PI3K-Akt Signaling Activates mTOR-Mediated Epileptogenesis in Organotypic Hippocampal Culture Model of Post-Traumatic Epilepsy
| Autor: | Marija Usenovic, Yero Saponjian, Kevin J. Staley, Yevgeny Berdichevsky, Mark M. Mahoney, Corrin A. Pimentel, Alexandra M. Dryer, Corrina A. Lucini |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Programmed cell death Time Factors Biology Pharmacology Kynurenic Acid Hippocampus Epileptogenesis Neuroprotection Article Phosphatidylinositol 3-Kinases Epilepsy Cytochrome b2 Organ Culture Techniques medicine Animals Lactic Acid Enzyme Inhibitors Evoked Potentials Protein kinase B PI3K/AKT/mTOR pathway Neurons Sirolimus Analysis of Variance Cell Death Dose-Response Relationship Drug TOR Serine-Threonine Kinases General Neuroscience medicine.disease Axons Rats Animals Newborn L-Lactate Dehydrogenase (Cytochrome) Excitatory Amino Acid Antagonists Microtubule-Associated Proteins Proto-Oncogene Proteins c-akt Signal Transduction medicine.drug |
| Zdroj: | The Journal of Neuroscience. 33:9056-9067 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.3870-12.2013 |
| Popis: | mTOR is activated in epilepsy, but the mechanisms of mTOR activation in post-traumatic epileptogenesis are unknown. It is also not clear whether mTOR inhibition has an anti-epileptogenic, or merely anticonvulsive effect. The rat hippocampal organotypic culture model of post-traumatic epilepsy was used to study the effects of long-term (four weeks) inhibition of signaling pathways that interact with mTOR. Ictal activity was quantified by measurement of lactate production and electrical recordings, and cell death was quantified with lactate dehydrogenase (LDH) release measurements and Nissl-stained neuron counts. Lactate and LDH measurements were well correlated with electrographic activity and neuron counts, respectively. Inhibition of PI3K and Akt prevented activation of mTOR, and was as effective as inhibition of mTOR in reducing ictal activity and cell death. A dual inhibitor of PI3K and mTOR, NVP-BEZ235, was also effective. Inhibition of mTOR with rapamycin reduced axon sprouting. Late start of rapamycin treatment was effective in reducing epileptic activity and cell death, while early termination of rapamycin treatment did not result in increased epileptic activity or cell death. The conclusions of the study are as follows: (1) the organotypic hippocampal culture model of post-traumatic epilepsy comprises a rapid assay of anti-epileptogenic and neuroprotective activities and, in this model (2) mTOR activation depends on PI3K-Akt signaling, and (3) transient inhibition of mTOR has sustained effects on epilepsy. |
| Databáze: | OpenAIRE |
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