HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Ischemic preconditioning by caspase cleavage of poly(ADP-ribose) polymerase-1.

Abstract
A transient, sublethal ischemic interval confers resistance to a subsequent, otherwise lethal ischemic insult, in a process termed ischemic preconditioning. Poly(ADP-ribose) polymerase-1 (PARP-1) normally functions in DNA repair, but extensive PARP-1 activation is a major cause of ischemic cell death. Because PARP-1 can be cleaved and inactivated by caspases, we investigated the possibility that caspase cleavage of PARP-1 could contribute to ischemic preconditioning. Murine cortical cultures were treated with glucose deprivation combined with 0.5 mm 2-deoxyglucose and 5 mm azide ("chemical ischemia") to model the reversible energy failure that occurs during transient ischemia in vivo. Cortical cultures preconditioned with 15 min of chemical ischemia showed increased resistance to subsequent, longer periods of chemical ischemia. These cultures were also more resistant to the PARP-1 activating agent, N-methyl-N'-nitro-N-nitrosoguanidine, suggesting reduced capacity for PARP-1 activation after preconditioning. Immunostaining for the 89 kDa PARP-1 cleavage fragment and for poly(ADP-ribose) formation confirmed that PARP-1 was cleaved and PARP-1 activity was attenuated in the preconditioned neurons. Preconditioning also produced an increase in activated caspase-3 peptide and an increase in caspase-3 activity in the cortical cultures. A cause-effect relationship between caspase activation, PARP-1 cleavage, and ischemic preconditioning was supported by studies using the caspase inhibitor Ac-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO). Cultures treated with DEVD-CHO after preconditioning showed reduced PARP-1 cleavage and reduced resistance to subsequent ischemia. These findings suggest a novel interaction between the caspase- and PARP-1-mediated cell death pathways in which sublethal caspase activation leads to PARP-1 cleavage, thereby increasing resistance to subsequent ischemic stress.
AuthorsPhilippe Garnier, Weihai Ying, Raymond A Swanson
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 23 Issue 22 Pg. 7967-73 (Sep 03 2003) ISSN: 1529-2401 [Electronic] United States
PMID12954857 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Caspase Inhibitors
  • Culture Media, Conditioned
  • Enzyme Inhibitors
  • Sodium Azide
  • Deoxyglucose
  • Poly(ADP-ribose) Polymerases
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases
  • Glucose
Topics
  • Animals
  • Astrocytes (cytology)
  • Caspase 3
  • Caspase Inhibitors
  • Caspases (metabolism)
  • Cell Death (drug effects)
  • Cells, Cultured
  • Coculture Techniques
  • Culture Media, Conditioned (pharmacology)
  • Deoxyglucose (pharmacology)
  • Drug Resistance
  • Energy Metabolism (drug effects)
  • Enzyme Activation (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Glucose (deficiency, metabolism)
  • Ischemic Preconditioning (methods)
  • Mice
  • Mice, Knockout
  • Neurons (cytology, drug effects, metabolism)
  • Poly(ADP-ribose) Polymerases (metabolism)
  • Sodium Azide (pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: