The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects

Abstract

Matrix metalloproteinases (MMPs) are synthesized by neurons and glia and released into the extracellular space, where they act as modulators of neuroplasticity and neuroinflammatory agents. Development of epilepsy (epileptogenesis) is associated with increased expression of MMPs and therefore they may represent potential therapeutic drug targets. Using qPCR and immunohistochemistry, we studied the expression of MMPs and their endogenous inhibitors TIMPs, in patients with status epilepticus (SE) or temporal lobe epilepsy (TLE), and in a rat TLE model. Furthermore, we tested the MMP2/9 inhibitor IPR-179 in the rapid kindling rat model and in the intrahippocampal kainic-acid mouse model. In both human and experimental epilepsy, MMP and TIMP expression was persistently dysregulated in the hippocampus compared to controls. IPR-179 treatment reduced seizure severity in the rapid kindling model and reduced the number of spontaneous seizures in the kainic-acid model (during and up to 7 weeks after delivery) without side effects while improving cognitive behavior. Moreover, our data suggest that IPR-179 prevented an MMP2/9-dependent switch-off normally restraining network excitability during the activity period. Since increased MMP expression is a prominent hallmark of the human epileptogenic brain and the MMP inhibitor IPR-179 has antiseizure and antiepileptogenic effects in rodent epilepsy models and attenuates seizure-induced cognitive decline, it deserves further investigation in clinical trials. Funding: The research leading to these results has received funding from the European Union's

Neurovascular unit dysfunction as a mechanism of seizures and epilepsy during aging

“…Higher matrix metalloproteinase (MMP) expression and activity are associated with BBB permeability 92 via degradation of the basal lamina and tight junction proteins and promote the infiltration of neutrophils into the brain parenchyma, 93 which can contribute to epileptogenesis. This is corroborated by studies performed in MMP knockout mice in which BBB dysfunction, brain inflammation, and epileptogenesis could be attenuated or decreased after an initial insult 94,95 …”

“…This is corroborated by studies performed in MMP knockout mice in which BBB dysfunction, brain inflammation, and epileptogenesis could be attenuated or decreased after an initial insult. 94,95 Pericytes are a cellular entry point and offer an opportunity to study new BBB restorative pharmacological strategies in central nervous system (CNS) diseases. 34,96,97 In general, the perivascular deconstruction, redistribution, and reactivity of pericytes, in coordination with glial cells, negatively impacts BBB permeability and contributes to brain inflammation.…”

“…Boosting the endogenous anti-inflammatory mechanisms represents an emerging approach, using peripheral T-regulatory cells 156 or Annexin-A1. [157][158][159] Other therapeutic approaches are PDGF/TGF targeting (using PDGF-BB, 100 Imatinib, 44 IPW, 6 or losartan, 112,[160][161][162][163][164][165] antioxidant treatment vitexin 166 or carveol 167 ), or matrix metalloproteinase inhibition 95,168 that were shown to reduce BBB permeability and brain inflammation, ictogenesis, or epileptogenesis. 169 However, the efficacy of these molecules in curbing age-related pathological changes or aggravations remains to be investigated.…”

Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk

“…During epileptogenesis, the perineuronal net (PNN), a condensed ECM structure that envelops fast-spiking interneurons and that is responsible for synaptic plasticity and excitation-inhibition stabilization, has shown evidence of degradation by endogenous proteases, resulting in impaired GABAergic inhibition ( Tewari et al, 2018 ). Matrix metalloproteinase-9 (MMP-9) is one such PNN protease, which has exhibited increased mRNA and protein levels after seizure in both animal models and patients, including generalized tonic–clonic events, ( Cudna et al, 2017 ) with inhibitors viewed as potential therapeutic drug targets ( Broekaart et al, 2021 ).…”

Pathological Targets for Treating Temporal Lobe Epilepsy: Discoveries From Microscale to Macroscale

“…In addition, the inhibitor of MMPs has been reported to have antiseizure and antiepileptogenic effects (135,136). A BBB-permeable MMP inhibitor IPR-179 was used on two TLE rodent models: a rapid-kindling rat model and KA mouse model (132,137,138). This inhibitor has a high affinity for MMP9 and low affinity for MMP2 (139).…”