Status epilepticus leads to the degradation of the endogenous inhibitor of caspase-activated DNase in rats.

Abstract

Specific biochemical hallmarks of apoptosis, namely internucleosomal DNA fragmentation and caspase-3 activation, appear in the aftermath of status epilepticus (SE). This led us to hypothesize that caspase-activated DNase (CAD) is involved in DNA fragmentation and apoptotic neuronal cell death following SE. The present study aimed to determine whether SE is associated with an activation of CAD, as reflected in the degradation of the CAD inhibitor, ICAD. SE was induced in adult male Sprague-Dawley rats by kainic acid (12 mg/kg i.p.) and seizures were terminated with diazepam after 2 h. At 24, 48, or 72 h after SE termination, protein levels of CAD and ICAD were measured by Western blotting (after sodium dodecyl sulfate-polyacrylamide gel electrophoresis) using specific antibodies. At 48 and 72 h after SE termination, ICAD protein levels significantly decreased (by more than 60%) in rhinal cortex and hippocampus as compared with those in the same tissue from animals not experiencing SE. No changes were detected in total CAD protein levels at any time point, resulting in an increase in the ratio of CAD to its inhibitor. The loss of ICAD following SE is indicative of a disinhibition of CAD, leading to DNA fragmentation. Consistent with this, we observed that the decrease in ICAD between 24 and 48 h was accompanied by a marked increase in DNA fragmentation. Our results support the proposal that CAD participates in caspase-3-mediated internucleosomal DNA fragmentation in the aftermath of SE.

• Authors: Alexei Kondratyev, Dawn Selby, Karen Gale
• Journal: Neuroscience letters (Neurosci Lett) Vol. 319 Issue 3 Pg. 145-8 (Feb 22 2002) ISSN: 0304-3940 [Print] Ireland
• PMID: 11834314 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anticonvulsants
• Apoptosis Regulatory Proteins
• Proteins
• caspase-activated DNase inhibitor
• Deoxyribonucleases
• caspase-activated deoxyribonuclease
• Diazepam
• Kainic Acid

Topics

• Animals
• Anticonvulsants (pharmacology)
• Apoptosis (physiology)
• Apoptosis Regulatory Proteins
• Brain (physiopathology)
• DNA Fragmentation (physiology)
• Deoxyribonucleases (antagonists & inhibitors, physiology)
• Diazepam (pharmacology)
• Enzyme Activation
• Hippocampus (physiopathology)
• Kainic Acid
• Male
• Neurons (physiology)
• Olfactory Pathways (physiopathology)
• Proteins (metabolism, physiology)
• Rats
• Rats, Sprague-Dawley
• Status Epilepticus (chemically induced, metabolism, physiopathology)