NPS 1506: A novel NMDA receptor antagonist - Neuroprotective effects in a model of closed head trauma in rats

We examined whether NPS 1506, a novel uncompetitive N-methyl-D-aspartate re ceptor antagonist, influences neurological outcome following closed head tr auma (CHT) in rats. One hundred ten rats were divided into 11 groups: CHT ( yes/no), treatment with NPS 1506 (yes/no), and time of euthanization (24 h/ 48 h). The dose of NPS 1506 was 1 mg/kg IV at 1 and 4 hours following CHT o r sham operation. Closed head trauma induced the following changes in the i njured hemisphere: Decreased specific gravity (sg) (1.036 +/- 0.006) and ma gnesium (Mg) (0.042 +/- 0.005 mu g/mg) at 24 hours, and potassium (K) at 24 (1.145 +/- 9.376 mu g/mg) and 48 hours, and increased water content (W) (8 4.9 +/- 2.5%) and sodium (Na) (2.135 +/- 0.699 mu g/mg) at 24 hours, and ca lcium (Ca) at 24 (0.543 +/- 0.157 mu g/mg) and 48 hours. These were reverse d by NPS 1506; sg of 1.043 +/- 0.004, Mg of 0.077 +/- 0.009 mu g/mg, K of 1 .930 +/- 0.238 mu g/mg, W of 81.5 +/- 1.9%, Ca of 0.043 +/- 0.023 mu g/mg, and Na of 0.688 +/- 0.110 mu g/mg. In groups not given NPS 1506, a nonsigni ficant decrease in neurological severity score (NSS) occurred at 24 and 48 hours as compared to NSS at 1 hour after CHT. In groups given NPS 1506, NSS at 24 and 48 hours decreased significantly (improved) compared to NSS at 1 hour, but not compared to NSS at 24 and 48 hours in groups not given NPS 1 506. NPS 1506 caused no significant change in ischemic tissue volume or hem orrhagic necrosis volume in the injured hemisphere at 24 hours or 48 hours. These findings indicate that NPS 1506 improved measures of brain tissue ed ema (at 24 hours but not at 48 hours) and ion homeostasis, and this improve ment was not related to other measures of outcome.