Light at the End of the “TUNEL”? Role of Ceramide in Seizure-induced Programmed Cell Death.

Mikati, M.A; Abi-Habib, R.J.; El Sabban, M.E.; Dbaibo, G.S.; Kurdi, R.M.; Kobeissi, M.; Farhar, F.; Asaad, W.; Stafstrom, Carl E.

Hippocampal Programmed Cell Death after Status Epilepticus: Evidence for NMDA-receptor and Ceramide-mediated Mechanisms 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 hours after KA injection. Ceramide, a known mediator of PCD in multiple neural and nonneural tissues, increased at 2 to 3 hours after KA intraperitoneal injection, and then decreased to control levels before increasing again from 12 to 30 hours after injection. MK-801 pretreatment prevented KA-induced increases in ceramide levels and DNA fragmentation, whether a reduction in seizure severity occurred or not (achieved with 5 mg/kg and 1 mg/kg of MK-801, 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) age-related differences occur 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.

CELL death; DEATH (Biology); SPASMS; EPILEPSY; BRAIN diseases

Epilepsy Currents, 2003, Vol 3, Issue 5, p157

1535-7597

Academic Journal

10.1046/j.1535-7597.2003.03502.x