
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands
Jan A. Gorter
Swammerdam Institute for Life Sciences Center for Neuroscience, University of Amsterdam, 1098 XH Amsterdam, The Netherlands
Roger Prades
Accure Therapeutics S.L., 08028 Barcelona, Spain
Eleonora Aronica
Amsterdam UMC, Location University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Erwin A. van Vliet
Amsterdam UMC, Location University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Matrix metalloproteinases (MMPs) are endopeptidases responsible for the cleavage of intra- and extracellular proteins. Several brain MMPs have been implicated in neurological disorders including epilepsy. We recently showed that the novel gelatinase inhibitor ACT-03 has disease-modifying effects in models of epilepsy. Here, we studied its effects on neuroinflammation and blood–brain barrier (BBB) integrity. Using the rapid kindling rat model of epilepsy, we examined whether ACT-03 affected astro- and microgliosis in the brain using immunohistochemistry. Cellular and molecular alterations were further studied in vitro using human fetal astrocyte and brain endothelial cell (hCMEC/D3) cultures, with a focus on neuroinflammatory markers as well as on barrier permeability using an endothelial and astrocyte co-culture model. We observed less astro- and microgliosis in the brains of kindled animals treated with ACT-03 compared to control vehicle-treated animals. In vitro, ACT-03 treatment attenuated stimulation-induced mRNA expression of several pro-inflammatory factors in human fetal astrocytes and brain endothelial cells, as well as a loss of barrier integrity in endothelial and astrocyte co-cultures. Since ACT-03 has disease-modifying effects in epilepsy models, possibly via limiting gliosis, inflammation, and barrier integrity loss, it is of interest to further evaluate its effects in a clinical trial.
