Exogenous and endogenous cannabinoids have been shown to have neuroprotective effects in vitro and in vivo. Although many of the pharmacological effects of cannabinoids have been identified, the mechanism of neuroprotection still represents a controversy. Here we demonstrate for the first time protective effects of the synthetic cannabinoid dexanabinol by inhibiting apoptosis in a neuron-like cell line using nuclear staining and FACS analysis and in primary neurons. We provide further evidence of inhibition of nuclear factor-kappakappa B (NF-kappaB) by dexanabinol: Dexanabinol inhibits (1) phosphorylation and degradation of the inhibitor of NF-kappaB IkappaBalpha and translocation of NF-kappaB to the nucleus; dexanabinol reduces (2) the transcriptional activity of NF-kappaB and (3) mRNA accumulation of the NF-kappaB target genes tumor necrosis factor-alpha and interleukin-6 (TNF-alpha and IL-6). Dexanabinol does not bind to cannabinoid (CB) receptors 1 and 2. To investigate the mechanism of action, we employed the non-antioxidant CB1 receptor agonist WIN 55,212-2 and the antioxidant cannabinol, which binds to CB1 receptors only weakly. Both cannabinoids mimicked the effect of dexanabinol on NF-kappaB and apoptosis. This suggests that neither the antioxidant properties of cannabinoids nor binding to CB1 or CB2 receptors are responsible for the inhibition of NF-kappaB activity and apoptosis. Our results clearly demonstrate that dexanabinol inhibits NF-kappaB. NF-kappaB has been shown to be involved in brain damage and to promote neuronal cell death in vitro and in in vivo models of ischemic and neurodegenerative neurological diseases.