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Official websites use. Share sensitive information only on official, secure websites. Fax: ; E-mail: ckoczor emory. MDMA ecstasy is an illicit drug that stimulates monoamine neurotransmitter release and inhibits reuptake. MDMA acute cardiotoxicity has been explored, but neither long-term MDMA cardiac pathological changes nor epigenetic changes have been evaluated. Microarray analyses were employed to identify cardiac gene expression changes and epigenetic DNA methylation changes. Changes in MAPK and circadian rhythm gene expression were identified as early as 10 days. Moreover, MDMA induced gene expression of key elements of circadian rhythm regulatory genes. This suggests a fundamental organism-level event to explain some of the etiologies of MDMA dysfunction in the heart. MDMA 3,4-methylenedioxymethamphetamine, ecstasy is an illicit drug that stimulates monoamine neurotransmitter release and inhibits neurotransmitter reuptake Kalant, MDMA exhibits acute cardiotoxicity including tachycardia and ventricular arrhythmia which are associated pathogenetically with cardiomyopathy CM Battaglia et al. Conceptually, CM is likened to an energy-starved engine, where left ventricle hypertrophy is part of a continuum to CM Ahmad et al. Acute MDMA cardiotoxicity has been explored, but persistent genetic or cardiac pathological changes resulting from either chronic MDMA or after its use and subsequent abstinence have not been evaluated systematically. We posited that MDMA induces cardiotoxic events that relate to alterations in gene expression and epigenetics through DNA methylation, one of the most common epigenetic mechanisms for gene expression control. Previous studies in human CM identified pathogenetic changes in gene expression mediated by epigenetic DNA methylation modulation Koczor et al. To test our hypothesis, we exposed inbred mice to MDMA parenterally and examined epigenetic, gross pathologic and pathophysiological events in the murine heart. Functional and structural parameters included echocardiographic measurements and cardiac pathological changes. Microarray data analysis of cardiac gene expression and epigenetic DNA methylation changes were analyzed followed by qPCR-validation of microarray data to confirm findings. Among the differentially expressed cardiac DNA methylation and gene expression changes identified following MDMA, the most prominent were those involving genes of the circadian rhythm pathways. This previously undiscovered finding in the MDMA-treated heart suggests a previously unexplored relationship between the psychological stimulatory effect of MDMA thought to be key to its addiction and the life-threatening cardiovascular effects seen in tragic cases of overdose. All reagents were analytical grade Sigma Aldrich, St. Louis, Missouri unless otherwise indicated. Mice were 8—12 weeks old, and both genders were used. At the termination of each experimental protocol, mice were anesthetized with Avertin 0. Wet heart weight was obtained at postmortem dissection and normalized to mouse body weight. Gene expression analysis was performed as previously detailed by our group in previous articles Koczor et al. Arrays were washed, and scanned using Roche Nimblegen MS scanner. Images were analyzed using Nimblescan software as directed by the manufacturer, including RNA normalization and generation of expression data. Expression results were analyzed by t test using Bioconductor for R, with each set compared with saline controls. Heatmaps were generated using R. Results are expressed as fold change of saline controls. DNA methylation analysis was performed as described by us previously Koczor et al. Samples of the methylated and input DNA were validated for enrichment. For DNA methylation analysis, Nimblegen 2. Arrays were scanned using a MS scanner and were analyzed using proprietary Nimblescan software. Final analysis included a p -score of the detected methylated DNA peak and annotation to the probe location. DNA methylation results were analyzed using Bioconductor for R. Statistical analyses other than those used for microarray analyses described earlier were performed using GraphPad Prism 5. Survival data was analyzed using a Log-rank test. Analyses of day MDMA compared that treated group to its vehicle treated control. Results showed a In the longer term experiments, mice receiving MDMA daily for 35 days also exhibited a Experimental timelines. Experiments were designed to identify the effects of MDMA following short- and long-term use. MDMA was administered once daily for 10 days in the short-term group and once-daily for 35 days in the long-term group. Saline controls were used for both. Cardiac physiology, histology, and survival. Echocardiographic measurements and gross heart measurements were obtained at completion of the experiment. A, Wet heart weight showed a significant E, LV cardiac myocytes from hearts of mice treated with saline for 10 days. G, LV cardiac myocytes from hearts of mice treated with saline for 35 days. No evidence of cytological abnormality. Nuclear hypertrophy black arrow and multifocal contraction band changes blue arrow. Full color version available online. Survival data from this relatively short-term study revealed some interesting points. No change in survival was observed in murine cohorts treated with day MDMA compared with that of saline controls data not shown. However, a significant decrease in survival occurred precipitously in the long-term MDMA treatment group that received continuous day MDMA treatment compared with saline vehicle controls Fig. One died on treatment day 29; 6 died on treatment day Experiments were designed to identify groups of differentially regulated genes and enable cross evaluation between experimental sets. Using microarray technology, we analyzed gene expression profiles for changes resulting from MDMA use. Differential cardiac gene expression following MDMA. Differentially expressed genes are identified in Supplementary Table S2. Multi-set analysis identified genes associated with MDMA administration protocols. Figure 4 A highlights grouping of genes between experimental sets and their interpreted results. Of the genes that were differentially expressed in all groups, only were shared between at least 2 groups Sections D—G, Fig. This sharing was independent of fold change in gene expression. Of these genes, all 31 showed parallel gene expression directionality ie, each of the genes was either downregulated in both groups or upregulated in both groups. Three genes were downregulated and 28 upregulated compared with controls Section E, Fig. Pathway analysis of the kind we employed was unable to identify significant interaction between these 31 cardiac genes. Comparing and day MDMA differentially expressed genes, 83 genes were shared between groups while 82 of those genes also showed parallel differential gene expression; 69 were downregulated, 13 were upregulated Section F, Fig. Finally, Myh7 was differentially expressed in all 3 groups, but had variable directionality of expression change Section G. The explanation for this observation requires further exploration. Multiset analysis of MDMA-induced differential gene expression. Genes were identified by whether they appeared in individual groups ie, , day MDMA, etc. A, Interpretation of gene grouping. Genes that appeared each of the sections were identified as being related to certain responses to MDMA. B, The number of differentially expressed genes that were present in each of the functional groups. Lists of genes in each group are presented in Supplementary Table S3. Based on the microarray data earlier, we validated the microarray findings of the genes of interest by focusing on those members of circadian rhythm and MAPK signaling pathways Table 1. With the exception of PER3, these results are concordant with microarray results. Validation of targets was performed of select genes identified by pathway analysis. A, Four members of the circadian rhythm pathway were differentially expressed following or day MDMA by microarray data. B, Three members of the MAPK pathway were selected for further analysis and to validate the microarray results. MAPK11 also showed downregulation, validating microarray results. First, DNA methylation changes were determined independent of gene expression changes to identify global trends in DNA methylation patterns. Global DNA methylation analysis. DNA methylation arrays were compared pair-wise to appropriate saline controls to identify a global analysis of gene promoter DNA methylation in each group. B, The percentage of peaks hypermethylated and hypomethylated in each group. Results are tabulated in Supplementary Table S4. Gene promoter DNA methylation of differentially expressed genes. The DNA methylation changes were identified for the differentially expressed genes identified in Supplementary Table S2. A, Key to graphs. Each graph shows the number of differentially expressed genes that had no change in DNA methylation grey and the number of genes with changes in DNA methylation blue. Of the genes in blue, the percentage of genes hypermethylated green or hypomethylated red are shown in the neighboring graph. None of the differentially methylated peaks observed in the Myh7 promoter from each of the treatment cohorts were identical. Two overarching and important findings resulted from these studies. Our studies address pathogenetic cardiac changes that persist after relatively long-term MDMA abuse and relatively short-term MDMA use followed by abstinence. These changes are associated with an increase in cardiac heart weight These results were confirmed by histological examination of the tissues Fig. Although DNA methylation and gene expression changes are intriguing by themselves, it may further reflect on the psychosocial aspects of MDMA abuse in which the stimulation to stay active relates to alterations of circadian rhythms that promote increased daylight activity and mobility. Although more studies will help unravel the relationship further, a pathophysiological link between DNA methylation changes and CM was concluded Koczor et al. Studying MDMA cardiac effects in humans is not possible; however, results from current murine studies in vivo indicate MDMA causes hypermethylation of cardiac DNA prior to any measurable cardiac functional decline. This point argues that differential DNA methylation may be a sufficient cause for CM or a biomarker for CM if an appropriate surrogate tissue is available. Microarray technology was used to identify differentially expressed genes following MDMA. Interestingly, genes involved in essential biological rhythms, so called circadian rhythm genes, are more affected by continuous MDMA administration. The observed difference in gene expression profiles may suggest different mechanisms of cardiac dysfunction from MDMA depending on dose and duration, but additional studies are required to clarify this relationship. Our findings here suggest that those CNS effects may be extended analogously to the cardiovascular system and possibly other susceptible organ systems. This apparent contradiction may be an effect of microarray overestimation of gene expression changes, lack of sensitivity in the qRT-PCR assay, or combinations of factors. Studies that quantitatively analyze protein abundance and function of these circadian rhythm gene products will help determine the molecular and functional changes elicited by MDMA administration. Whether the changes in cardiac circadian gene expression is caused directly by interaction of MDMA with cardiac circadian control or is a secondary effect of CNS neurohumoral effects caused by MDMA neurotoxicity also requires experimental investigation, but is beyond the scope of this initial article. All of these genes were differentially expressed as a result of short-term 10 days MDMA; their expression did not change whether MDMA was continued or replaced by saline injections. The interrelationship or molecular impact of these gene expression changes is unknown, but their continued presence following MDMA supports a hypothesis that MDMA induces durable changes in cardiac gene expression. Of the 31 genes, 4 displayed DNA methylation changes. No change in cardiac function was observed. MDMA reduces gene expression following its administration either 10 or 35 days , and the circadian rhythm pathway appears significantly impacted in the heart by MDMA use. DNA methylation changes correlated with almost 1 in 5 differentially expressed genes, showing a trend toward hypermethylation in the gene promoters of differentially expressed genes and a global trend toward hypermethylation. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Toxicol Sci. Find articles by Christopher A Koczor. Find articles by Ivan Ludlow. Find articles by Zhe Jiao. Find articles by Earl Fields. Find articles by Tomika Ludaway. Find articles by Rodney Russ. Find articles by Rebecca A Torres. Find articles by William Lewis. Issue date Nov. All rights reserved. For Permissions, please e-mail: journals. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.
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At this time of day, the park is filled with runners, cyclists, seniors out for a stroll, tourists trailing suitcases behind them, mothers watching their children on the swings, gardeners, local police cars — and a handful of drug dealers. As soon as this reporter enters the Retiro at this spot, a dealer approaches. What do you want? The dealer is speaking in English, taking his potential customer for a foreigner. Later he becomes suspicious, as though he might be trying to sell to a plainclothes policeman. But finally names and phone numbers are exchanged. The authorities acknowledge this, but the amounts are insignificant compared with the large seizures that take place in the country. The dealers rarely carry more than a few grams on them, and when the quantity is larger, the deal is generally done outside the park. And in any case it is not hard for the dealers to get rid of their wares if the police decide to clamp down: the bushes, trash cans, hoses and sewers all come in handy for stashing the drugs. The police are in permanent circulation within the park — plainclothes policemen from the National Police force and uniformed municipal officers. The sellers are not Spaniards, they are all foreigners, and they usually leave it hidden around. Sometimes they get into arguments over who is controlling the market, and there are even robberies among themselves. The most delicate moment in petty drug dealing is when the transaction is actually taking place. Carrying hashish or marijuana for personal consumption is not a punishable offense, but dealing is. But the sellers at Retiro park are always the same, and they know how the police officers work — both those in uniform and the plainclothes ones as well. They even know each other in some cases, which means that arrests and full-on raids are pretty rare. Alejandro says he knows some of the people who regularly sell by the swings that his children go to in the afternoon. Apart from the drug dealing and the hustling, the main crime in the park is theft. The better the weather, the more visitors. And the more visitors, the more robberies. Those taking a nap or amorous couples are easy prey for the light-fingered, not to mention the peeping toms. English version by Heather Galloway. Luis de Vega. Madrid - Feb 27, - CET. Copy link. Palomo Madrid. Disfruta de nuestras lecciones personalizadas, breves y divertidas. Disfrute de nuestras lecciones personalizadas, breves y divertidas. Italiano online. Nuevo curso 'online'. Crucigramas minis. Crucigramas Tarkus. Sudokus mini. Sopas de letras. Global MBA. Clases virtuales. Posgrado en Recursos Humanos. Palabra secreta.
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