Nitric oxide (NO) contributes to delayed hypoxic-ischemic brain injury. We found that inhibition of nitric oxide synthase (NOS) with 5mg/kg of L-nitroarginine methyl ester (L-NAME) given s.c. at the onset of recovery reduced brain atrophy in 7day old (P7) rats. Excess NO can be produced for days after recovery. Objective: To determine if neuroprotection can be achieved if L-NAME administration is delayed. Method: We produced a hypoxic-ischemic insult to the right cerebral hemisphere (H) of 78 P7 rats by permanent R common carotid artery ligation and exposure to 8% oxygen for 2.25h at 36.8C. A single treatment of L-NAME (5mg/kg) was administered after 1h, 4h, or 15h of recovery to groups of rats, a control group received Saline. At 14d recovery the pups were decapitated and the brains immersion fixed. From a 2mm thick consistently positioned coronal section through the damaged region, the loss of area of the damaged R vs L H was expressed as% RH atrophy: Atrophy was 28.7±17.0% (Mean ±SD) in the 27 Saline treated, 25.7±16.1% in the L-NAME 1h group (n=18), 26.3±17.9% in the L-NAME 4h group (n=18) and only 13.1±12.9% in the L-NAME 15h group(n=15),p<0.01 ANOVA (L-NAME 15h vs Saline). In 61 other rats we produced an identical cerebral insult and treated with Saline or L-NAME at 15h recovery only. Some rats (n=15 in each group) were killed at 42h recovery for measurement of RH swelling (wet-dry method), the rest recovered for 7days and the hemispheres were weighed fresh to calculate the% R hemisphere wt deficit. RH Swelling was 4.8±4.2% in the L-NAME 15h group vs15.1±8.4% in the Saline treated,P<.001. The% RH weight deficit was 8.8±15.2% in L-NAME 15h group (n=17) and 22.9±15.7% in the Saline treated(n=14),p=0.02. Conclusion: Delayed inhibition of NOS with L-NAME until 15h of recovery reduced early and late indicators of post hypoxic-ischemic brain injury in P7 rats by ≈67%.
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(Spon by: Charles Palmer)
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Palmer, C., Roberts, R. DELAYED INHIBITION OF NITRIC OXIDE PRODUCTION REDUCES POST HYPOXIC-ISCHEMIC BRAIN INJURY IN NEONATAL RATS † 1752. Pediatr Res 41 (Suppl 4), 294 (1997). https://doi.org/10.1203/00006450-199704001-01771
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DOI: https://doi.org/10.1203/00006450-199704001-01771