Inhibition of caspases prevents cell death of hippocampal CA1 neurons, but not impairment of hippocampal long-term potentiation following global ischemia.
An essential role for caspases in programmed neuronal cell death has been demonstrated in various in vitro studies, and synthetic caspase inhibitors have recently been shown to prevent neuronal cell loss in animal models of focal cerebral ischemia and traumatic brain injury, respectively. The therapeutic utility of caspase inhibitors, however, will depend on preservation of both structural and functional integrity of neurons under stressful conditions. The present study demonstrates that expression and proteolytic activity of caspase-3 is up-regulated in the rat hippocampus after transient forebrain ischemia. Continuous i.c.v. infusion of the caspase inhibitor N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone significantly attenuated caspase-3-like enzymatic activity, and blocked delayed cell loss of hippocampal CA1 neurons after ischemia. Administration of N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone, however, did not prevent impairment of induction of long-term potentiation in post-ischemic CA1 cells, suggesting that caspase inhibition alone does not preserve neuronal functional plasticity.
Gillardon
F
F
Max-Planck-Institut für Neurologische Forschung, Köln, Germany. gillardo@ing.boehringer-ingelheim.com
Kiprianova
I
I
Sandkühler
J
J
Hossmann
K A
KA
Spranger
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000032:analysis; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000098:blood supply / Q000166:cytology* / Q000201:enzymology; D020287:In Situ Nick-End Labeling; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009842:Oligopeptides / Q000494:pharmacology; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D051636:X-Linked Inhibitor of Apoptosis Protein
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D011506:Proteins; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases