3,4-Methylenedioxymethamphetamine Alters Left Ventricular Function and Activates Nuclear Factor-Kappa B (NF-kB) in a Time and Dose Dependent Manner

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) is an illicit psychoactive drug with cardiovascular effects that have not been fully described. In the current study, we observed the effects of acute MDMA on rabbit left ventricular function. We also observed the effects of MDMA on nuclear factor-kappa B (NF-κB) activity in cultured rat ventricular myocytes (H9c2). In the rabbit, MDMA (2 mg/kg) alone caused a significant increase in heart rate and a significant decrease in the duration of the cardiac cycle. Inhibition of nitric oxide synthase (NOS) by pretreatment with L-NAME (10 mg/kg) alone caused significant dysfunction in heart rate, systolic pressure, diastolic pressure, duration of relaxation, duration of cardiac cycle, and mean left ventricular pressure. Pretreatment with L-NAME followed by treatment with MDMA caused significant dysfunction in additional parameters that were not abnormal upon exposure to either compound in isolation: duration of contraction, inotropy, and pulse pressure. Exposure to 1.0 mM MDMA for 6 h or 2.0 μM MDMA for 12 h caused increased nuclear localization of NF-κB in cultured H9c2 cells. The current results suggest that MDMA is acutely detrimental to heart function and that an intact cardiovascular NOS system is important to help mitigate early sequelae in some functional parameters. The delayed timing of NF-κB activation suggests that this factor may be relevant to MDMA induced cardiomyopathy of later onset.

Effects of adenosine A2a receptor agonist and antagonist on hippocampal nuclear factor-kB expression preceded by MDMA toxicity

“…In line with this observation, two previous studies have reported that increased NF-kB expression in the myocardium and liver following MDMA administration appeared to activate NF-kB following MDMA exposure, which in turn upregulated the expression of cytokines and cellular adhesion molecules that have important roles in inflammatory responses ( 20 ). The activation of these genes by MDMA suggests that the cells are subjected to and that a cellular compensatory response is initiated to counteract the exposure and promote survival ( 14 , 20 ).There is some evidence linking MDMA exposure to increased lymphocyte infiltration and inflammatory damage to the myocardium ( 39 ). The cellular and molecular mechanisms involved in causing these effects have not been fully elucidated.…”

“…Several studies have demonstrated that MDMA neurotoxicity can be mediated, in part, via activation of neuroinflammatory responses ( 18 - 19 ). The oxidative stress created by MDMA in these studies can promote NF-kB activation, modulate downstream genetic expression, and induce an inflammatory response ( 20 ). Oxidative stress has been proposed as a potential mechanism of ethanol-induced neurodegeneration in the developing, mature, and aging cerebellum ( 21 ).…”