MicroRNA-542-3p Regulates P-glycoprotein Expression in Rat Epilepsy via the Toll-like Receptor 4/Nuclear Factor-kappaB Signaling Pathway

Abstract

Background: The function of microRNA-542-3p (miR-542-3p) in rat epilepsy is still unclear. Methods: The levels of miR-542-3p and toll-like receptor 4 (TLR4) were determined through quantitative real-time PCR. The protein levels were examined via the western blot analysis. The relationship between miR-542-3p and TLR4 was confirmed through luciferase assay. Pathological changes were analyzed via Hematoxylin-eosin (HE) and Nissl staining. Results: The rats and hippocampal cells were treated with kainic acid (KA) in vivo and in vitro. miR-542-3p was low in KA-treated rats, hippocampal cells and cerebrospinal fluid of patients with epilepsy. Further functional analysis showed that miR-542-3p overexpression inhibited KAinduced average seizure frequency, damage of hippocampal neuron and cell apoptosis, leading to the alleviation of the brain injury in epilepsy rats. miR-542-3p was determined to downregulate TLR4 expression. The relationship between miR-542-3p and TLR4 was confirmed. TLR4 knockdown reduced KA-induced nuclear factor-kappa B p65 (NF-κB p65), multidrug resistance 1 (MDR1), P-glycoprotein (P-gp) and apoptosis-associated protein levels. Further, for NF-κB p65, MDR1, P-gp and apoptosis-associated protein levels detection, miR-542-3p mimic showed a suppressive effect on these KA-induced protein levels, whereas TLR4 overexpression ameliorated the miR-542-3p-induced these protein levels in KA-treated epilepsy rats. Conclusion: We identified that miR-542-3p attenuated seizure-induced brain injury and the expression of P-gp in epilepsy rats through inhibiting TLR4/NF-κB signaling pathway, which might contribute to improved epilepsy therapy.

Role of HMGB1/TLR4 and IL-1β/IL-1R1 Signaling Pathways in Epilepsy

“…In addition, micro-RNA plays a role in HMGB1-mediated epilepsy. Both miR-129-5p and miR-542-3p inhibit the development of epilepsy by suppressing HMGB1 expression and inhibiting the TLR4/NF-kB signaling pathway ( 38 , 39 ). TLR4 agonists, LPS and MPL, can attenuate seizure severity in pilocarpine-induced rats with temporal lobe epilepsy ( 40 ), and pentoxifylline may represent a promising drug to inhibit epilepsy progression by targeting the HMGB1/TLR4/RAGE signaling pathway in pentylenetetrazol (PTZ)-kindling rats ( 41 ).…”

Transporter Regulation in Critical Protective Barriers: Focus on Brain and Placenta

“…Indeed, in TLR-4-deficient drug-resistant epileptic rats, the levels of the cytokines and NF-κB were significantly reduced, and this was accompanied by a reduction in P-gp abundance and expression in the hippocampus and amygdala [ 114 ]. A link between TLR-4, NF-κB, and P-gp expression was also observed, determining the function of miR-542-3p in a rat epilepsy model, where this particular miRNA was shown to modify TLR-4 expression [ 115 ]. In addition to the cytokines, seizure-induced tissue damage has been linked to enhanced release of HMGB1, which is assumed to play a role in inflammation and BBB disruption [ 116 , 117 ].…”

Serum Extracellular Vesicle–Derived miR-124-3p as a Diagnostic and Predictive Marker for Early-Stage Acute Ischemic Stroke

“…Reportedly, the microRNA expression profile is altered in AIS blood samples, suggesting that miRNAs are involved in the progress of AIS ( Wu et al, 2012 ; Bhalala et al, 2013 ). Furthermore, several miRNAs have been identified as novel therapeutic targets for AIS ( He et al, 2019 ; Yan et al, 2019 ). However, none of these have been applied in clinical practice ( Harpaz et al, 2017 ).…”