RAGE POTENTIATES NEURONAL DAMAGE IN KAINIC ACID AND PILOCARPINE SEIZURE MODELS
Abstract number :
1.043
Submission category :
Year :
2002
Submission ID :
3390
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Guy M. McKhann II, Alexander A. Sosunov, Hui Ping Zhang, David M. Stern, Shi Du Yan. Neurological Surgery and Surgery, Columbia University, New York, NY
RATIONALE: RAGE (Receptor for Advanced Glycation Endproducts) is a member of the immunoglobulin superfamily of cell surface molecules with a diverse repertoire of ligands. Based on its capacity to bind AGEs (advanced glycation endproducts), beta-sheet fibrils, S100/calgranulins and amphoterin, RAGE appears to function as a progression factor promoting pathologic cellular activation in a range of situations. We hypothesized that RAGE activation promotes seizure-induced cell death following experimentally induced status epilepticus.
METHODS: Transgenic mice were generated with targeted neuronal overexpression of either wild-type RAGE (Tg wtRAGE) or dominant-negative RAGE, a form lacking the receptor[ssquote]s cytosolic tail ( Tg DN-RAGE). Both groups of Tg mice and age- and strain-matched littermate controls were challenged with either systemic kainic acid or pilocarpine. Homozygous RAGE null mice were similarly studied. Acute seizure-induced neuronal damage was examined over the next 1-5 days by silver and FluoroJade staining.
RESULTS: Both Tg wtRAGE and Tg DN-RAGE displayed prominent upregulation of RAGE. Overexpression of these transgenes did not affect seizure severity or seizure-induced mortality in response to either pilocarpine or kainic acid administration. However, following status epilepticus induced by either of these agents, seizure-induced neuronal damage was significantly increased in the CA1 and CA3 hippocampal subfields in Tg wtRAGE (p[lt]0.05), compared with littermate controls. In contrast, damage was strongly reduced in Tg DN-RAGE mice (p[lt]0.05). Consistent with these data, RAGE null mice displayed a 70-80% reduction in cell death in CA1 and CA3 regions, compared with littermate controls (p[lt]0.05).
CONCLUSIONS: Following kainic acid- or pilocarpine-induced status epilepticus, RAGE promotes hippocampal neuronal damage. Blockade of RAGE-ligand interaction may provide a novel neuroprotective strategy for the prevention of seizure-induced neurotoxicity.
[Supported by: AG60901,AG16223 (HPZ, DS, SDY); New York Academy of Medicine Elsberg Award, Klingenstein Foundation (GM)]