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 injury 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 slices subjected to fluid percussion. Treatment with the nitric oxide synthase (NOS) inhibitor, methyl-L-arginine 170 microM for 35 min after trauma injury, improved CA1 antidromic population spike (PS) recovery to 91 +/- 2%, compared to unmediated slices which recovered to only a mean of 20 +/- 4%, 90 min after trauma. Similarly, hemoglobin 50 microM, which directly binds NO, protected against traumatic neuronal injury and yielded a mean CA1 PS recovery of 92 +/- 1%. Treatment with inhibitors of poly-ADP-ribosylation was also strongly protective, with the vitamin nicotinamide 10 mM and 3-aminobenzamide 1 mM yielding PS recoveries of 98 +/- 2% and 90 +/- 3%, respectively. Protection was also seen with inhibitors of mono-ADP-ribosylation, including novobiocin 500 microM and meta-iodobenzylguanidine 20 microM which yielded recoveries of 89 +/- 6% and 96 +/- 26%. Novobiocin also protected against direct application of NO and NMDA. These findings suggest that NO and ADP-ribosylation are mediators of acute traumatic neuronal injury.
Wallis
R A
RA
Department of Neurology UCLA, Sepulveda 91343, USA.
Panizzon
K L
KL
Girard
J M
JM
D000246:Adenosine Diphosphate Ribose / Q000037:antagonists & inhibitors*; D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000503:physiopathology; D004594:Electrophysiology; D005071:Evoked Potentials; D006454:Hemoglobins / Q000627:therapeutic use; D006624:Hippocampus / Q000293:injuries* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine / Q000627:therapeutic use
D006454:Hemoglobins; D018696:Neuroprotective Agents; D000246:Adenosine Diphosphate Ribose; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase