Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1
5-Year Impact Factor – 2.2
Scopus CiteScore – 3.7 (CiteScore Tracker 3.3)
Index Copernicus  – 161.11; MNiSW – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2020, vol. 29, nr 7, July, p. 793–801

doi: 10.17219/acem/121929

Publication type: original article

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

miR-21-5p protects hippocampal neurons of epileptic rats via inhibiting STAT3 expression

Xiaolei Zhang1,A,D,F, Xianfeng Li2,A,C,D,F, Bin Li3,B,F, Chengfeng Sun4,B,F, Peng Zhang5,E,F

1 Department of Neurology, Jining Combine Traditional Chinese and Western Medicine Hospital, China

2 Department of Neurosurgery, Penglai People’s Hospital, Yantai, China

3 Second Department of Neurology, The Second People’s Hospital of Liaocheng, China

4 Department of Traditional Chinese Medicine, Linyi County Hospital of Traditional Chinese Medicine, Dezhou, China

5 Department of Neurology, Gaomi People’s Hospital, Weifang, China


Background. Epilepsy is a common chronic neurological disorder worldwide.
Objectives. To investigate the effects of miR-21-5p and signal transducer and activator of transcription-3 (STAT3) expressions on the apoptosis of hippocampal neurons in epileptic rats.
Material and Methods. We created a rat model of epilepsy and examined the relationship between miR-21-5p and STAT3 using a bioinformatics website and dual the luciferase reporter (DLR) assay. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot were used to detect the expression levels of miR-21-5p and STAT3 in hippocampal neurons as well as the protein expression levels of cleaved caspase-3, Bax and Bcl-2, which were related to apoptosis of hippocampal neuron. The apoptosis and survival of hippocampal neurons were detected using TUNEL and Nissl staining. Expressions of inflammatory factors interleukin (IL)-6 and tumor necrosis factor α (TNF-α) in serum were examined with enzyme-linked immunosorbent assay (ELISA).
Results. miR-21-5p can bind to STAT3. Compared with the miR-21-5p inhibitor negative control (NC) group, the expression levels of caspase-3 and Bax were higher and the expression level of Bcl-2 was lower in the miR-21-5p inhibitor group, whereas the caspase-3 and Bax levels were lower and Bcl-2 level was higher in the si-STAT3 (interfering STAT3 gene expression by transfecting small interfering RNA) group (all p < 0.05). Treatment with miR-21-5p inhibitor can lead to significant loss and apoptosis of hippocampal neurons, while interfering with STAT3 expression can reduce the loss and apoptosis of the neurons (all p < 0.05). Compared with the miR-21-5p inhibitor NC group, the level of IL-6 was lower in the si-STAT3 group and higher in the miR-21-5p inhibitor group (both p < 0.05).
Conclusion. miR-21-5p can inhibit STAT3 expression and reduce apoptosis and loss of hippocampal neurons and IL-6 level, thereby achieving protective effects on hippocampal neurons of epileptic rats.

Key words

epilepsy, STAT3, hippocampal neuron, miR-21-5p, epileptic rats

References (34)

  1. Vezzani A, Fujinami RS, White HS, et al. Infections, inflammation and epilepsy. Acta Neuropathol. 2016;131(2):211–234.
  2. Herzberg JL, Fenwick PB. The aetiology of aggression in temporal-lobe epilepsy. Br J Psychiatry. 1988:153:50–55.
  3. Orsini A, Zara F, Striano P. Recent advances in epilepsy genetics. Neurosci Lett. 2018;667:4–9.
  4. Zack M, Kobau R. Letter re: Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies. Neurology. 2017;89(6):641.
  5. Devinsky O, Hesdorffer DC, Thurman DJ, Lhatoo S, Richerson G. Sudden unexpected death in epilepsy: Epidemiology, mechanisms, and prevention. Neurology. 2016;15(10):1075–1088.
  6. Jacobs J, Staba R, Asano E, et al. High-frequency oscillations (HFOs) in clinical epilepsy. Prog Neurobiol. 2012;98(3):302–315.
  7. O’Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: A review. Epilepsy Behav. 2017;70(Pt B):341–348.
  8. Shioya M, Obayashi S, Tabunoki H, et al. Aberrant microRNA expression in the brains of neurodegenerative diseases: miR-29a decreased in Alzheimer disease brains targets neurone navigator 3. Neuropathol Appl Neurobiol. 2010;36(4):320–330.
  9. Dong RF, Zhang B, Tai LW, Liu HM, Shi FK, Liu NN. The neuroprotective role of miR-124-3p in a 6-hydroxydopamine-induced cell model of Parkinson’s disease via the regulation of ANAX5. J Cell Biochem. 2018;119(1):269–277.
  10. Sun ZZ, Lv ZY, Tian WJ, Yang Y. MicroRNA-132 protects hippocampal neurons against oxygen-glucose deprivation-induced apoptosis. Int J Immunopathol Pharmacol. 2017;30(3):253–263.
  11. Ge X, Huang S, Gao H, et al. miR-21-5p alleviates leakage of injured brain microvascular endothelial barrier in vitro through suppressing inflammation and apoptosis. Brain Res. 2016;1650:31–40.
  12. Yao X, Wang Y, Zhang D. microRNA-21 confers neuroprotection against cerebral ischemia-reperfusion injury and alleviates blood–brain barrier disruption in rats via the MAPK signaling pathway. J Mol Neurosci. 2018;65(1):43–53.
  13. Buller B, Liu X, Wang X, et al. MicroRNA-21 protects neurons from ischemic death. FEBS J. 2010;277(20):4299–4307.
  14. Wan J, Fu AK, Ip FC, et al. Tyk2/STAT3 signaling mediates beta-amyloid-induced neuronal cell death: Implications in Alzheimer’s disease. J Neurosci. 2010;30(20):6873–6881.
  15. Hu GQ, Du X, Li YJ, Gao XQ, Chen BQ, Yu L. Inhibition of cerebral ischemia/reperfusion injury-induced apoptosis: Nicotiflorin and JAK2/STAT3 pathway. Neural Regen Res. 2017;12(1):96–102.
  16. Curia G, Longo D, Biagini G, Jones RS, Avoli M. The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods. 2008;172(2–4):143–157.
  17. Racine RJ. Modification of seizure activity by electrical stimulation. I. After-discharge threshold. Electroencephalogr Clin Neurophysiol. 1972;32(3):269–279.
  18. Aronica E, Fluiter K, Iyer A, et al. Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. Eur J Neurosci. 2010;31(6):1100–1107.
  19. Peng J, Omran A, Ashhab MU, et al. Expression patterns of miR-124, miR-134, miR-132, and miR-21 in an immature rat model and children with mesial temporal lobe epilepsy. J Mol Neurosci. 2013;50(2):291–297.
  20. Zhang H, Wang Y, Lv Q, Gao J, Hu L, He Z. MicroRNA-21 overexpression promotes the neuroprotective efficacy of mesenchymal stem cells for treatment of intracerebral hemorrhage. Front Neurol. 2018;9:931.
  21. Ge X, Han Z, Chen F, et al. MiR-21 alleviates secondary blood–brain barrier damage after traumatic brain injury in rats. Brain Res. 2015;1603:150–157.
  22. Zhang L, Dong LY, Li YJ, Hong Z, Wei WS. miR-21 represses FasL in microglia and protects against microglia-mediated neuronal cell death following hypoxia/ischemia. Glia. 2012;60:1888–1895.
  23. Chen R, Tai Y, Zhang Y, et al. MicroRNA-21 attenuates oxygen and glucose deprivation induced apoptotic death in human neural stem cells with inhibition of JNK and p38 MAPK signaling. Neurosci Lett. 2019;690:11–16.
  24. Wang LC, Liao LX, Zhao MB, Dong X, Zeng KW, Tu PF. Protosappanin A exerts anti-neuroinflammatory effect by inhibiting JAK2-STAT3 pathway in lipopolysaccharide-induced BV2 microglia. Chin J Nat Med. 2017;15(9):674–679.
  25. Mao J, Yang J, Zhang Y, et al. Arsenic trioxide mediates HAPI microglia inflammatory response and subsequent neuron apoptosis through p38/JNK MAPK/STAT3 pathway. Toxicol Appl Pharmacol. 2016;303:79–89.
  26. Ma X, Zhou Y, Chai Y, Wang X, Huang X. STAT3 controls maturation and terminal differentiation in mouse hippocampal neurons. J Mol Neurosci. 2017;61(1):88–95.
  27. Han Z, Chen F, Ge X, Tan J, Lei P, Zhang J. miR-21 alleviated apoptosis of cortical neurons through promoting PTEN-Akt signaling pathway in vitro after experimental traumatic brain injury. Brain Res. 2014;1582:12–20.
  28. Zhou S, Zhang S, Wang Y, et al. MiR-21 and miR-222 inhibit apoptosis of adult dorsal root ganglion neurons by repressing TIMP3 following sciatic nerve injury. Neurosci Lett. 2015;586:43–49.
  29. Shi L, Chen J, Yang J, Pan T, Zhang S, Wang Z. MiR-21 protected human glioblastoma U87MG cells from chemotherapeutic drug temozolomide induced apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 activity. Brain Res. 2010;1352:255–264.
  30. Szobi A, Rajtik T, Carnicka S, Ravingerova T, Adameova A. Mitigation of postischemic cardiac contractile dysfunction by CaMKII inhibition: Effects on programmed necrotic and apoptotic cell death. Mol Cell Biochem. 2014;388(1–2):269–276.
  31. Fan Y, Lu H, An L, et al. Effect of active fraction of Eriocaulon sieboldianum on human leukemia K562 cells via proliferation inhibition, cell cycle arrest and apoptosis induction. Environ Toxicol Pharmacol. 2016;43:13–20.
  32. Lv J, Liang Y, Tu Y, Chen J, Xie Y. Hypoxic preconditioning reduces propofol-induced neuroapoptosis via regulation of Bcl-2 and Bax and downregulation of activated caspase-3 in the hippocampus of neonatal rats. Neurol Res. 2018;40(9):767–773.
  33. Zhang C, Chen Z, Meng X, Li M, Zhang L, Huang A. The involvement and possible mechanism of pro-inflammatory tumor necrosis factor alpha (TNF-alpha) in thoracic ossification of the ligamentum flavum. PLoS One. 2017;12(6):e0178986.
  34. Cosenza S, Ruiz M, Maumus M, Jorgensen C, Noel D. Pathogenic or therapeutic extracellular vesicles in rheumatic diseases: Role of mesenchymal stem cell-derived vesicles. Int J Mol Sci. 2017;18(4):889.