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

Page: [433 - 440] Pages: 8

  • * (Excluding Mailing and Handling)

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.

Keywords: miR-542-3p, TLR4, NF-κB, P-gp, epilepsy, hematoxylin-eosin.

[1]
Thurman DJ, Beghi E, Begley CE, et al. ILAE Commission on Epidemiology. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia 2011; 52(Suppl. 7): 2-26.
[http://dx.doi.org/10.1111/j.1528-1167.2011.03121.x] [PMID: 21899536]
[2]
Eadie MJ. Shortcomings in the current treatment of epilepsy. Expert Rev Neurother 2012; 12(12): 1419-27.
[http://dx.doi.org/10.1586/ern.12.129] [PMID: 23237349]
[3]
Zhu X, Yao Y, Liu Y, et al. Regulation of ADAM10 by microRNA-23a contributes to epileptogenesis in pilocarpine-induced status epilepticus mice. Front Cell Neurosci 2019; 13: 180.
[http://dx.doi.org/10.3389/fncel.2019.00180] [PMID: 31114485]
[4]
Ben-Ari Y. Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 1985; 14(2): 375-403.
[http://dx.doi.org/10.1016/0306-4522(85)90299-4] [PMID: 2859548]
[5]
Henshall DC, Simon RP. Epilepsy and apoptosis pathways. J Cereb Blood Flow Metab 2005; 25(12): 1557-72.
[http://dx.doi.org/10.1038/sj.jcbfm.9600149] [PMID: 15889042]
[6]
Holmes GL, Sarkisian M, Ben-Ari Y, Chevassus-Au-Louis N. Mossy fiber sprouting after recurrent seizures during early development in rats. J Comp Neurol 1999; 404(4): 537-53.
[http://dx.doi.org/10.1002/(SICI)1096-9861(19990222)404:4<537:AID-CNE9>3.0.CO;2-#] [PMID: 9987996]
[7]
French JA. Refractory epilepsy: Clinical overview. Epilepsia 2007; 48(Suppl. 1): 3-7.
[http://dx.doi.org/10.1111/j.1528-1167.2007.00992.x] [PMID: 17316406]
[8]
Löscher W, Schmidt D. Modern antiepileptic drug development has failed to deliver: Ways out of the current dilemma. Epilepsia 2011; 52(4): 657-78.
[http://dx.doi.org/10.1111/j.1528-1167.2011.03024.x] [PMID: 21426333]
[9]
Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology 2012; 78(20): 1548-54.
[http://dx.doi.org/10.1212/WNL.0b013e3182563b19] [PMID: 22573629]
[10]
Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004; 116(2): 281-97.
[http://dx.doi.org/10.1016/S0092-8674(04)00045-5] [PMID: 14744438]
[11]
Bonazzi VF, Stark MS, Hayward NK. MicroRNA regulation of melanoma progression. Melanoma Res 2012; 22(2): 101-13.
[http://dx.doi.org/10.1097/CMR.0b013e32834f6fbb] [PMID: 22209751]
[12]
Maes OC, Chertkow HM, Wang E, Schipper HM. MicroRNA: Implications for alzheimer disease and other human CNS disorders. Curr Genomics 2009; 10(3): 154-68.
[http://dx.doi.org/10.2174/138920209788185252] [PMID: 19881909]
[13]
Feng J, Sun G, Yan J, et al. Evidence for X-chromosomal schizophrenia associated with microRNA alterations. PLoS One 2009; 4(7)e6121
[http://dx.doi.org/10.1371/journal.pone.0006121] [PMID: 19568434]
[14]
Hommers LG, Domschke K, Deckert J. Heterogeneity and individuality: microRNAs in mental disorders. J Neural Transm (Vienna) 2015; 122(1): 79-97.
[http://dx.doi.org/10.1007/s00702-014-1338-4] [PMID: 25395183]
[15]
Hu K, Zhang C, Long L, et al. Expression profile of microRNAs in rat hippocampus following lithium-pilocarpine-induced status epilepticus. Neurosci Lett 2011; 488(3): 252-7.
[http://dx.doi.org/10.1016/j.neulet.2010.11.040] [PMID: 21094214]
[16]
Pichardo-Casas I, Goff LA, Swerdel MR, et al. Expression profiling of synaptic microRNAs from the adult rat brain identifies regional differences and seizure-induced dynamic modulation. Brain Res 2012; 1436: 20-33.
[http://dx.doi.org/10.1016/j.brainres.2011.12.001] [PMID: 22197703]
[17]
McKiernan RC, Jimenez-Mateos EM, Sano T, et al. Expression profiling the microRNA response to epileptic preconditioning identifies miR-184 as a modulator of seizure-induced neuronal death. Exp Neurol 2012; 237(2): 346-54.
[http://dx.doi.org/10.1016/j.expneurol.2012.06.029] [PMID: 22771761]
[18]
Hu K, Xie YY, Zhang C, et al. MicroRNA expression profile of the hippocampus in a rat model of temporal lobe epilepsy and miR-34a-targeted neuroprotection against hippocampal neurone cell apoptosis post-status epilepticus. BMC Neurosci 2012; 13: 115.
[http://dx.doi.org/10.1186/1471-2202-13-115] [PMID: 22998082]
[19]
Gast A, Bermejo JL, Claus R, et al. Association of inherited variation in Toll-like receptor genes with malignant melanoma susceptibility and survival. PLoS One 2011; 6(9) e24370
[http://dx.doi.org/10.1371/journal.pone.0024370] [PMID: 21931695]
[20]
Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 2009; 1(4) a000034
[http://dx.doi.org/10.1101/cshperspect.a000034] [PMID: 20066092]
[21]
Oberg F, Haseeb A, Ahnfelt M, Pontén F, Westermark B, El-Obeid A. Herbal melanin activates TLR4/NF-kappaB signaling pathway. Phytomedicine 2009; 16(5): 477-84.
[http://dx.doi.org/10.1016/j.phymed.2008.10.008] [PMID: 19103478]
[22]
Shi Y, Zhang L, Teng J, Miao W. HMGB1 mediates microglia activation via the TLR4/NF-κB pathway in coriaria lactone induced epilepsy. Mol Med Rep 2018; 17(4): 5125-31.
[http://dx.doi.org/10.3892/mmr.2018.8485] [PMID: 29393419]
[23]
Liu AH, Wu YT, Wang YP. MicroRNA-129-5p inhibits the development of autoimmune encephalomyelitis-related epilepsy by targeting HMGB1 through the TLR4/NF-kB signaling pathway. Brain Res Bull 2017; 132: 139-49.
[http://dx.doi.org/10.1016/j.brainresbull.2017.05.004] [PMID: 28528202]
[24]
Ogretmen B, Safa AR. Negative regulation of MDR1 promoter activity in MCF-7, but not in multidrug resistant MCF-7/Adr, cells by cross-coupled NF-kappa B/p65 and c-Fos transcription factors and their interaction with the CAAT region. Biochemistry 1999; 38(7): 2189-99.
[http://dx.doi.org/10.1021/bi982236+] [PMID: 10026303]
[25]
Bentires-Alj M, Barbu V, Fillet M, et al. NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 2003; 22(1): 90-7.
[http://dx.doi.org/10.1038/sj.onc.1206056] [PMID: 12527911]
[26]
Brandt C, Bethmann K, Gastens AM, Löscher W. The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis 2006; 24(1): 202-11.
[http://dx.doi.org/10.1016/j.nbd.2006.06.014] [PMID: 16928449]
[27]
Riganti C, Salaroglio IC, Pinzòn-Daza ML, et al. Temozolomide down-regulates P-glycoprotein in human blood-brain barrier cells by disrupting Wnt3 signaling. Cell Mol Life Sci 2014; 71(3): 499-516.
[http://dx.doi.org/10.1007/s00018-013-1397-y] [PMID: 23771630]
[28]
Vinciguerra A, Formisano L, Cerullo P, et al. MicroRNA-103-1 selectively downregulates brain NCX1 and its inhibition by anti-miRNA ameliorates stroke damage and neurological deficits. Mol Ther 2014; 22(10): 1829-38.
[http://dx.doi.org/10.1038/mt.2014.113]
[29]
Gao X, Guo M, Meng D, et al. Silencing microRNA-134 alleviates hippocampal damage and occurrence of spontaneous seizures after intraventricular kainic acid-induced status epilepticus in rats. Front Cell Neurosci 2019; 13: 145.
[http://dx.doi.org/10.3389/fncel.2019.00145] [PMID: 31031600]
[30]
Zheng P, Bin H, Chen W. Inhibition of microRNA-103a inhibits the activation of astrocytes in hippocampus tissues and improves the pathological injury of neurons of epilepsy rats by regulating BDNF. Cancer Cell Int 2019; 19: 109.
[http://dx.doi.org/10.1186/s12935-019-0821-2] [PMID: 31049031]
[31]
Wang L, Song LF, Chen XY, et al. MiR-181b inhibits P38/JNK signaling pathway to attenuate autophagy and apoptosis in juvenile rats with kainic acid-induced epilepsy via targeting TLR4. CNS Neurosci Ther 2019; 25(1): 112-22.
[http://dx.doi.org/10.1111/cns.12991] [PMID: 29808547]
[32]
Terrone G, Balosso S, Pauletti A, Ravizza T, Vezzani A. Inflammation and reactive oxygen species as disease modifiers in epilepsy. Neuropharmacology 2019; 14 107742https://www.scien-cedirect.com/science/article/abs/pii/S0028390819303016
[33]
Hui Y, Yin Y. MicroRNA-145 attenuates high glucose-induced oxidative stress and inflammation in retinal endothelial cells through regulating TLR4/NF-kappaB signaling. Life Sci 2018; 207: 212-8.https://www.ncbi.nlm.nih.gov/pubmed/29883722
[PMID: 29883722]
[34]
Yang L, Gao C. MiR-590 inhibits endothelial cell apoptosis by inactivating the TLR4/NF-kappaB pathway in atherosclerosis. Yonsei Med J 2019; 60(3): 298-307.https://www.ncbi.nlm.nih.gov/pubmed/30799593
[PMID: 30799593]
[35]
Deng X, Shao Y, Xie Y, et al. MicroRNA-146a-5p downregulates the expression of P-glycoprotein in rats with lithium-pilocarpine-induced status epilepticus. Biol Pharm Bull 2019; 42(5): 744-50.https://www.ncbi.nlm.nih.gov/pubmed/31061316
[PMID: 31061316]
[36]
Xie Y, Shao Y, Deng X, et al. MicroRNA-298 reverses multidrug resistance to antiepileptic drugs by suppressing MDR1/P-gp expression in vitro. Front Neurosci 2018; 12: 602.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121027/]
[PMID: 30210283]