Cocaine induces cell death and activates the transcription nuclear factor kappa-B in PC12 cells.
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.
Lepsch
Lucilia B
LB
Department of Pharmacology Institute of Biomedical Sciences, University of São Paulo, Avenida Professor Lineu Prestes, 1524, 05508-900-São Paulo, Brazil. lepsch@usp.br
Munhoz
Carolina D
CD
Kawamoto
Elisa M
EM
Yshii
Lidia M
LM
Lima
Larissa S
LS
Curi-Boaventura
Maria F
MF
Salgado
Thais M L
TM
Curi
Rui
R
Planeta
Cleopatra S
CS
Scavone
Cristoforo
C
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology / Q000633:toxicity*; D053938:DNA Fragmentation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016716:PC12 Cells; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012980:Sodium Salicylate / Q000494:pharmacology; D013049:Spectrin / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors
D001552:Benzazepines; D019208:Brain-Derived Neurotrophic Factor; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C534628:SCH 23390; D013859:Thiocarbamates; D013049:Spectrin; C066229:prolinedithiocarbamate; D000072000:NF-KappaB Inhibitor alpha; D011392:Proline; D053148:Caspase 3; D003042:Cocaine; D012980:Sodium Salicylate