A Nonpsychotropic Cannabinoid, HU-211, Has Cerebroprotective Effects After Closed Head Injury in the Rat

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Abstract
HU-211 is a synthetic, nonpsychotropic cannabinoid, which has been shown to act as a noncompetitive N-methyl-d-asparate (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.