Neurociencia: epilepsia y rapamicina.

6964 • The Journal of Neuroscience, May 27, 2009 • 29(21):6964 – 6972

Neurobiology of Disease

The Mammalian Target of Rapamycin Signaling Pathway Mediates Epileptogenesis in a Model of Temporal Lobe Epilepsy
Ling-Hui Zeng, Nicholas R. Rensing, and Michael Wong
Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis,Missouri 63110

Understanding molecular mechanisms mediating epileptogenesis is critical for developing more effective therapies for epilepsy. We recently found that the mammalian target of rapamycin (mTOR) signaling pathway is involved in epileptogenesis, and mTOR inhibitors prevent epilepsy in a mouse model of tuberous sclerosis complex. Here, we investigated the potential role of mTOR in a ratmodel of temporal lobe epilepsy initiated by status epilepticus. Acute kainate-induced seizures resulted in biphasic activation of the mTOR pathway, as evident by an increase in phospho-S6 (P-S6) expression. An initial rise in P-S6 expression started 1 h after seizure onset, peaked at 3– 6 h, and returned to baseline by 24 h in both hippocampus and neocortex, reflecting widespread stimulation of mTORsignaling by acute seizure activity. After resolution of status epilepticus, a second increase in P-S6 was observed in hippocampus only, which started at 3 d, peaked 5–10 d, and persisted for several weeks after kainate injection, correlating with the development of chronic epileptogenesis within hippocampus. The mTOR inhibitor rapamycin, administered before kainate, blocked both the acute andchronic phases of seizure-induced mTOR activation and decreased kainate-induced neuronal cell death, neurogenesis, mossy fiber sprouting, and the development of spontaneous epilepsy. Late rapamycin treatment, after termination of status epilepticus, blocked the chronic phase of mTOR activation and reduced mossy fiber sprouting and epilepsy but not neurogenesis or neuronal death. These findingsindicate that mTOR signaling mediates mechanisms of epileptogenesis in the kainate rat model and that mTOR inhibitors have potential antiepileptogenic effects in this model.

Introduction
Epilepsy affects 1% of people and is associated with significant morbidity and mortality. Approximately one-third of epileptic patients are intractable to currently available treatments (Schuele and Luders, 2008).In responsive cases, medications can suppress ¨ seizures symptomatically, but there is minimal evidence that existing “antiepileptic” drugs correct the underlying brain abnormalities causing epilepsy (epileptogenesis) or alter the natural history of epilepsy. Thus, it is now recognized that novel therapeutic approaches are needed with true antiepileptogenic actions that can prevent or reverse thecellular and molecular mechanisms of epileptogenesis (Dichter, 2006; Loscher and Schmidt, ¨ 2006; Stefan et al., 2006). To develop such treatments, a better understanding of the biological processes mediating epileptogenesis is required. In many epilepsy models, an initial brain insult triggers a cascade of cellular events, which, after a latent period of epileptogenesis, leads to chronichyperexcitability and seizures. For example, in pharmacological seizures models in rodents, an episode of
Received Jan. 6, 2009; revised Jan. 28, 2009; accepted April 29, 2009. This work was supported by National Institutes of Health (NIH) Grants K02 NS045583 and R01 NS056872 (M.W.), the Tuberous Sclerosis Alliance (M.W.), and NIH Neuroscience Blueprint Center Core Grant P30 NS057105 (to WashingtonUniversity). Correspondence should be addressed to Dr. Michael Wong, Department of Neurology, Box 8111, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail: wong_m@wustl.edu. DOI:10.1523/JNEUROSCI.0066-09.2009 Copyright © 2009 Society for Neuroscience 0270-6474/09/296964-09$15.00/0

status epilepticus is induced by chemoconvulsant agents, such as kainate...