mu-Calpain activation, DNA fragmentation, and synergistic effects of caspase and calpain inhibitors in protecting hippocampal neurons from ischemic damage.
The differentiated cells seem to share the ability to induce their own death by the activation of an internally encoded suicide program. When activated, this suicide program initiates a characteristic form of cell death called apoptosis. A central challenge in apoptosis research is understanding the mechanisms by which apoptotic cascades are initiated and affected. We tested a potential role for calpain in the programmed cell death under ischemic conditions and found that calpain is (1) activated at a time preceding morphological changes, DNA fragmentation and death, (2) that calpain is translocated to the nucleus before DNA laddering, (3) pretreatment with caspase inhibitors and/or calpain inhibitors block not only the proteolytic actions of the enzyme, but also the cell death process itself in the CA1 subfield after transient global ischemia in a synergistic manner. In conclusion, the present results contribute additional evidence that proteases may play a functional role in apoptotic cell death and extend them to include the possibility that endogenous proteases are capable of inducing the striking DNA fragmentation and chromatin condensation, which are the principle criteria currently used to define apoptotic death. Moreover, the synergistic effect of caspase and calpain inhibitors in protecting neurons form ischemic damage suggests that there is a cross-talk between caspase and calpain during apoptosis.
Rami
A
A
Anatomisches Institut III-Dr. Senckenbergische Anatomie, Universitätsklinikum, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. Rami@em.uni-frankfurt.de
Agarwal
R
R
Botez
G
G
Winckler
J
J
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001557:Benzenesulfonates; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D061945:Caspase Inhibitors; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D004396:Coloring Agents; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004338:Drug Combinations; D004357:Drug Synergism; D006023:Glycoproteins / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D010078:Oxazines; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D000590:Amino Acid Chloromethyl Ketones; D001557:Benzenesulfonates; D061945:Caspase Inhibitors; D004396:Coloring Agents; D015853:Cysteine Proteinase Inhibitors; D004338:Drug Combinations; D006023:Glycoproteins; D018696:Neuroprotective Agents; D010078:Oxazines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C039304:calpain inhibitors; C086337:acid fuchsin; D002154:Calpain; D020169:Caspases; C007063:Celestine Blue