Department of Pharmacology Institute of Biomedical Sciences, University of São Paulo, Avenida Professor Lineu Prestes, 1524, 05508-900-São Paulo, Brazil.
Mol Brain. 2009 Feb 1;2:3. doi: 10.1186/1756-6606-2-3.
Cocaine is a worldwide used drug and its abuse is associated with physical, psychiatric and social problems. The mechanism by which cocaine causes neurological damage is very complex and involves several neurotransmitter systems. For example, cocaine increases extracellular levels of dopamine and free radicals, and modulates several transcription factors. NF-kappaB is a transcription factor that regulates gene expression involved in cellular death. Our aim was to investigate the toxicity and modulation of NF-kappaB activity by cocaine in PC 12 cells. Treatment with cocaine (1 mM) for 24 hours induced DNA fragmentation, cellular membrane rupture and reduction of mitochondrial activity. A decrease in Bcl-2 protein and mRNA levels, and an increase in caspase 3 activity and cleavage were also observed. In addition, cocaine (after 6 hours treatment) activated the p50/p65 subunit of NF-kappaB complex and the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, attenuated the NF-kappaB activation. Inhibition of NF-kappaB activity by using PDTC and Sodium Salicilate increased cell death caused by cocaine. These results suggest that cocaine induces cell death (apoptosis and necrosis) and activates NF-kappaB in PC12 cells. This activation occurs, at least partially, due to activation of D1 receptors and seems to have an anti-apoptotic effect on these cells.
可卡因是一种在全球范围内使用的毒品,其滥用与身体、精神和社会问题有关。可卡因导致神经损伤的机制非常复杂,涉及多种神经递质系统。例如,可卡因增加多巴胺和自由基的细胞外水平,并调节几种转录因子。NF-κB 是一种转录因子,可调节涉及细胞死亡的基因表达。我们的目的是研究可卡因对 PC12 细胞 NF-κB 活性的毒性和调节作用。用可卡因(1mM)处理 24 小时可诱导 DNA 片段化、细胞膜破裂和线粒体活性降低。还观察到 Bcl-2 蛋白和 mRNA 水平降低,caspase 3 活性和裂解增加。此外,可卡因(处理 6 小时后)激活了 NF-κB 复合物的 p50/p65 亚基,用 D1 受体拮抗剂 SCH 23390 预处理细胞可减弱 NF-κB 的激活。使用 PDTC 和 Sodium Salicilate 抑制 NF-κB 活性会增加可卡因引起的细胞死亡。这些结果表明,可卡因诱导 PC12 细胞死亡(凋亡和坏死)并激活 NF-κB。这种激活至少部分是由于 D1 受体的激活,并且似乎对这些细胞具有抗凋亡作用。