Journal of Molecular Neuroscience

, Volume 65, Issue 2, pp 234–245 | Cite as

Down-regulation of Long Noncoding RNA MALAT1 Protects Hippocampal Neurons Against Excessive Autophagy and Apoptosis via the PI3K/Akt Signaling Pathway in Rats with Epilepsy

  • Qiang Wu
  • Xuewei Yi


Epilepsy is a common chronic brain disorder and is characterized by an enduring predisposition to generate seizures. The hippocampus is especially vulnerable to seizure-induced damage. In this study, we explore the ability of long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) to influence the autophagy and apoptosis of hippocampal neurons in epilepsy and the underlying mechanism involving the PI3K/Akt signaling pathway. Seventy-two Sprague-Dawley rats were assigned to normal, sham, Ep, Ep + si-NC, Ep + si-MALAT1, and Ep + si-MALAT1 + LY groups. Fluorescence in situ hybridization kit was employed to determine the MALAT1 in the brain tissues. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed to determine the expression of MALAT1, mRNAs, and proteins. The autophagy of hippocampal neurons was evaluated under a transmission electron microscope and their apoptosis was evaluated using TUNEL staining. We found that MALAT1 and c-Met were enriched while microRNA-101 (miR-101) decreased in rats with epilepsy. The demonstration showed that MALAT1 binds to miR-101, thus regulating c-Met. In rats with epilepsy, MALAT1 depletion mediated by anti-MALAT1 siRNA resulted in activation of PI3K/Akt signaling pathway and loss of hippocampal neurons. LY294002, an inhibitor of PI3K/Akt signaling pathway, could reverse the events caused by MALAT1 knockdown. Taken together, these findings indicate that down-regulation of MALAT1 activates the PI3K/Akt signaling pathway to protect hippocampal neurons against autophagy and apoptosis in rats with epilepsy.


Long noncoding RNA MALAT1 PI3K/Akt signaling pathway Epilepsy Hippocampal neuron 



We would like to acknowledge the helpful comments received from reviewers.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.


  1. Beghi E, Berg A, Carpio A, Forsgren L, Hesdorffer DC, Hauser WA, Malmgren K, Shinnar S, Temkin N, Thurman D, Tomson T (2005) Comment on epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46(10):1698–1699; author reply 1701-1692. CrossRefPubMedGoogle Scholar
  2. Bernard D, Prasanth KV, Tripathi V, Colasse S, Nakamura T, Xuan Z, Zhang MQ, Sedel F, Jourdren L, Coulpier F, Triller A, Spector DL, Bessis A (2010) A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J 29(18):3082–3093. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Dong Y, Liang G, Yuan B, Yang C, Gao R, Zhou X (2015) MALAT1 promotes the proliferation and metastasis of osteosarcoma cells by activating the PI3K/Akt pathway. Tumour Biol :J Int Soc Oncodev Biol Med 36(3):1477–1486. CrossRefGoogle Scholar
  4. Du G, Zhao Z, Chen Y, Li Z, Tian Y, Liu Z, Liu B, Song J (2016) Quercetin attenuates neuronal autophagy and apoptosis in rat traumatic brain injury model via activation of PI3K/Akt signaling pathway. Neurol Res 38:1–8. CrossRefGoogle Scholar
  5. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshe SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S (2014) ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55(4):475–482. CrossRefPubMedGoogle Scholar
  6. Gao Y, Li J, Wu L, Zhou C, Wang Q, Li X, Zhou M, Wang H (2016) Tetrahydrocurcumin provides neuroprotection in rats after traumatic brain injury: autophagy and the PI3K/AKT pathways as a potential mechanism. J Surg Res 206(1):67–76. CrossRefPubMedGoogle Scholar
  7. Gu MY, Kim J, Yang HO (2016) The neuroprotective effects of justicidin A on amyloid beta25-35-induced neuronal cell death through inhibition of tau hyperphosphorylation and induction of autophagy in SH-SY5Y cells. Neurochem Res 41(6):1458–1467. CrossRefPubMedGoogle Scholar
  8. Gutschner T, Diederichs S (2012) The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol 9(6):703–719. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, Revenko A, Arun G, Stentrup M, Gross M, Zornig M, MacLeod AR, Spector DL, Diederichs S (2013) The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res 73(3):1180–1189. CrossRefPubMedGoogle Scholar
  10. Hirata H, Hinoda Y, Shahryari V, Deng G, Nakajima K, Tabatabai ZL, Ishii N, Dahiya R (2015) Long noncoding RNA MALAT1 promotes aggressive renal cell carcinoma through Ezh2 and interacts with miR-205. Cancer Res 75(7):1322–1331. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Hu Z, Lin Y, Chen H, Mao Y, Wu J, Zhu Y, Xu X, Xu X, Li S, Zheng X, Xie L (2013) MicroRNA-101 suppresses motility of bladder cancer cells by targeting c-Met. Biochem Biophys Res Commun 435(1):82–87. CrossRefPubMedGoogle Scholar
  12. Jung KA, Choi BH, Kwak MK (2015) The c-MET/PI3K signaling is associated with cancer resistance to doxorubicin and photodynamic therapy by elevating BCRP/ABCG2 expression. Mol Pharmacol 87(3):465–476. CrossRefPubMedGoogle Scholar
  13. Klitgaard H, Matagne A, Nicolas JM, Gillard M, Lamberty Y, De Ryck M, Kaminski RM, Leclercq K, Niespodziany I, Wolff C, Wood M, Hannestad J, Kervyn S, Kenda B (2016) Brivaracetam: rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment. Epilepsia 57(4):538–548. CrossRefPubMedGoogle Scholar
  14. Kraus TFJ, Haider M, Spanner J, Steinmaurer M, Dietinger V, Kretzschmar HA (2017) Altered long noncoding RNA expression precedes the course of Parkinson’s disease—a preliminary report. Mol Neurobiol 54(4):2869–2877. CrossRefPubMedGoogle Scholar
  15. Kryger R, Fan L, Wilce PA, Jaquet V (2012) MALAT-1, a non protein-coding RNA is upregulated in the cerebellum, hippocampus and brain stem of human alcoholics. Alcohol 46(7):629–634. CrossRefPubMedGoogle Scholar
  16. Li Z, Li J, Tang N (2017a) Long noncoding RNA Malat1 is a potent autophagy inducer protecting brain microvascular endothelial cells against oxygen-glucose deprivation/reoxygenation-induced injury by sponging miR-26b and upregulating ULK2 expression. Neuroscience 354:1–10. CrossRefPubMedGoogle Scholar
  17. Li Z, Xu C, Ding B, Gao M, Wei X, Ji N (2017b) Long non-coding RNA MALAT1 promotes proliferation and suppresses apoptosis of glioma cells through derepressing Rap1B by sponging miR-101. J Neuro-Oncol 134(1):19–28. CrossRefGoogle Scholar
  18. Liang J, Xu L, Zhou F, Liu AM, Ge HX, Chen YY, Tu M (2017) MALAT1/miR-127-5p regulates osteopontin (OPN)-mediated proliferation of human chondrocytes through PI3K/Akt pathway. J Cell Biochem 119:431–439. CrossRefPubMedGoogle Scholar
  19. Liu W, Zhang Q, Zhang J, Pan W, Zhao J, Xu Y (2017) Long non-coding RNA MALAT1 contributes to cell apoptosis by sponging miR-124 in Parkinson disease. Cell Biosci 7:19. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Luo Q, Chen Y (2016) Long noncoding RNAs and Alzheimer’s disease. Clin Interv Aging 11:867–872. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Maycotte P, Jones KL, Goodall ML, Thorburn J, Thorburn A (2015) Autophagy supports breast cancer stem cell maintenance by regulating IL6 secretion. Mol Cancer Res: MCR 13(4):651–658. CrossRefPubMedGoogle Scholar
  22. Moshe SL, Perucca E, Ryvlin P, Tomson T (2015) Epilepsy: new advances. Lancet 385(9971):884–898. CrossRefPubMedGoogle Scholar
  23. Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR (2010) Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia 51(5):883–890. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32(3):281–294CrossRefPubMedGoogle Scholar
  25. Shen L, Chen L, Wang Y, Jiang X, Xia H, Zhuang Z (2015) Long noncoding RNA MALAT1 promotes brain metastasis by inducing epithelial-mesenchymal transition in lung cancer. J Neuro-Oncol 121(1):101–108. CrossRefGoogle Scholar
  26. Shi R, Weng J, Zhao L, Li XM, Gao TM, Kong J (2012) Excessive autophagy contributes to neuron death in cerebral ischemia. CNS Neurosci Ther 18(3):250–260. CrossRefPubMedGoogle Scholar
  27. Singh SS, Yap WN, Arfuso F, Kar S, Wang C, Cai W, Dharmarajan AM, Sethi G, Kumar AP (2015) Targeting the PI3K/Akt signaling pathway in gastric carcinoma: a reality for personalized medicine? World J Gastroenterol 21(43):12261–12273. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Vezzani A, Fujinami RS, White HS, Preux PM, Blumcke I, Sander JW, Loscher W (2016) Infections, inflammation and epilepsy. Acta Neuropathol 131(2):211–234. CrossRefPubMedGoogle Scholar
  29. Vilardo E, Barbato C, Ciotti M, Cogoni C, Ruberti F (2010) MicroRNA-101 regulates amyloid precursor protein expression in hippocampal neurons. J Biol Chem 285(24):18344–18351. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Wan P, Su W, Zhuo Y (2017) The role of long noncoding RNAs in neurodegenerative diseases. Mol Neurobiol 54(3):2012–2021. CrossRefPubMedGoogle Scholar
  31. Wang D, Ding L, Wang L, Zhao Y, Sun Z, Karnes RJ, Zhang J, Huang H (2015) LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer. Oncotarget 6(38):41045–41055. PubMedPubMedCentralCrossRefGoogle Scholar
  32. Wu P, Zuo X, Deng H, Liu X, Liu L, Ji A (2013) Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases. Brain Res Bull 97:69–80. CrossRefPubMedGoogle Scholar
  33. Xiao Z, Peng J, Yang L, Kong H, Yin F (2015) Interleukin-1beta plays a role in the pathogenesis of mesial temporal lobe epilepsy through the PI3K/Akt/mTOR signaling pathway in hippocampal neurons. J Neuroimmunol 282:110–117. CrossRefPubMedGoogle Scholar
  34. Xu S, Sui S, Zhang J, Bai N, Shi Q, Zhang G, Gao S, You Z, Zhan C, Liu F, Pang D (2015) Downregulation of long noncoding RNA MALAT1 induces epithelial-to-mesenchymal transition via the PI3K-AKT pathway in breast cancer. Int J Clin Exp Pathol 8(5):4881–4891PubMedPubMedCentralGoogle Scholar
  35. Xue Y, Xie N, Cao L, Zhao X, Jiang H, Chi Z (2011) Diazoxide preconditioning against seizure-induced oxidative injury is via the PI3K/Akt pathway in epileptic rat. Neurosci Lett 495(2):130–134. CrossRefPubMedGoogle Scholar
  36. Yao J, Wang XQ, Li YJ, Shan K, Yang H, Wang YN, Yao MD, Liu C, Li XM, Shen Y, Liu JY, Cheng H, Yuan J, Zhang YY, Jiang Q, Yan B (2016) Long non-coding RNA MALAT1 regulates retinal neurodegeneration through CREB signaling. EMBO Mol Med 8(4):346–362. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Yeh PS, Wang W, Chang YA, Lin CJ, Wang JJ, Chen RM (2016) Honokiol induces autophagy of neuroblastoma cells through activating the PI3K/Akt/mTOR and endoplasmic reticular stress/ERK1/2 signaling pathways and suppressing cell migration. Cancer Lett 370(1):66–77. CrossRefPubMedGoogle Scholar
  38. Zhang L, Wang H, Xu J, Zhu J, Ding K (2014) Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways. Toxicol Lett 228(3):248–259. CrossRefPubMedGoogle Scholar
  39. Zhang B, Zhang JW, Wang WP, Dong RF, Tian S, Zhang C (2017) Effect of lamotrigine on epilepsy-induced cognitive impairment and hippocampal neuronal apoptosis in pentylenetetrazole-kindled animal model. Synapse 71(2).

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyXinxiang Central HospitalXinxiangPeople’s Republic of China

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