NDT_A_270614 2519..2528

1Department of Pediatrics, The First People’s Hospital of Jinan, Jinan, Shandong 250011, People’s Republic of China; 2Department of Surgery 1, Chiping County People’s Hospital, Liaocheng, Shandong 252100, People’s Republic of China; 3Department of Obstetrics, Zhangqiu People’s Hospital of Jinan City, Jinan, Shandong 250200, People’s Republic of China; 4Department of Pediatrics, Jining First People’s Hospital, Jining, Shandong 272000, People’s Republic of China Purpose: Temporal lobe epilepsy (TLE) is a common neurological disorder, which is characterized by recurrent spontaneous seizures. Exploring the mechanisms of epileptogenesis has been considered as a priority. The aim of this study is to investigate the effects of LncRNA MEG3 in spontaneous recurrent epileptiform discharges (SREDs) and rats with TLE. Methods: Rat model of TLE was produced by intraperitoneal injection of lithium chloride and pilocarpine. Rat hippocampal neuronal model of SREDs was established by Mg-free treatment. MEG3 was overexpressed by transfection of AAV-MEG3 in TLE and SREDs model. The expression of MEG3, interleukin-1β (IL-1β), interleukin-6 (IL-6) and recombinant human tumor necrosis factor-alpha (TNF-α) was detected by reverse transcriptionquantitative polymerase chain reaction (RT-qPCR). Malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were detected by corresponding kit. The apoptosis of hippocampal neurons was detected by terminal deoxynucleotidyl transferase transfer-mediated dUTP nick end-labeling (TUNEL) assay and flow cytometry. The expression of proteins related to apoptosis (Caspase-3, Bax, and Bcl-2) and the PI3K/AKT/mTOR pathway was detected by Western blot. Results: MEG3 expression was downregulated in SREDs and rats with TLE. Overexpression of MEG3 reduced the expression of IL-1β, IL-6, and TNF-α, MDA content, apoptosis rate of hippocampal neuron, increased SOD activity, and inhibited the PI3K/AKT/ mTOR pathway in rats with TLE. In addition, overexpression of MEG3 enhanced cell viability and inhibited apoptosis through the activation of the PI3K/AKT/mTOR pathway in SREDs. Conclusion: MEG3 reduced proinflammatory cytokines, oxidative stress, and apoptosis rate of hippocampal neuron and enhanced cell viability through the activation of the PI3K/AKT/ mTOR pathway in SREDs and rats with TLE. Our findings may contribute to find a new therapeutic target for the treatment of epilepsy.

[1]  Xiangdan Li,et al.  LncRNA FTX inhibits hippocampal neuron apoptosis by regulating miR-21-5p/SOX7 axis in a rat model of temporal lobe epilepsy. , 2019, Biochemical and biophysical research communications.

[2]  R. Chatterjee,et al.  Altered Levels of Long NcRNAs Meg3 and Neat1 in Cell And Animal Models Of Huntington’s Disease , 2018, RNA biology.

[3]  W. Duan,et al.  MicroRNA‑155 contributes to the occurrence of epilepsy through the PI3K/Akt/mTOR signaling pathway. , 2018, International journal of molecular medicine.

[4]  Xianzhi Liu,et al.  LncRNA UCA1 inhibits epilepsy and seizure-induced brain injury by regulating miR-495/Nrf2-ARE signal pathway. , 2018, The international journal of biochemistry & cell biology.

[5]  Weihua Hu,et al.  Long non-coding RNA H19 contributes to apoptosis of hippocampal neurons by inhibiting let-7b in a rat model of temporal lobe epilepsy , 2018, Cell Death & Disease.

[6]  Fei Yang,et al.  Notch Signaling Regulates Microglial Activation and Inflammatory Reactions in a Rat Model of Temporal Lobe Epilepsy , 2018, Neurochemical Research.

[7]  Dawei Xu,et al.  Long non-coding RNA ENST01108 promotes carcinogenesis of glioma by acting as a molecular sponge to modulate miR-489. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[8]  P. Xie,et al.  PTEN knockdown with the Y444F mutant AAV2 vector promotes axonal regeneration in the adult optic nerve , 2018, Neural regeneration research.

[9]  Yulan Zhu,et al.  Wnt/β‐catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid‐induced epilepsy , 2017, Cell biochemistry and function.

[10]  R. Zhan,et al.  Long noncoding RNA MEG3 mediated angiogenesis after cerebral infarction through regulating p53/NOX4 axis. , 2017, Biochemical and biophysical research communications.

[11]  K. Wang,et al.  Dynamic regulation effect of long non-coding RNA-UCA1 on NF-kB in hippocampus of epilepsy rats. , 2017, European review for medical and pharmacological sciences.

[12]  Xu Qi,et al.  Long non-coding RNA SNHG14 promotes microglia activation by regulating miR-145-5p/PLA2G4A in cerebral infarction , 2017, Neuroscience.

[13]  Tiedong Sun,et al.  Nerve Growth Factor Protects Against Alcohol-Induced Neurotoxicity in PC12 Cells via PI3K/Akt/mTOR Pathway , 2017, Alcohol and alcoholism.

[14]  Y. Zhou,et al.  Long noncoding RNA SPRY4-IT1 is a prognostic factor for poor overall survival and has an oncogenic role in glioma. , 2016, European review for medical and pharmacological sciences.

[15]  X. Yue,et al.  The clinical efficacy and safety of levetiracetam add-on therapy for child refractory epilepsy. , 2016, European review for medical and pharmacological sciences.

[16]  Kawinthra Khwanraj,et al.  Comparative mRNA Expression of eEF1A Isoforms and a PI3K/Akt/mTOR Pathway in a Cellular Model of Parkinson's Disease , 2016, Parkinson's disease.

[17]  Changshui Xu,et al.  LncRNA NONRATT021972 siRNA attenuates P2X7 receptor expression and inflammatory cytokine production induced by combined high glucose and free fatty acids in PC12 cells , 2016, Purinergic Signalling.

[18]  B. Zhao,et al.  Epigenetic repression of long non-coding RNA MEG3 mediated by DNMT1 represses the p53 pathway in gliomas. , 2016, International journal of oncology.

[19]  A. Auvinen,et al.  Epilepsy, excess deaths and years of life lost from external causes , 2016, European Journal of Epidemiology.

[20]  Jeffrey Noebels,et al.  Sudden unexpected death in epilepsy: Identifying risk and preventing mortality , 2015, Epilepsia.

[21]  Chun Luo,et al.  MiR-181a influences the cognitive function of epileptic rats induced by pentylenetetrazol. , 2015, International journal of clinical and experimental pathology.

[22]  Qinwen Wang,et al.  PI3K/AKT/mTOR Signaling-Mediated Neuropeptide VGF in the Hippocampus of Mice Is Involved in the Rapid Onset Antidepressant-Like Effects of GLYX-13 , 2015, The international journal of neuropsychopharmacology.

[23]  David Heras-Sandoval,et al.  The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. , 2014, Cellular signalling.

[24]  Željka Vuković-Arar,et al.  Head trauma and posttraumatic epilepsy in Slavonski Brod, East Croatia, 1988-2008. , 2014, Collegium Antropologicum.

[25]  L. Kuznetsova,et al.  [Neuroimmunological aspects of the pathogenesis of epilepsy]. , 2014, Uspekhi fiziologicheskikh nauk.

[26]  Pengjun Wang,et al.  Overexpression of the long non‐coding RNA MEG3 impairs in vitro glioma cell proliferation , 2012, Journal of cellular biochemistry.

[27]  Shang-Der Chen,et al.  The potential role of mitochondrial dysfunction in seizure-associated cell death in the hippocampus and epileptogenesis , 2010, Journal of bioenergetics and biomembranes.

[28]  Y. Gupta,et al.  Protective effect of curcumin against seizures and cognitive impairment in a pentylenetetrazole-kindled epileptic rat model. , 2010, Life sciences.

[29]  S. Fulda,et al.  The PI3K/Akt/mTOR pathway as therapeutic target in neuroblastoma. , 2009, Current cancer drug targets.

[30]  G. Bernardi,et al.  Selective CB2 Receptor Agonism Protects Central Neurons from Remote Axotomy-Induced Apoptosis through the PI3K/Akt Pathway , 2009, The Journal of Neuroscience.

[31]  E. Aronica,et al.  Glia as a source of cytokines: Implications for neuronal excitability and survival , 2008, Epilepsia.

[32]  A. Sureda,et al.  Antioxidant response and oxidative damage in brain cortex after high dose of pilocarpine , 2007, Brain Research Bulletin.

[33]  A. Kocer,et al.  Erdosteine ameliorates PTZ-induced oxidative stress in mice seizure model , 2005, Brain Research Bulletin.

[34]  R. Clark,et al.  To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress-activated signaling pathways and apoptotic pathways , 2003, Progress in Neurobiology.

[35]  Betty M Tyler,et al.  The intracerebral administration of phenytoin using controlled-release polymers reduces experimental seizures in rats , 2002, Epilepsy Research.

[36]  Johan Bengzon,et al.  Neuronal apoptosis after brief and prolonged seizures. , 2002, Progress in brain research.

[37]  J. Velazquez,et al.  Oxidative stress is involved in seizure-induced neurodegeneration in the kindling model of epilepsy , 2000, Neuroscience.