CA-45 ACCUMULATION IN RAT-BRAIN AFTER CLOSED-HEAD INJURY - ATTENUATION BY THE NOVEL NEUROPROTECTIVE AGENT HU-211

Ca-45 accumulation was studied autoradiographically as a marker for le thally injured brain tissue following closed head injury (CHI), and ap plied to an investigation of the neuroprotective effect of the non-psy choactive cannabinoid(+)-(3S,4S)-7-hydroxy-D-6 tetrahydro-cannabinol 1 ,1-dimethylheptyl (HU-211). Amassment of Ca-45 in rat brain was examin ed 24 or 72 h after induction of CHI in the left hemisphere by a weigh t-drop device. Concentration of Ca-45 within 15 different brain region s was assessed by relative optical density. There was increased Ca-45 accumulation in the hemisphere ipsilateral to the side of the insult a s compared with the contralateral hemisphere. The highest density of r adioactive labeling was found in the anterior cortex and in the fronta l parts of the parietal cortex, with accumulation expanding as a funct ion of time post injury. On the third day following trauma the amount of accumulated Ca-45 was higher than that at 24 h after CHI, with more distant Ca-45-accumulating structures involved: the ventral posterola teral nucleus of the thalamus and the substantia nigra. Histological e xamination revealed necrotic tissue in the regions accumulating Ca-45. HU-211, a stereoselective inhibitor of the N-methyl-D-aspartate (NMDA ) receptor, was injected immediately after induction of trauma. One da y after trauma, HU-211 had significantly decreased both the volume of the Ca-45 accumulating zone and the concentration of the amassed radio isotope. In the HU-211 treated rats a considerable reduction in radioa ctive labeling was also found 72 h after trauma. The ability of HU-211 to decrease Ca-45 accumulation after head trauma is probably due to i ts ability to attenuate Ca2+ fluxes through the NMDA receptor-mediated calcium channels and to reduce the depolarization evoked Ca2+ fluxes. On the basis of our results, HU-211 seems to be a promising therapeut ic agent for head trauma in humans.