Hippocampal Programmed Cell Death after Status Epilepticus: Evidence for NMDA-Receptor and Ceramide-Mediated Mechanisms
Mohamad A. Mikati
Departments of Pediatrics,
Biochemistry,
Adult and Pediatric Epilepsy Program, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Search for more papers by this authorRalph J. Abi-Habib
Departments of Pediatrics,
Biochemistry,
Adult and Pediatric Epilepsy Program, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Search for more papers by this authorRana M. Kurdi
Departments of Pediatrics,
Adult and Pediatric Epilepsy Program, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Search for more papers by this authorMohamad Kobeissi
Departments of Pediatrics,
Adult and Pediatric Epilepsy Program, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Search for more papers by this authorFiras Farhat
Departments of Pediatrics,
Adult and Pediatric Epilepsy Program, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Search for more papers by this authorMohamad A. Mikati
Departments of Pediatrics,
Biochemistry,
Adult and Pediatric Epilepsy Program, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Search for more papers by this authorRalph J. Abi-Habib
Departments of Pediatrics,
Biochemistry,
Adult and Pediatric Epilepsy Program, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Search for more papers by this authorRana M. Kurdi
Departments of Pediatrics,
Adult and Pediatric Epilepsy Program, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Search for more papers by this authorMohamad Kobeissi
Departments of Pediatrics,
Adult and Pediatric Epilepsy Program, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Search for more papers by this authorFiras Farhat
Departments of Pediatrics,
Adult and Pediatric Epilepsy Program, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Search for more papers by this authorAbstract
Summary: Purpose: Status epilepticus (SE) can result in acute neuronal injury with subsequent long-term age-dependent behavioral and histologic sequelae. To investigate potential mechanisms that may underlie SE-related neuronal injury, we studied the occurrence of programmed cell death (PCD) in the hippocampus in the kainic acid (KA) model.
Methods: In adult rats, KA-induced SE resulted in DNA fragmentation documented at 30 h after KA injection. Ceramide, a known mediator of PCD in multiple neural and nonneural tissues, increased at 2–3 h after KA intraperitoneal injection, and then decreased to control levels before increasing again from 12 to 30 h after injection. MK801 pretreatment prevented KA-induced increases in ceramide levels and DNA fragmentation, whether there was reduction in seizure severity or not (achieved with 5 mg/kg and 1 mg/kg of MK801, respectively).
Results: Both ceramide increases and DNA fragmentation were observed after KA-induced SE in adult and in P35 rats. Ceramide did not increase after KA-induced SE in P7 pups, which also did not manifest any DNA fragmentation. Intrahippocampal injection of the active ceramide analogue C2-ceramide produced widespread DNA fragmentation, whereas the inactive ceramide analogue C2-dihydroceramide did not.
Conclusions: Our data support the hypotheses that (a) N-methyl-d-aspartate–receptor activation results in ceramide increases and in DNA fragmentation; (b) ceramide is a mediator of PCD after SE; and (c) there are age-related differences in PCD and in the ceramide response after SE. Differences in the ceramide response could, potentially, be responsible for observed age-related differences in the response to SE.
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