Cocaine induces cell death and activates the transcription nuclear factor kappa-b in pc12 cells

Lucilia B Lepsch,Rui Curi,Carolina D Munhoz,Cristoforo Scavone,Lidia M Yshii,Elisa M Kawamoto,Thais Ml Salgado,Maria F Curi-Boaventura,Larissa S Lima,Cleopatra S Planeta

doi:10.1186/1756-6606-2-3

Lucilia B Lepsch, Rui Curi + Show 8 more

Open Access

https://doi.org/10.1186/1756-6606-2-3

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Journal: Molecular Brain	Publication Date: Feb 1, 2009
Citations: 59	License type: cc-by

Affiliation: Universidade de São Paulo

Abstract

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-κB is a transcription factor that regulates gene expression involved in cellular death. Our aim was to investigate the toxicity and modulation of NF-κB 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-κB complex and the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, attenuated the NF-κB activation. Inhibition of NF-κB 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-κB 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.

Highlights

Cocaine is a drug of abuse with a prevalence of 2.8% in USA and 0.3% worldwide
Cocaine caused a time and concentration dependent activation of Nuclear factor-κB (NF-κB) in PC12 cells Nuclear extracts from cells treated with 1 mM cocaine for 6 hours presented three DNA/protein complexes indicated by EMSA assay (Figure 1A)
The antibodies against the p52 and c-Rel subunits did not affect DNA-protein complex (Figure 1C). This suggests that p50/p65 heterodimers were included in 32P-NF-κB/protein complex 1

Summary

Introduction

Cocaine is the second highest drug of abuse in USA, according to the United Nations Office on Drug and Crime (UNODC) This results in the stimulation of the brain reward pathway that can lead to the development of addiction [1,2]. Cocaine can induce neurological impairment (deficits in cognition, motivation, insight and attention), behavioral disinhibition, emotional instability, impulsiveness, and movement disorders [5,6]. The cellular mechanisms underlying this deficit have not been identified yet, several lines of investigation suggest that either necrotic or apoptotic neuronal death may account for drug-of-abuse-induced neurological impairment [9]

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