Spatio-temporal profile of DNA fragmentation and its relationship to patterns of epileptiform activity following focally evoked limbic seizures.
The specific electrographic activity responsible for seizure-induced DNA damage remains little explored. We therefore examined the regional and temporal appearance of DNA fragmentation and cell death and its relationship to specific electrographic seizure patterns in a rat model of focally evoked limbic epilepsy. Animals received intra-amygdaloid injection of kainic acid (KA) to induce seizures for 45 min during continuous electroencephalographic (EEG) monitoring, after which diazepam (30 mg/kg) was administered. DNA polymerase I-mediated biotin-dATP nick translation (PANT) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) were used to detect single- and double-stranded DNA breaks, respectively. Injection of 0.01 microg KA induced seizures characterized by ictal fast activity but without consequent brain injury. By contrast, 0.1 microg KA induced an additional pattern of seizure activity characterized by bursts of high frequency polyspike paroxysmal discharges. In these animals, there was a significant reduction in numbers of pyramidal neurons within the ipsilateral and contralateral CA3 subfield of the hippocampus, detectable as little as 4 h following seizures. PANT- and TUNEL-positive cells appeared in similar numbers 16 h following seizure cessation within the CA3, declining after 72-96 h. Varying the duration of polyspike paroxysmal discharges determined that as little as 30 s elicited maximal injury. These data suggest single- and double-stranded DNA breaks are generated during the cell death process and are consequent on a specific component of seizure activity electrographically determined.
Henshall
D C
DC
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. dhenshal@lhs.org
Sinclair
J
J
Simon
R P
RP
D000818:Animals; D016923:Cell Death; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists; D007839:Functional Laterality; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D007608:Kainic Acid; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid