Upregulation of nitric oxide synthase II contributes to apoptotic cell death in the hippocampal CA3 subfield via a cytochrome c/caspase-3 signaling cascade following induction of experimental temporal lobe status epilepticus in the rat.
Status epilepticus results in preferential neuronal cell loss in the hippocampus. We evaluated the hypothesis that the repertoire of intracellular events in the vulnerable hippocampal CA3 subfield after induction of experimental temporal lobe status epilepticus entails upregulation of nitric oxide synthase II (NOS II), followed by the release of mitochondrial cytochrome c that triggers the cytosolic caspase-3 cascade, leading to apoptotic cell death. In Sprague-Dawley rats, significant and temporally correlated upregulation of NOS II (3-24h), but not NOS I or II expression, enhanced cytosolic translocation of cytochrome c (days 1 and 3), augmented activated caspase-3 in cytosol (days 1, 3 and 7) and DNA fragmentation (days 1, 3 and 7) was detected bilaterally in the hippocampal CA3 subfield after elicitation of sustained seizure activity by microinjection of kainic acid into the unilateral CA3 subfield. Application bilaterally into the hippocampal CA3 subfield of a selective NOS II inhibitor, S-methylisothiourea, significantly blunted these apoptotic events; a selective NOS I inhibitor, N(omega)-propyl-l-arginine or a potent NOS III inhibitor, N(5)-(1-iminoethyl)-l-ornithine was ineffective. We conclude that upregulation of NOS II contributes to apoptotic cell death in the hippocampal CA3 subfield via a cytochrome c/caspase-3 signaling cascade following the induction of experimental temporal lobe status epilepticus.
Chuang
Y C
YC
Department of Neurology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan, ROC.
Chen
S D
SD
Lin
T K
TK
Liou
C W
CW
Chang
W N
WN
Chan
S H H
SH
Chang
A Y W
AY
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000502:physiology*; D045304:Cytochromes c / Q000502:physiology*; D003600:Cytosol / Q000201:enzymology; D053938:DNA Fragmentation / Q000187:drug effects; D004569:Electroencephalography / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004833:Epilepsy, Temporal Lobe / Q000503:physiopathology*; D005455:Fluorescent Antibody Technique; D007839:Functional Laterality / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D008297:Male; D018613:Microscopy, Confocal; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013226:Status Epilepticus / Q000503:physiopathology*; D015854:Up-Regulation / Q000187:drug effects*
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D045304:Cytochromes c; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3