Chronic Cocaine-Induced Cardiac Oxidative Stress and Mitogen-Activated Protein Kinase Activation: The Role of Nox2 Oxidase

Abstract

Chronic cocaine exposure is associated with severe cardiac complications, but the mechanisms of cocaine cardiotoxicity remain unclear, and current therapies are unsatisfactory. We investigated the hypothesis of oxidative stress-mediated cardiotoxicity and the role of NADPH oxidase in this process in a mouse model of chronic escalating "binge" cocaine administration (milligrams per kilogram): days 1 to 4 at 3 ϫ 15 mg, days 5 to 8 at 3 ϫ 20 mg, days 9 to 12 at 3 ϫ 25 mg, and days 13 to 14 at 3 ϫ 30 mg. Compared with vehicle controls, chronic binge cocaine administration significantly increased the cardiac NADPH-dependent O 2 . production (1.96-Ϯ 0.4-fold) as detected by tiron (an O 2 . scavenger)-inhibitable lucigenin chemiluminescence and dihydroethidium fluorescence. Cocaine-induced reactive oxygen species (ROS) production was associated with significant increases (ϳ2-fold) in the protein expressions of Nox2 (an isoform of NADPH oxidase) and its regulatory subunits: p22 phox

Cocaine Up-regulation of the Norepinephrine Transporter Requires Threonine 30 Phosphorylation by p38 Mitogen-activated Protein Kinase

“…Rat PFC and HTR cells express p38 MAPK as well as activated p38 MAPK (phospho-p38 MAPK). The MAPK pathway plays a key role in neuroadaptations induced by drugs of abuse (26,49,50). The present study demonstrates that cocaine-induced NET up-regulation (increased NE transport and surface NET level) is p38 MAPK dependent.…”

“…Specific NE uptake was measured by subtracting NE uptake measured in the presence of 10 M DMI from total uptake measured in the absence of DMI. NE uptake in cells transfected with WT-hNET or T30A-hNET was measured in the presence of cocaine concentrations from 10 nM to 1 mM to calculate K i values by nonlinear least-squares fits, using two-parameter logistic equations (Kaleidagraph, Synergy Software, Reading, PA): the percentage of specific NE transport remaining ϭ 100/[1 ϩ (IC 50 …”

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

“…Cocaine is known to produce stress signals and MAPK activation in cardiomyocytes (55), and it is possible such mechanisms may exist in the brain, contributing to behavioral plasticity. A single injection of SB203580 prior to cocaine significantly blocked cocaine-evoked locomotor sensitization when given prior to cocaine challenge.…”

Cocaine induces oxidative damage to skin via xanthine oxidase and nitric oxide synthase

“…Given that the model is based on cell culture, the procedure of cocaine treatment was different compared to in vivo environment. Since HaCaT cells represent human keratinocytes cells, which are known to be less vulnerable to different stressors than other types of cells [58], they were treated with higher cocaine concentration compared to other cells as described in the literature: nerve cells [71], hepatocytes [6,72] and cardiac myocytes [3]. Indeed, a significant decrease in cell viability was observed only from cocaine dose of 4 mM (Fig.…”