Regulation of cell death and epileptogenesis by the mammalian target of rapamycin (mTOR): a double-edged sword?
Identification of cell signaling mechanisms mediating seizure-related neuronal death and epileptogenesis is important for developing more effective therapies for epilepsy. The mammalian target of rapamycin (mTOR) pathway has recently been implicated in regulating neuronal death and epileptogenesis in rodent models of epilepsy. In particular, kainate-induced status epilepticus causes abnormal activation of the mTOR pathway, and the mTOR inhibitor, rapamycin, can decrease the development of neuronal death and chronic seizures in the kainate model. Here, we discuss the significance of these findings and extend them further by identifying upstream signaling pathways through which kainate status epilepticus activates the mTOR pathway and by demonstrating limited situations where rapamycin may paradoxically increase mTOR activation and worsen neuronal death in the kainate model. Thus, the regulation of seizure-induced neuronal death and epileptogenesis by mTOR is complex and may have dual, opposing effects depending on the physiological and pathological context. Overall, these findings have important implications for designing potential neuroprotective and antiepileptogenic therapies that modulate the mTOR pathway.
Zeng
Ling-Hui
LH
Department of Pharmacy, Zhejiang University City College, Hangzhou, Zhejiang, China.
McDaniel
Sharon
S
Rensing
Nicholas R
NR
Wong
Michael
M
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004827:Epilepsy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D018092:Kainic Acid Receptors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013226:Status Epilepticus / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D018696:Neuroprotective Agents; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D018092:Kainic Acid Receptors; D058570:TOR Serine-Threonine Kinases