MiRNA-let-7i modulates status epilepticus via the TLR4 pathway

Abstract

BackgroundStatus epilepticus (SE) is a neurological emergency associated with high mortality and morbidity. Many SE episodes cannot be quickly and effectively terminated with current medications. miRNA-Let-7i, a member of the miRNA-Let-7 family, has been found to be associated with a variety of brain pathophysiological and neurological diseases. However, its role in SE remains elusive and requires further clarification.MethodsThe expression of miRNA-Let-7i was detected in temporal lobe epilepsy (TLE) patients and SE model rats using the real-time quantitative polymerase chain reaction (RT-qPCR) method. Behavioral assays were performed in pilocarpine-induced SE model, and a whole-cell current clamp technique was employed to examine neuronal excitability. Neuronal apoptosis was evaluated by Nissl staining and terminal deoxynucleotidyl transferase-mediated dUTP end-labeling (TUNEL) assays.ResultsThe expression of miRNA-Let-7i was significantly reduced in the cortex and hippocampus of SE rats. The miRNA-Let-7i agomir and antagomir effectively regulated the levels of miRNA-Let-7i. In particular, the agomir significantly reduced the degree of SE and prolonged the latent period of SE, whereas the antagomir increased the degree of seizures and shortened the latent period. In addition, the agomir significantly decreased the frequency of action potentials, while the antagomir significantly increased it. Nissl staining and TUNEL assays demonstrated that the agomir increased the survival and decreased the apoptosis, while the antagomir had the opposite effects. In addition, a Toll-like receptor 4 (TLR4) inhibitor rescued the effects of antagomir on SE behavior and expression of IL-6 and TNF-α. Similar results on miRNA-Let-7i expression and effects of TLR4 inhibition were found in brain tissues of TLE patients.ConclusionsThe miRNA-Let-7i − TLR4 regulatory pathway is involved in SE, which provides insights into the pathogenesis of SE.