Activation of Cell Death Related Signaling Pathways in Seizure Induced Neuronal Injury.
Abstract number :
3.031
Submission category :
Year :
2001
Submission ID :
402
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
Y. Zheng, Ph.D., Epilepsy Research Lab, Neurology Service, Massachusetts General Hospital, Harvard Med. Sch., Boston, MA; T. Beer, B.S., Epilepsy Research Lab, Neurology Services, Massachusetts General Hospital, Harvard Med. Sch., Boston, MA; A.J. Cole, M
RATIONALE: Considerable evidence supports the role of apoptosis in seizure-induced neuronal injury. In order to better understand the cell signals that trigger neuronal death after seizure, we studied the activation of several cell death related signaling pathways.
RESULTS: We used both the lithium-pilocarpine rodent model and a cultured hippocampal neuron model. Limbic status epilepticus was induced in rats following Lithium Chloride pretreatment (127mg/Kg), using pilocarpine (30 mg/Kg). Grade IV seizures were observed and the brains were harvested at 1-48 hr after the onset of seizure. TUNEL staining, a marker of neuronal injury was first detected 24 hr after seizures in hippocampus. Activated (cleaved) caspase-3 was detected at early 3 hr after seizure (mostly in hilus). Expression was continually detected through 48 hr after seizure, mostly in the CA1 region. Activated capase-9 was increased within 2 hr, but close to basal levels at 5 hr, in CA1 and CA3 after seizure. Total caspase-3 and stress-response p53 expressions were also up regulated within 2 hr after seizure. Similarly, in a cultured hippocampal neuron model of seizure, the neurons are cultured in medium containing Mg2+ and kynurenic acid for 4 to 6 weeks. After replace the medium with HBSS buffer for 30 min, the neurons manifest seizure like activity and largely die within 24 hr. We used LDH release as a marker of neuronal injury. Cleavage of caspase-3 was detected as early as 2 hr, then at 4 hr, 12 hr, and 24 hr after seizure like activity. Phosphorylation of p44/42 MAP kinase (ERK1/2) was increased rapidly after seizure but decreased to normal level 2 hr after seizure. Expression of JNKs was increased after seizure but p38 was not significantly changed.
CONCLUSIONS: These data suggest that caspase activation is a critical mediator of seizure-induced neuronal injury. This apoptosis activation process is associated with several stress response pathways, including the p53 and MAPK families.
Support: Supported by NINDS R01 NS36624.
1. Recipient of Epilepsy Foundation Research Training Fellowship.
*. Corresponding author.