TRAUMATIC NEUROPROTECTION WITH INHIBITORS OF NITRIC-OXIDE AND ADP-RIBOSYLATION

N-Methyl-D-aspartate (NMDA) receptor activation is known to contribute to neuronal damage from head trauma. Additionally, NMDA neurotoxicity occurs in part through the generation of nitric oxide (NO), and injur y from NO has been shown to be mediated by ADP-ribosylation. Therefore , we investigated whether inhibitors of NO and ADP-ribosylation would protect against acute CA1 traumatic neuronal injury in hippocampal sli ces subjected to fluid percussion. Treatment with the nitric oxide syn thase (NOS) inhibitor, methyl-L-arginine 170 mu M for 35 min after tra uma injury, improved CA1 antidromic population spike (PS) recovery to 91 +/- 2%, compared to unmediated slices which recovered to only a mea n of 20 +/- 4%, 90 min after trauma. Similarly, hemoglobin 50 mu M, wh ich directly binds NO, protected against traumatic neuronal injury and yielded a mean CA1 PS recovery of 92 +/- 1%. Treatment with inhibitor s of poly-ADP-ribosylation was also strongly protective, with the vita min nicotinamide 10 mM and 3-aminobenzamide 1 mM yielding PS recoverie s of 98 +/- 2% and 90 +/- 3%, respectively. Protection was also seen w ith inhibitors of mono-ADP-ribosylation, including novobiocin 500 mu M and meta-iodobenzylguanidine 20 mu M which yielded recoveries of 89 /- 6% and 96 +/- 26%. Novobiocin also protected against direct applica tion of NO and NMDA. These findings suggest that NO and ADP-ribosylati on are mediators of acute traumatic neuronal injury.