Matrix Metalloproteinase 9 in Epilepsy: The Role of Neuroinflammation in Seizure Development

Abstract

Matrix metalloproteinase 9 is a proteolytic enzyme which is recently one of the more often studied biomarkers. Its possible use as a biomarker of neuronal damage in stroke, heart diseases, tumors, multiple sclerosis, and epilepsy is being widely indicated. In epilepsy, MMP-9 is suggested to play a role in epileptic focus formation and in the stimulation of seizures. The increase of MMP-9 activity in the epileptic focus was observed both in animal models and in clinical studies. MMP-9 contributes to formation of epileptic focus, for example, by remodeling of synapses. Its proteolytic action on the elements of blood-brain barrier and activation of chemotactic processes facilitates accumulation of inflammatory cells and induces seizures. Also modification of glutamatergic transmission by MMP-9 is associated with seizures. In this review we will try to recapitulate the results of previous studies about MMP-9 in terms of its association with epilepsy. We will discuss the mechanisms of its actions and present the results revealed in animal models and clinical studies. We will also provide a comparison of the results of various studies on MMP-9 levels in the context of its possible use as a biomarker of the activity of epilepsy.

Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

“…This would allow patient stratification to test the candidate anti-inflammatory drugs and for designing affordable and adequately powered antiepileptogenesis trials, and to monitor treatment response. In this context, much progress has been made and several noninvasive inflammation-related humoral 44,[146][147][148][149] (blood/cerebrospinal fluid) and imaging measures [150][151][152][153][154][155][156][157] have been identified ( Table 2). Such biomarkers could be used to increase the sensitivity and precision of the available clinical indicators.…”

Metaloproteinaza macierzy pozakomórkowej 9 i epileptogeneza – kluczowa rola enzymu i strategie zmierzające do zapobiegania rozwojowi choroby

“…The objective of this review is to detail various ways, by which MMP-9 is contributing to epileptogenesis, and arrive at holistic view of MMP-9 role in the processes as epilepsy advances, what will help us to construe how potential modifications of its activity may be either beneficial or detrimental for epileptogenic brain. The scientific potential of the issue is confirmed by the fact that this topic has already been covered in comprehensive reviews [8][9][10].…”

“…Restricted and time-dependent activity of MMP-9 is a result of tight regulation of its expression and activity, which occurs together with co-released MMP-9 endogenous inhibitor TIMP-1 [24]. Notably, the misbalance between MMP-9 and TIMP is associated with numerous CNS diseases [2,8,11]. The possible mechanism involved may be excessive or reduced proteolysis depending on quantity of MMP-9 available at the synapse, or depletion of free TIMP molecules, resulting in reduced TIMP functionality.…”

“…It can impact the development of epilepsy directly (via influx of potassium) or as a result of glial activation, impaired potassium buffering, inflammation, and synaptogenesis triggered by serum proteins which penetrate the brain via leaky BBB [45]. Studies in animal models suggest, that BBB leakage can be detected within minutes after SE induction, be extensive during the latent period and not abate completely until the chronic epileptic phase is reached [8].…”

Biomarkers of Epileptogenesis: The Focus on Glia and Cognitive Dysfunctions

“…Finally, matrix methalloproteinases may be an interesting marker of astrocytic activation measurable in blood [101,102] which should be investigated more in-depth.…”