Hippocampal programmed cell death after status epilepticus: evidence for NMDA-receptor and ceramide-mediated mechanisms.
OBJECTIVE
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.
Mikati
Mohamad A
MA
Adult and Pediatric Epilepsy Program, Department of Pediatrics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon. mamikati@aub.edu.lb
Abi-Habib
Ralph J
RJ
El Sabban
Marwan E
ME
Dbaibo
Ghassan S
GS
Kurdi
Rana M
RM
Kobeissi
Mohamad
M
Farhat
Firas
F
Asaad
Wissal
W
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002518:Ceramides / Q000096:biosynthesis* / Q000494:pharmacology / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007608:Kainic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology
D002518:Ceramides; C064769:N-acetylsphingosine; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D013110:Sphingosine; D007608:Kainic Acid