LONG-TERM EFFECT OF HU-211, A NOVEL NONCOMPETITIVE NMDA ANTAGONIST, ON MOTOR AND MEMORY FUNCTIONS AFTER CLOSED-HEAD INJURY IN THE RAT

HU-211 is a synthetic, non-psychotropic cannabinoid which acts as a no n-competitive NMDA antagonist and antioxidant. We studied the drug's t herapeutic window as well as its long-term effect on cognitive and mot or functions in a model of closed head injury (CHI) in the rat. A weig ht-drop device was used to induce CHI in ether anesthetized male rats. HU-211 (5 mg/kg) was administered i.v. to the experimental groups. Fo r the therapeutic window study, drug was injected at 4 or 6 h after CH I. Edema (water content) and clinical status (neurological severity sc ore, NSS) were evaluated at 24 h. Reduction of edema was slight, where as improvement of NSS was significant when the drug was administered a t 4 or 6 h (P=0.0023 and 0.059, respectively). To determine the drug's long-term effect, it was administered 1 h after CHI and additional do ses were later given. NSS was evaluated for a period of 30 d. A single dose of HU-211 given 1 h post-CHI improved the clinical outcome durin g the 30 d period (P<0.01). Repetitive doses of HU-211 injected during the post traumatic period had similar effects. Cognitive functions we re evaluated in the Morris water maze, with rats trained either before or after CHI. CHI resulted in a highly significant impairment of thes e abilities, whereas HU-211 treatment 1 h after CHI improved performan ce. Our results indicate that HU-211 is a potent cerebroprotective age nt, with a therapeutic window of about 4 h. The beneficial response ob tained even after a single dose was long lasting, and ameliorated impa irment of both motor and cognitive functions following CHI.