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 receptor antagonist, influences neurological outcome following closed head trauma (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 or sham operation. Closed head trauma induced the following changes in the injured hemisphere: Decreased specific gravity (sg) (1.036 ± 0.006) and magnesium (Mg) (0.042 ± 0.005 &mgr;g/mg) at 24 hours, and potassium (K) at 24 (1.145 ± 0.376 &mgr;g/mg) and 48 hours, and increased water content (W) (84.9 ± 2.5%) and sodium (Na) (2.135 ± 0.699 &mgr;g/mg) at 24 hours, and calcium (Ca) at 24 (0.543 ± 0.157 &mgr;g/mg) and 48 hours. These were reversed by NPS 1506; sg of 1.043 ± 0.004, Mg of 0.077 ± 0.009 &mgr;g/mg, K of 1.930 ± 0.238 &mgr;g/mg, W of 81.5 ± 1.9%, Ca of 0.043 ± 0.023 &mgr;g/mg, and Na of 0.688 ± 0.110 &mgr;g/mg. In groups not given NPS 1506, a nonsignificant 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 1506. NPS 1506 caused no significant change in ischemic tissue volume or hemorrhagic necrosis volume in the injured hemisphere at 24 hours or 48 hours. These findings indicate that NPS 1506 improved measures of brain tissue edema (at 24 hours but not at 48 hours) and ion homeostasis, and this improvement was not related to other measures of outcome.