V. Nadler et al., CA-45 ACCUMULATION IN RAT-BRAIN AFTER CLOSED-HEAD INJURY - ATTENUATION BY THE NOVEL NEUROPROTECTIVE AGENT HU-211, Brain research, 685(1-2), 1995, pp. 1-11
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.