Post-ischemic treatment withe delta-9-THc protects against ischemia-induced neuronal injury with a bell-shaped-dose-response curve

During the last two decades, it has become clear that exogenous natural and synthetic cannabinoids exert neuroprotective functions in several models of neurotoxicity (Hampson et al., 1998; Nagayama et al. 1999; Panikashvli et al., 2001; Braida et al. 2000, 2003; van der Stelt et al., 2001a, 2001b; Veldhuis et al., 2003; Marsicano et al., 2003). About Δ9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, a neuroprotection either in vitro ( Hampson et al., 1998) or in vivo (Louw et al., 2000; Van der Stelt et al., 2001) in rat cortical neurons and in a model of rat forebrain ischemia has been found, respectively. To further investigate the effect of THC against neuronal injury in vivo, we injected the compound 5 minutes after transient global cerebral ischemia in Mongolian gerbils using a wide range of doses (0.05 - 2 mg/kg i.p.).To quantify the ischemic damage we measured from 1 hour to 7 days after recirculation, electroencephalographic (EEG) mean total spectral power, spontaneous motor activity, cognitive function, rectal temperature and hippocampal neuronal count. THC antagonized the electroencephalographic flattening of total spectral power and hyperlocomotion on day 7 and 1, respectively, with a dose-dependent bell-shaped curve: the neuroprotective effect was greatest with 1 mg/kg. The same dose, which decreased rectal temperature within the first hour, completely reversed ischemia-induced cognitive deficit, in the passive avoidance test evaluated on day 3. Experiments are in progress to clarify the mechanism by which THC shows its protective effect through the blockade of CB1, VR1vanilloid and opioid system.