Carracedo Arkaitz, Geelen Math J H, Diez María, Hanada Kentaro, Guzmán Manuel, Velasco Guillermo
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.
Biochem J. 2004 Jun 1;380(Pt 2):435-40. doi: 10.1042/BJ20031714.
Cannabinoids induce apoptosis on glioma cells via stimulation of ceramide synthesis de novo, whereas they do not affect viability of primary astrocytes. In the present study, we show that incubation with Delta9-tetrahydrocannabinol did not induce accumulation of ceramide on astrocytes, although incubation of these cells in a serum-free medium (with or without cannabinoids) led to stimulation of ceramide synthesis de novo and sensitization to oxidative stress. Thus treatment with H2O2 induced apoptosis of 5-day-serum-deprived astrocytes and this effect was abrogated by pharmacological blockade of ceramide synthesis de novo. The sensitizing effect of ceramide accumulation may depend on p38 mitogen-activated protein kinase activation rather than on other ceramide targets. Finally, a protective role of cannabinoids on astrocytes is shown as a long-term incubation with cannabinoids prevented H2O2-induced loss of viability in a CB1 receptor-dependent manner. In summary, our results show that whereas challenge of glioma cells with cannabinoids induces accumulation of de novo -synthesized ceramide and apoptosis, long-term treatment of astrocytes with these compounds does not stimulate this pathway and also abrogates the sensitizing effects of ceramide accumulation.
大麻素通过刺激神经酰胺的从头合成诱导胶质瘤细胞凋亡，而它们不影响原代星形胶质细胞的活力。在本研究中，我们发现，用Δ9-四氢大麻酚孵育不会诱导星形胶质细胞中神经酰胺的积累，尽管将这些细胞在无血清培养基中孵育（无论有无大麻素）会导致神经酰胺从头合成的刺激以及对氧化应激的敏感性增加。因此，用H2O2处理可诱导5天血清剥夺的星形胶质细胞凋亡，并且这种作用可通过神经酰胺从头合成的药理学阻断而消除。神经酰胺积累的致敏作用可能取决于p38丝裂原活化蛋白激酶的激活，而不是其他神经酰胺靶点。最后，大麻素对星形胶质细胞的保护作用表现为，与大麻素长期孵育以CB1受体依赖性方式防止了H2O2诱导的活力丧失。总之，我们的结果表明，用大麻素攻击胶质瘤细胞会诱导从头合成的神经酰胺积累和凋亡，而用这些化合物长期处理星形胶质细胞不会刺激该途径，并且还消除了神经酰胺积累的致敏作用。
