Differential regulation of apoptosis-related genes in resistant and vulnerable subfields of the rat epileptic hippocampus.
Animals exposed to kainic acid (KA) induced status epilepticus display a striking pattern of selective neuronal vulnerability in the hippocampus. Neurons in the hilus/CA3 and CA1 subfields appear particularly sensitive whereas dentate gyrus (DG) granule cells are resistant. The molecular basis for this differential susceptibility remains largely unknown. Recently, an involvement of nitric oxide, c-Jun amino-terminal kinases (JNK) and interleukin-1 beta converting enzyme (ICE)-related proteases has been proposed in KA induced neuronal cell death. In the present study, we have determined the regional expression of transcripts for two modulating genes operating in these pathways, i.e., the endogenous protein inhibitor of neuronal nitric oxide synthase (PIN), and a cytoplasmic inhibitor of the JNK signal transduction pathway, designated JNK interacting protein-1 (JIP-1) and of the gene for the apoptosis-executing protease Caspase-3 in KA-treated animals. The expression of PIN and JIP-1 was found significantly upregulated in granule cells of the resistant DG. In contrast, an induction of the ICE-related protease Caspase-3 was observed in vulnerable hippocampal regions, i.e. CA1, CA3 and hilus. These results point towards PIN and JIP-1 as antiapoptotic factors contributing to selective resistance of granule cells, whereas Caspase-3 may be involved in cell death of hippocampal CA1, CA3 and hilar neurons in the kainate epilepsy model.
Becker
A J
AJ
Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
Gillardon
F
F
Blümcke
I
I
Langendörfer
D
D
Beck
H
H
Wiestler
O D
OD
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001923:Brain Chemistry / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000235:genetics; D018891:Dentate Gyrus / Q000737:chemistry* / Q000201:enzymology*; D018690:Excitatory Amino Acid Agonists; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D017403:In Situ Hybridization; D007608:Kainic Acid; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000503:physiopathology*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018690:Excitatory Amino Acid Agonists; C110528:Mapk8ip1 protein, rat; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D007608:Kainic Acid