TY - JOUR
T1 - 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
AU - Broekaart, D.W.M.
AU - Zimmer, T.S.
AU - Cohen, S.T.
AU - Tessers, R.
AU - Anink, J.J.
AU - de Vries, H.E.
AU - Gorter, J.A.
AU - Prades, R.
AU - Aronica, E.
AU - van Vliet, E.A.
N1 - Funding Information: The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 602102 (EPITARGET; to EAVV, JAG, and EA), EpilepsieNL, project number 16-05 (to D.W.M.B. and EAVV) and 20-11 (EAVV), and the European Union Horizon 2020 WIDESPREAD-05-2020-Twinning, EpiEpiNet under grant agreement 952455 (EA, JAG and EAVV). Publisher Copyright: © 2022 by the authors.
PY - 2022/9/1
Y1 - 2022/9/1
N2 - 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.
AB - 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.
KW - astrocytes
KW - blood–brain barrier
KW - brain inflammation
KW - extracellular matrix
KW - matrix metalloproteinases
KW - microglia
KW - pro-inflammatory factors
UR - https://pure.uva.nl/ws/files/94646402/biomedicines_10_02117_s001.zip
UR - http://www.scopus.com/inward/record.url?scp=85138612234&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/biomedicines10092117
DO - https://doi.org/10.3390/biomedicines10092117
M3 - Article
C2 - 36140216
SN - 2227-9059
VL - 10
JO - Biomedicines
JF - Biomedicines
IS - 9
M1 - 2117
ER -