title: Elucidating the neurotoxic effects of MDMA and its analogs.
abstract: OBJECTIVE
  There is a rapid increase in the use of methylenedioxymethamphetamine (MDMA) and its structural congeners/analogs globally. MDMA and MDMA-analogs have been synthesized illegally in furtive dwellings and are abused due to its addictive potential. Furthermore, MDMA and MDMA-analogs have shown to have induced several adverse effects. Hence, understanding the mechanisms mediating this neurotoxic insult of MDMA-analogs is of immense importance for the public health in the world.
  
  
  METHODS
  We synthesized and investigated the neurotoxic effects of MDMA and its analogs [4-methylenedioxyamphetamine (MDA), 2, 6-methylenedioxyamphetamine (MDMA), and N-ethyl-3, 4-methylenedioxyamphetamine (MDEA)]. The stimulatory or the dopaminergic agonist effects of MDMA and MDMA-analogs were elucidated using the established 6-hydroxydopamine lesioned animal model. Additionally, we also investigated the neurotoxic mechanisms of MDMA and MDMA-analogs on mitochondrial complex-I activity and reactive oxygen species generation.
  
  
  RESULTS
  MDMA and MDMA-analogs exhibited stimulatory activity as compared to amphetamines and also induced several behavioral changes in the rodents. MDMA and MDMA-analogs enhanced the reactive oxygen generation and inhibited mitochondrial complex-I activity which can lead to neurodegeneration. Hence the mechanism of neurotoxicity, MDMA and MDMA-analogs can enhance the release of monoamines, alter the monoaminergic neurotransmission, and augment oxidative stress and mitochondrial abnormalities leading to neurotoxicity.
  
  
  CONCLUSIONS
  Thus, our study will help in developing effective pharmacological and therapeutic approaches for the treatment of MDMA and MDMA-analog abuse.
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Senthilkumar S
authors.initials: SS
authors.lastname: Karuppagounder
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Dwipayan
authors.initials: D
authors.lastname: Bhattacharya
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Manuj
authors.initials: M
authors.lastname: Ahuja
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Vishnu
authors.initials: V
authors.lastname: Suppiramaniam
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Deruiter
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Randall
authors.initials: R
authors.lastname: Clark
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA. Electronic address: dhanamu@auburn.edu.
authors.forename: Muralikrishnan
authors.initials: M
authors.lastname: Dhanasekaran
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018491:Dopamine Agonists / Q000633:toxicity*; D042967:Electron Transport Complex I / Q000378:metabolism*; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000633:toxicity*; D016627:Oxidopamine; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D018491:Dopamine Agonists; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D016627:Oxidopamine; D042967:Electron Transport Complex I; D018817:N-Methyl-3,4-methylenedioxyamphetamine
keywords: Drugs of abuse; MDMA & analogs; Mitochondrial dysfunction; Neurotoxicity; Oxidative stress