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

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.

A Comprehensive View of the Neurotoxicity Mechanisms of Cocaine and Ethanol

“…Moreover, cocaine-induced PC 12 cell death was associated with a decrease of the levels of anti-apoptotic Bcl-2 protein, but no change in the pro-apoptotic Bax, altering, therefore, the Bax/Bcl-2 ratio, leading to the activation of caspase-3 that triggers cell apoptosis (Lepsch et al 2009). In agreement with these results, Costa et al (2013) verified a significant increase of Bax/Bcl-X L ratio in microglial cells, with activation of caspase-3, indicating the kinetics of cell death in the presence of cocaine.…”

Role of Mitochondria on the Neurological Effects of Cocaine

“…Cocaine exposure was shown to dissipate ΔΨ m in rat cortical neurons (Cunha-Oliveira et al, 2006a, in isolated brain mitochondria (Cunha-Oliveira et al, 2013d), and in C6 astroglioma cells (Badisa, Darling-Reed, & Goodman, 2010). Further evidence for the activation of the intrinsic apoptotic signaling by cocaine includes alterations in Bcl-2 and Bax protein levels (Dey, Mactutus, Booze, & Snow, 2007;Lepsch et al, 2009;Xiao & Zhang, 2008), cytochrome c (Cunha- Oliveira et al, 2006aOliveira et al, , 2010, and AIF (AlvaroBartolome et al, 2011) release from mitochondria, and caspase-9 activation (Cunha- Oliveira et al, 2006a). This apoptotic signaling is associated with mitochondrial dysfunction in rat cortical neurons, occurring simultaneously with decreased ATP levels and increased intracellular calcium concentration (Cunha-Oliveira et al, 2010), which may be partially explained by the loss of ΔΨ m that drives mitochondrial calcium uptake.…”

Mitochondrial complex I dysfunction induced by cocaine and cocaine plus morphine in brain and liver mitochondria

“…Neurotoxicity of cocaine has been associated with mitochondrial-mediated apoptotic cell death, including changes in Bcl-2 and Bax expression (Dey et al, 2007;Lepsch et al, 2009;Xiao and Zhang, 2008), loss of mitochondrial potential, cytochrome c release and activation of initiator caspases from the intrinsic pathway (Cunha-Oliveira et al, 2008). Cocaine has been shown to induce hepatotoxicity (Van Thiel and Perper, 1992) and mitochondrial dysfunction in hepatic cells (Devi and Chan, 1997).…”