Roles of Matrix Metalloproteinases and Their Targets in Epileptogenesis and Seizures

Abstract

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors, which together regulate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathological conditions. Recent studies have suggested that prolonged seizures are associated with high MMP levels in serum and neural tissues, and certain extracellular macromolecule targets may influence the pathogenesis of epilepsy and seizure. In this review, we discuss the roles of MMP activation in animal models of epilepsy.KEY WORDS: Matrix metalloproteinase; Tissue inhibitor of metalloproteinase; Epilepsy; Seizure; Nerve growth factors.

Microglia are less pro‐inflammatory than myeloid infiltrates in the hippocampus of mice exposed to status epilepticus

“…We showed that myeloid infiltrates express high levels of MMP-9 and 12, whereas microglia express only MMP-12. MMP-9 has been already described to play a major role in the BBB leakage as well as in synaptic remodelling during epileptogenesis (Mizoguchi et al, 2011;Mizoguchi and Yamada, 2013). Our data suggests that both cell types might be implicated in the BBB leakage observed early after SE, facilitating leukocytes infiltration in the brain parenchyma and introduces MMP-12 as a new molecular target for therapy.…”

“…This increased immunoreactivity was colocalized with vascular and astrocytic injuries and was interpreted as a consequence of extracellular matrix remodelling by MMPs (Lucchi et al, 2015). MMP-9 has been already described to play a major role in the BBB leakage as well as in synaptic remodelling during epileptogenesis (Mizoguchi et al, 2011;Mizoguchi and Yamada, 2013). MMP-9 has been already described to play a major role in the BBB leakage as well as in synaptic remodelling during epileptogenesis (Mizoguchi et al, 2011;Mizoguchi and Yamada, 2013).…”

“…Myeloid Infiltrates Express High Levels of Matrix Metalloproteinases (MMP)29 and 12 in the Early Phase of Epileptogenesis Recent studies have demonstrated a possible role for MMPs, especially MMP-9 in the development of seizures (Mizoguchi and Yamada, 2013;Mizoguchi et al, 2011;Suenaga et al, 2008). Moreover, increased laminin immunoreactivity was observed in the early phase of epileptogenesis (Gualtieri et al, 2012;Lucchi et al, 2015), suggesting that laminin degradation might be a key step in the blood brain barrier (BBB) leakage that occurs after SE.…”

Alterations in the α2δ ligand, thrombospondin‐1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies

“…In the developing CNS, astrocyte-secreted thrombospondin-1 promotes synaptogenesis, neuronal migration, and axonal growth. 31,32 Of interest, matrix metalloproteinases (MMPs), which cleave extracellular matrix (EM) proteins and regulate synaptogenesis, have an active role in epileptogenesis in different experimental animal models, 33 and the EM protein, SC1, translocates from neuronal cell bodies to excitatory nerve terminals following status epilepticus in the rat lithium-pilocarpine model. Several lines of evidence suggest that an abnormal synaptogenesis contributes to epileptogenesis, that is, to the process by which the brain develops epilepsy.…”

“…30 Other proteins that regulate synaptogenesis, such as synapsin II and synaptophysin, have been also implicated in the pathophysiology of epilepsy. 31,32 Of interest, matrix metalloproteinases (MMPs), which cleave extracellular matrix (EM) proteins and regulate synaptogenesis, have an active role in epileptogenesis in different experimental animal models, 33 and the EM protein, SC1, translocates from neuronal cell bodies to excitatory nerve terminals following status epilepticus in the rat lithium-pilocarpine model. 34 Recent evidence suggests that thrombospondin-1, by promoting the formation of new excitatory synapses, contributes to the development of a hyperexcitable neuronal network, which is a critical event in epilepsy.…”