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 indep endently lead to cell death by energy depletion: resequestration of calcium mobilized from intracellular stores consumes ATP, and activated poly(ADP-r ibose) polymerase (PARP) uses oxidized nicotinamide adenine dinucleotide to form poly ADP-ribosyl nuclear proteins associated with DNA damage. Using P -31 nuclear magnetic resonance spectroscopy, we have monitored intracellula r pH and cellular energy metabolites in ex vivo neonatal rat cerebral corte x before, during, and after substrate and oxygen deprivation. In an insult that exhibited secondary energy failure and apoptosis we identified a relat ive 25% augmentation of high-energy gp phosphates at the end of recovery wh en the ryanodine-receptor antagonist, dantrolene, was introduced in the ear ly (Oto 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, in hibition of PARP with 3-methoxybenzamide was as effective (P < 0.05) as ear ly 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-me thoxybenzamide effect. Therefore, in this vascular-independent neonatal pre paration, postischemic mobilization of calcium from intracellular stores is associated with PARP-retated energy depletion. Inhibition of either of the se processes confers improved postischemic bioenergetic recovery in the dev eloping brain.