Jüttler Eric, Potrovita Ioana, Tarabin Victoria, Prinz Simone, Dong-Si Tuan, Fink George, Schwaninger Markus
Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
Neuropharmacology. 2004 Sep;47(4):580-92. doi: 10.1016/j.neuropharm.2004.05.009.
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.
外源性和内源性大麻素已在体外和体内显示出神经保护作用。尽管大麻素的许多药理作用已被确定，但其神经保护机制仍存在争议。在此，我们首次通过核染色和流式细胞术分析，在神经元样细胞系以及原代神经元中，证明了合成大麻素右吗喃醇通过抑制细胞凋亡发挥保护作用。我们进一步提供了右吗喃醇抑制核因子-κB（NF-κB）的证据：右吗喃醇抑制（1）NF-κB抑制因子IkappaBalpha的磷酸化和降解以及NF-κB向细胞核的转位；右吗喃醇降低（2）NF-κB的转录活性以及（3）NF-κB靶基因肿瘤坏死因子-α和白细胞介素-6（TNF-α和IL-6）的mRNA积累。右吗喃醇不与大麻素（CB）受体1和2结合。为了研究其作用机制，我们使用了非抗氧化CB1受体激动剂WIN 55,212-2和仅与CB1受体弱结合的抗氧化剂大麻酚。两种大麻素均模拟了右吗喃醇对NF-κB和细胞凋亡的作用。这表明大麻素的抗氧化特性以及与CB1或CB2受体的结合均不是抑制NF-κB活性和细胞凋亡的原因。我们的结果清楚地表明右吗喃醇抑制NF-κB。在缺血性和神经退行性神经疾病的体外和体内模型中，NF-κB已被证明与脑损伤有关并促进神经元细胞死亡。
