Early postischemic dantrolene-induced amelioration of poly(ADP-ribose) polymerase-related bioenergetic failure in neonatal rat brain slices.
In the infant brain, ischemia-induced ionic and enzyme mechanisms may independently lead to cell death by energy depletion: resequestration of calcium mobilized from intracellular stores consumes ATP, and activated poly(ADP-ribose) polymerase (PARP) uses oxidized nicotinamide adenine dinucleotide to form polyADP-ribosyl nuclear proteins associated with DNA damage. Using 31P nuclear magnetic resonance spectroscopy, we have monitored intracellular pH and cellular energy metabolites in ex vivo neonatal rat cerebral cortex before, during, and after substrate and oxygen deprivation. In an insult that exhibited secondary energy failure and apoptosis we identified a relative 25% augmentation of high-energy phosphates at the end of recovery when the ryanodine-receptor antagonist, dantrolene, was introduced in the early (0- to 40-minute) but not late (40- to 120-minute) stage of recovery (P < 0.05). In contrast to the absence of a late dantrolene-sensitive effect, inhibition of PARP with 3-methoxybenzamide was as effective (P < 0.05) as early dantrolene, even when introduced after a 40-minute delay. The dantrolene and 3-methoxybenzamide effects on high-energy phosphates were not additive, rather the early dantrolene-sensitive effect nullified the potential 3-methoxybenzamide effect. Therefore, in this vascular-independent neonatal preparation, postischemic mobilization of calcium from intracellular stores is associated with PARP-related energy depletion. Inhibition of either of these processes confers improved postischemic bioenergetic recovery in the developing brain.
Tasker
R C
RC
Paediatric Intensive Care Unit, Great Ormond Street Hospital for Children, The Royal College of Surgeons, London, England.
Sahota
S K
SK
Cotter
F E
FE
Williams
S R
SR
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D053938:DNA Fragmentation / Q000502:physiology; D003620:Dantrolene / Q000494:pharmacology*; D004734:Energy Metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D015424:Reperfusion; D013379:Substrate Specificity
D001549:Benzamides; D004791:Enzyme Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D003620:Dantrolene; C025159:3-methoxybenzamide