Rapamycin provides anti-epileptogenic effect in a rat model of post-traumatic epilepsy via deactivation of mTOR signaling pathway

The mammalian target of rapamycin (mTOR) signaling pathway has attracted much attention in recent years. However, the contribution of mTOR activation to the development of post-traumatic epilepsy (PTE) remains largely unknown. The purpose of the present study was to investigate the activation of mTOR signaling in a rat model of FeCl2-induced PTE, and to explore the potential effect of its specific inhibitor rapamycin. The results indicated that the expression levels of p-mTOR and p-P70S6K, the overactivation biomarkers of mTOR signaling, increased significantly in hippocampal and perilesional cortex following PTE induction. Notably, they were significantly decreased in the aformementioned brain regions following rapamycin treatment. Furthermore, the frequency and number of behavioral seizures and epileptic brain injury were also greatly reduced. These results suggest that hyperactivation of the mTOR signaling pathway is a crucial mechanism of PTE development, and it may be considered a novel therapeutic target for PTE treatment.

[1]  S. Bland,et al.  Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior , 2017, Behavioural Brain Research.

[2]  S. Fan,et al.  Elevated levels of p-Mnk1, p-eIF4E and p-p70S6K proteins are associated with tumor recurrence and poor prognosis in astrocytomas , 2017, Journal of Neuro-Oncology.

[3]  T. Sun,et al.  Rapamycin Reduced Ischemic Brain Damage in Diabetic Animals Is Associated with Suppressions of mTOR and ERK1/2 Signaling , 2016, International journal of biological sciences.

[4]  P. Crino.  The mTOR signalling cascade: paving new roads to cure neurological disease , 2016, Nature Reviews Neurology.

[5]  S. Koh,et al.  The Akt/mTOR/p70S6K Pathway Is Involved in the Neuroprotective Effect of Erythropoietin on Hypoxic/Ischemic Brain Injury in a Neonatal Rat Model , 2016, Neonatology.

[6]  I. Timofeev,et al.  In vivo models of cortical acquired epilepsy , 2016, Journal of Neuroscience Methods.

[7]  E. Aronica,et al.  Blood–brain barrier leakage after status epilepticus in rapamycin‐treated rats II: Potential mechanisms , 2016, Epilepsia.

[8]  Bret N. Smith,et al.  Effects of Rapamycin Treatment on Neurogenesis and Synaptic Reorganization in the Dentate Gyrus after Controlled Cortical Impact Injury in Mice , 2015, Front. Syst. Neurosci..

[9]  Ji-Xin Shi,et al.  Decreased progranulin levels in patients and rats with subarachnoid hemorrhage: a potential role in inhibiting inflammation by suppressing neutrophil recruitment , 2015, Journal of Neuroinflammation.

[10]  K. Kelly,et al.  Posttraumatic seizures and epilepsy in adult rats after controlled cortical impact , 2015, Epilepsy Research.

[11]  Dipan C. Patel,et al.  Oxidative stress in murine Theiler's virus-induced temporal lobe epilepsy , 2015, Experimental Neurology.

[12]  B. Porter,et al.  Perineuronal net degradation in epilepsy , 2015, Epilepsia.

[13]  A. Anderson,et al.  mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia , 2015, Epilepsia.

[14]  Andrei Irimia,et al.  Epileptogenic focus localization in treatment-resistant post-traumatic epilepsy , 2015, Journal of Clinical Neuroscience.

[15]  Lin Zhu,et al.  Rapamycin protects against apoptotic neuronal death and improves neurologic function after traumatic brain injury in mice via modulation of the mTOR-p53-Bax axis. , 2015, The Journal of surgical research.

[16]  R. D’Ambrosio,et al.  Subtypes of post-traumatic epilepsy: clinical, electrophysiological, and imaging features. , 2014, Journal of neurotrauma.

[17]  Xin-Wei Gong,et al.  Effective Connectivity of Hippocampal Neural Network and Its Alteration in Mg2+-Free Epilepsy Model , 2014, PloS one.

[18]  Peter M. Klein,et al.  AMPA Receptor antagonist NBQX attenuates later‐life epileptic seizures and autistic‐like social deficits following neonatal seizures , 2013, Epilepsia.

[19]  Yevgeny Berdichevsky,et al.  PI3K-Akt Signaling Activates mTOR-Mediated Epileptogenesis in Organotypic Hippocampal Culture Model of Post-Traumatic Epilepsy , 2013, The Journal of Neuroscience.

[20]  M. Wong.  Mammalian Target of Rapamycin (mTOR) Pathways in Neurological Diseases , 2013, Biomedical journal.

[21]  Jan A Gorter,et al.  Finding a better drug for epilepsy: The mTOR pathway as an antiepileptogenic target , 2012, Epilepsia.

[22]  Qi Xu,et al.  Mapping the Spatio-Temporal Pattern of the Mammalian Target of Rapamycin (mTOR) Activation in Temporal Lobe Epilepsy , 2012, PloS one.

[23]  Peter M. Klein,et al.  The Interaction between Early Life Epilepsy and Autistic-Like Behavioral Consequences: A Role for the Mammalian Target of Rapamycin (mTOR) Pathway , 2012, PloS one.

[24]  D. Sabatini,et al.  mTOR Signaling in Growth Control and Disease , 2012, Cell.

[25]  P. Buckmaster,et al.  Rapamycin suppresses axon sprouting by somatostatin interneurons in a mouse model of temporal lobe epilepsy , 2011, Epilepsia.

[26]  C. Cho.  Frontier of Epilepsy Research - mTOR signaling pathway , 2011, Experimental & Molecular Medicine.

[27]  S. Kozma,et al.  Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage , 2011, Proceedings of the National Academy of Sciences.

[28]  L. Zeng,et al.  The Mammalian Target of Rapamycin Signaling Pathway Mediates Epileptogenesis in a Model of Temporal Lobe Epilepsy , 2009, The Journal of Neuroscience.

[29]  J. Olsen,et al.  Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study , 2009, The Lancet.

[30]  J. Sancho-Rieger,et al.  [Preventive and therapeutic attitude in post-traumatic epileptic seizures]. , 2002, Revista de neurologia.

[31]  W. Triggs,et al.  Amygdalar Injection of FeCl3Causes Spontaneous Recurrent Seizures , 1998, Experimental Neurology.

[32]  W. Triggs,et al.  Effect of phenytoin and corticosteroids on seizures and lipid peroxidation in experimental posttraumatic epilepsy. , 1984, Journal of neurosurgery.

[33]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. 3. Mechanisms. , 1972, Electroencephalography and clinical neurophysiology.

[34]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. II. Motor seizure. , 1972, Electroencephalography and clinical neurophysiology.