Drug-induced hypothermia begun 5 minutes after injury with a poly(adenosine 5′-diphosphate-ribose) polymerase inhibitor reduces hypoxic brain injury in rat pups*

Objective Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown promise in hypoxic ischemic brain damage. We wished to see if GPI-6150 (1,11b-dihydro-[2H]benzopyrano[4,3,2-de]isoquinolin-3-one), a specific PARP inhibitor, would reduce brain injury in a newborn animal model. Design Randomized controlled trial. Setting University laboratory. Subjects Seven-day-old rat pups. Intervention Subjects had the right carotid artery ligated and then received either vehicle or 5, 15, or 30 mg/kg GPI-6150 intraperitoneally 5 mins after the hypoxia. Hypoxia was produced by exposing the pups to 8% oxygen for 2.5 hrs. Measurements and main results Twenty-two days later, the brains were scored from normal to severely damaged and were weighed by a blinded observer. Twenty-four of 53 (45%) vehicle-treated pups, 11 of 22 (50%) 5 mg/kg treated pups, 22 of 23 (96%) 15 mg/kg treated pups (p <.01 vs. vehicle), and 16 of 31 (52%) 30 mg/kg treated pups were scored as normal. Right hemisphere weight was reduced by 15 +/- 2.6% in the vehicle group, 5.9 +/- 2.8% in the 5 mg/kg group, -0.4 +/- 1.7% in the 15 mg/kg group (p <.01 vs. vehicle), and 13.3 +/- 3.1% in the 30 mg/kg group. GPI-6150 decreased rectal temperature from 33 +/- 0.4 to 29 +/- 0.7 degrees C for 3 hrs after dosing, but temperatures returned to normal by 6 hrs. We maintained the body temperature at 35 degrees C for 6 hrs after injury in a group of pups treated with 15 mg/kg. Nine of 25 (41%) vehicle-treated and 15 of 26 (58%) GPI-6150-treated pups were scored as normal (p = nonsignificant). Right hemisphere weight was reduced by 25 +/- 4% in the vehicle group and 20 +/- 5% in the GPI-6150 group (p = nonsignificant). Conclusions GPI-6150 at a dose of 15 mg/kg dramatically decreased the number of pups sustaining brain injury, relative to vehicle, but is dependent on an induced decrease in core temperature to produce the effect.