Abstract
BackgroundTemporal lobe epilepsy (TLE) is a chronic neurological disease, in which about 30% of patients cannot be treated adequately with anti-epileptic drugs. Brain inflammation and remodeling of the extracellular matrix (ECM) seem to play a major role in TLE. Matrix metalloproteinases (MMPs) are proteolytic enzymes largely responsible for the remodeling of the ECM. The inhibition of MMPs has been suggested as a novel therapy for epilepsy; however, available MMP inhibitors lack specificity and cause serious side effects. We studied whether MMPs could be modulated via microRNAs (miRNAs). Several miRNAs mediate inflammatory responses in the brain, which are known to control MMP expression. The aim of this study was to investigate whether an increased expression of MMPs after interleukin-1β (IL-1β) stimulation can be attenuated by inhibition of the inflammation-associated miR-155.MethodsWe investigated the expression of MMP2, MMP3, MMP9, and MMP14 in cultured human fetal astrocytes after stimulation with the pro-inflammatory cytokine IL-1β. The cells were transfected with miR-155 antagomiR, and the effect on MMP3 expression was investigated using real-time quantitative PCR and Western blotting. Furthermore, we characterized MMP3 and miR-155 expression in brain tissue of TLE patients with hippocampal sclerosis (TLE-HS) and during epileptogenesis in a rat TLE model.ResultsInhibition of miR-155 by the antagomiR attenuated MMP3 overexpression after IL-1β stimulation in astrocytes. Increased expression of MMP3 and miR-155 was also evident in the hippocampus of TLE-HS patients and throughout epileptogenesis in the rat TLE model.ConclusionsOur experiments showed that MMP3 is dynamically regulated by seizures as shown by increased expression in TLE tissue and during different phases of epileptogenesis in the rat TLE model. MMP3 can be induced by the pro-inflammatory cytokine IL-1β and is regulated by miR-155, suggesting a possible strategy to prevent epilepsy via reduction of inflammation.
Highlights
Temporal lobe epilepsy (TLE) is a chronic neurological disease, in which about 30% of patients cannot be treated adequately with anti-epileptic drugs
RT-qPCR analysis demonstrated that gene expression of MMP3 and MMP9 was increased following IL-1β stimulation (p < 0.001, Fig. 1a), and the induction was especially prominent for MMP3
Modulation of MMP3 expression in human fetal astrocytes by miRNA-155 after IL-1β stimulation Since MMP3 gene and protein expression was increased in human fetal astrocytes after IL-1β stimulation, we investigated whether MMP3 expression could be modulated
Summary
Temporal lobe epilepsy (TLE) is a chronic neurological disease, in which about 30% of patients cannot be treated adequately with anti-epileptic drugs. Brain inflammation and remodeling of the extracellular matrix (ECM) seem to play a major role in TLE. Epilepsy is a common neurological disease characterized by spontaneous recurrent seizures, affecting more than 50 million people worldwide. It is defined by any of the following conditions: (1) at least two unprovoked (or reflex) seizures occurring > 24 h apart. In the electrical post-status epilepticus (SE) rat TLE model, a large-scale transcriptome study revealed that the expression of MMP2, MMP3, MMP9 and MMP14 in the brain was increased and dynamically regulated at different stages of epileptogenesis [26].
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