HU-211 is a synthetic, nonpsychotropic cannabinoid, which has been shown to act as a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. The cerebroprotective effects of this compound were assessed in a model of closed head injury in rats. Head trauma (HT) was induced in ether-anesthetized rats by a weight-drop device; recovery was followed up to 48 h. The clinical status of the rats was evaluated at 1, 24, and 48 h after injury, and the extent of edema formation was determined by specific gravity (SG) and water content measurements at 24 or 48 h. The integrity of the blood-brain barrier (BBB) was investigated using Evans-Blue extravasation at 4 h after HT. HU-211 at a dose of 25 mg/kg in middle-chain triglycerides (MCT) oil was given intraperitoneally immediately and 1, 2, or 3 h after impact, and its effect on the various parameters was studied. The drug was found to be very effective in improving motor function recovery. When the drug was given 1 h after HT, the percent of rats able to perform beam walking task on 8.5- and 5-cm wide beams was increased from 30% and 0% to 79% (p = 0.0172) and 57% (p = 0.0029), respectively. The percent of rats able to balance on a 1.5-cm beam for 20 and 40 sec was also significantly increased, from 9% and 0% to 72% (p = 0.0037) and 50% (p = 0.078), respectively. The drug was also effective in reducing the BBB breakdown by more than four fold, as compared with control (548 +/- 94 versus 128 +/- 19 ng Evans blue/g tissue; p < 0.05) and attenuating cerebral edema. SG was 1.0367 +/- 0.0007 versus 1.0399 +/- 0.0005, and percent water content was 83.06 +/- 0.57 versus 80.78 +/- 0.36 (p < 0.05) in control and HU-211 treated rats, respectively. Similar significant protection was found when the drug was injected 2 h after the injury; however, at 3 h the effect was somewhat less pronounced. We suggest that this novel drug is a potential cerebroprotector in head trauma with a therapeutic window of at least 2 to 3 h.