We have shown that Allopurinol (Allo) can reduce hypoxic-ischemic (HI) brain injury in 7 day old (P7) rats even when Allo (135mg/kg) is injected s.c. 15 min after termination of the insult. The post resuscitation time window during which Allo can reduce brain injury has not been explored. Objective: To determine if delayed administration of Allo, up to 4h after a HI insult to the brain of the P7 rat, can reduce brain injury. We produced a HI insult to the R cerebral hemisphere of 80 P7 rats by permanent R common carotid artery ligation and exposure to 8% oxygen for 2.25h at 36.8C. The rats then recovered with their dams in room air. Twenty rats per group were treated with a single s.c. injection of Saline (at 30min of recovery) or Allo (135mg/kg) at 30min, 60min, or 120min of recovery from the insult. At 42h of recovery we decapitated the rats and calculated% R hemisphere swelling (wet-dry wt. method). The RH swelled 23.7±10.7% (Mean ±SD) in the Saline group; In the Allo 30min group 7.4±10.3%; in the Allo 60min group 10.6±13.8% and in the Allo 120min group 17.5±8.7%, P = <0.001(Allo 30 and 60 vs Saline). In 44 other rats we produced an identical cerebral insult and treated with a single dose of Saline or Allo (135mg/kg) s.c. at 1 or 4h of recovery. At 14d recovery the rats were decapitated, the brains removed and immersion fixed. From three 2mm thick consistently positioned coronal sections through the damaged region of each brain, the average loss of area of the damaged R vs LH was expressed as%RH atrophy: RH atrophy was 41.1±18.2% (Mean ±SD) in the Saline treated group (n=15). In the Allo 1h group (n=13), it was 23.0±14.9% and in the Allo 4h group(n=16) it was 22.8±15.2%, P = <0.01 (Allo 1h and 4h groups vs Saline). Conclusion: A single dose of Allo (135mg/kg) s.c. administered 4 hours after the HI insult, markedly reduced brain injury in neonatal rats. This study suggest that the time window for neuroprotective intervention following birth asphyxia may span hours.
