The Experts below are selected from a list of 846 Experts worldwide ranked by ideXlab platform

Márcia Carvalho - One of the best experts on this subject based on the ideXlab platform.

  • Metabolic signature of Methylone in primary mouse hepatocytes, at subtoxic concentrations.
    Archives of Toxicology, 2019
    Co-Authors: Ana Margarida Araújo, Félix Carvalho, Márcia Carvalho, Maria De Lourdes Bastos, Paula Guedes De Pinho
    Abstract:

    Methylone (3,4-methylenedioxymethcathinone) is one of the most popular new psychoactive drugs worldwide. Although advertised as a safe drug, its use has been associated to several cases of liver damage. In this work, a metabolomics approach based on gas chromatography-mass spectrometry (GC-MS) combined with chemometric analyses was used to characterize the disturbances occurring in the intra- and extracellular metabolome of primary mouse hepatocytes exposed to two subtoxic concentrations (LC01 and LC10) of Methylone to better understand the early hepatotoxic events. Results showed a characteristic metabolic fingerprint for Methylone, where aspartate, cysteine, 2-methyl-1-pentanol, 4-methylheptane, dodecane, 2,4-dimethyl-1-heptene, 1,3-di-tert-butylbenzene, acetophenone, formaldehyde and glyoxal levels were significantly changed at both concentrations tested. Furthermore, subtoxic concentrations of Methylone caused profound changes in several biochemical pathways, suggesting adaptations in energy production processes (TCA cycle, amino acids metabolism and pyruvate metabolism), cellular antioxidant defenses (glutamate, cysteine and glutathione metabolism) and hepatic enzymes (associated to hydrocarbons, alcohols, aldehydes and ketones metabolism). This metabolic response to the initial Methylone challenge most probably reflects the activation of protective mechanisms to restore cellular homeostasis. Overall, this study highlights the potential of untargeted metabolomic analysis to reveal the hepatic metabolic signature of Methylone at subtoxic concentrations, and also provides clues to clarify the early mechanisms underlying the toxicity triggered by this new psychoactive substance, opening a new perspective for the study of toxicity mechanisms of new xenobiotics.

  • neurotoxicity of β keto amphetamines deathly mechanisms elicited by Methylone and mdpv in human dopaminergic sh sy5y cells
    ACS Chemical Neuroscience, 2017
    Co-Authors: Maria Joao Valente, Félix Carvalho, Maria De Lourdes Bastos, Paula Guedes De Pinho, Eduarda Fernandes, Márcia Carvalho
    Abstract:

    Synthetic cathinones (β-keto amphetamines) act as potent CNS stimulants similarly to classical amphetamines, which raise concerns about their potential neurotoxic effects. The present in vitro study aimed to explore and compare the mechanisms underlying the neurotoxicity of two commonly abused cathinone derivatives, 3,4-methylenedioxymethcathinone (Methylone) and 3,4-methylenedioxypyrovalerone (MDPV), with those of 3,4-methylenedioxymethamphetamine (MDMA), using undifferentiated and differentiated SH-SY5Y cells. Following a 24 h exposure period, Methylone and MDPV induced loss of cell viability in a concentration-dependent manner, in the following order of potency: MDPV ≈ MDMA > Methylone. Dopaminergic differentiated cells evidenced higher sensitivity to the neurotoxic effects of both cathinones and MDMA than the undifferentiated ones, but this effect was not inhibited by the DAT inhibitor GBR 12909. Intracellular oxidative stress mediated by Methylone and MDPV was demonstrated by the increase in reactive...

Paula Guedes De Pinho - One of the best experts on this subject based on the ideXlab platform.

  • Enantioselectivity on the absorption of Methylone and pentedrone using Caco-2 cell line: Development and validation of an UHPLC method for cathinones quantification
    Toxicology and Applied Pharmacology, 2020
    Co-Authors: Bárbara Silva, Paula Guedes De Pinho, Carla Fernandes, Renata Silva, Fernando Remião
    Abstract:

    Abstract Synthetic cathinones, such as Methylone and pentedrone, are psychoactive derivatives of cathinone, sold in the internet as “plant food” or “bath salts”. However, the level at which these compounds and their enantiomers cross the intestinal barrier has not been yet determined. Thus, the present study aimed to analyze the enantioselectivity on the permeability of these drugs through the intestinal barrier by using the Caco-2 cell line, a widely used in vitro model for drug permeability studies. To achieve this goal, an UHPLC-UV method was developed and validated to quantify both synthetic cathinones. The developed UHPLC-UV method revealed high selectivity and a linearity from 1 to 500 μM with correlation coefficients always higher than 0.999. The method has an accuracy that ranged between 89 and 107%, inter-day and intra-day precisions with coefficients of variation below 10%, limits of detection and quantification of 0.31 μM and 0.93 μM for Methylone and 0.17 μM and 0.52 μM for pentedrone, respectively. In Caco-2 cells, a differentiated passage of the enantiomers across monolayer was observed for both cathinones. For pentedrone, the difference was observed after the first hour, being R-(−)-pentedrone the most permeable compound. Regarding Methylone, the difference was noted after one hour and 30 min, with S-(−)-Methylone being the most absorbed enantiomer. In conclusion, a fully validated method was successfully applied for studying the permeability of Methylone and pentedrone enantiomers in an in vitro model of human intestine, which allowed to discover, for the first time, the enantioselectivity in drug permeability of this class of drugs.

  • Metabolic signature of Methylone in primary mouse hepatocytes, at subtoxic concentrations.
    Archives of Toxicology, 2019
    Co-Authors: Ana Margarida Araújo, Félix Carvalho, Márcia Carvalho, Maria De Lourdes Bastos, Paula Guedes De Pinho
    Abstract:

    Methylone (3,4-methylenedioxymethcathinone) is one of the most popular new psychoactive drugs worldwide. Although advertised as a safe drug, its use has been associated to several cases of liver damage. In this work, a metabolomics approach based on gas chromatography-mass spectrometry (GC-MS) combined with chemometric analyses was used to characterize the disturbances occurring in the intra- and extracellular metabolome of primary mouse hepatocytes exposed to two subtoxic concentrations (LC01 and LC10) of Methylone to better understand the early hepatotoxic events. Results showed a characteristic metabolic fingerprint for Methylone, where aspartate, cysteine, 2-methyl-1-pentanol, 4-methylheptane, dodecane, 2,4-dimethyl-1-heptene, 1,3-di-tert-butylbenzene, acetophenone, formaldehyde and glyoxal levels were significantly changed at both concentrations tested. Furthermore, subtoxic concentrations of Methylone caused profound changes in several biochemical pathways, suggesting adaptations in energy production processes (TCA cycle, amino acids metabolism and pyruvate metabolism), cellular antioxidant defenses (glutamate, cysteine and glutathione metabolism) and hepatic enzymes (associated to hydrocarbons, alcohols, aldehydes and ketones metabolism). This metabolic response to the initial Methylone challenge most probably reflects the activation of protective mechanisms to restore cellular homeostasis. Overall, this study highlights the potential of untargeted metabolomic analysis to reveal the hepatic metabolic signature of Methylone at subtoxic concentrations, and also provides clues to clarify the early mechanisms underlying the toxicity triggered by this new psychoactive substance, opening a new perspective for the study of toxicity mechanisms of new xenobiotics.

  • Multi-milligram resolution and determination of absolute configuration of pentedrone and Methylone enantiomers
    Journal of Chromatography B, 2018
    Co-Authors: Bárbara Silva, Ana Margarida Araújo, Paula Guedes De Pinho, José Alberto Pereira, Sara Cravo, Carla Fernandes, Madalena Pinto, Fernando Remião
    Abstract:

    Abstract The enantioresolution of pentedrone and Methylone was carried out at a multi-milligram scale by liquid chromatography on a Chiralpak AS® stationary phase. The excellent enantioresolution using this column allowed to collect highly pure enantiomeric fractions, achieving enantiomeric ratios higher than 98%. An overall recovery of 72% was achieved for pentedrone enantiomers and 80% for Methylone. Furthermore, the absolute configuration of the enantiomers of both cathinones was determined for the first time by electronic circular dichroism (ECD) spectroscopy, with the aid of theoretical calculations, as (+)‑(S) and (−)‑(R)-pentedrone, and (−)‑(S) and (+)‑(R)‑Methylone.

  • neurotoxicity of β keto amphetamines deathly mechanisms elicited by Methylone and mdpv in human dopaminergic sh sy5y cells
    ACS Chemical Neuroscience, 2017
    Co-Authors: Maria Joao Valente, Félix Carvalho, Maria De Lourdes Bastos, Paula Guedes De Pinho, Eduarda Fernandes, Márcia Carvalho
    Abstract:

    Synthetic cathinones (β-keto amphetamines) act as potent CNS stimulants similarly to classical amphetamines, which raise concerns about their potential neurotoxic effects. The present in vitro study aimed to explore and compare the mechanisms underlying the neurotoxicity of two commonly abused cathinone derivatives, 3,4-methylenedioxymethcathinone (Methylone) and 3,4-methylenedioxypyrovalerone (MDPV), with those of 3,4-methylenedioxymethamphetamine (MDMA), using undifferentiated and differentiated SH-SY5Y cells. Following a 24 h exposure period, Methylone and MDPV induced loss of cell viability in a concentration-dependent manner, in the following order of potency: MDPV ≈ MDMA > Methylone. Dopaminergic differentiated cells evidenced higher sensitivity to the neurotoxic effects of both cathinones and MDMA than the undifferentiated ones, but this effect was not inhibited by the DAT inhibitor GBR 12909. Intracellular oxidative stress mediated by Methylone and MDPV was demonstrated by the increase in reactive...

  • Neurotoxicity of β‑Keto Amphetamines: Deathly Mechanisms Elicited by Methylone and MDPV in Human Dopaminergic SH-SY5Y Cells
    2017
    Co-Authors: Maria João Valente, Maria De Lourdes Bastos, Paula Guedes De Pinho, Eduarda Fernandes, Félix Carvalho, Márcia Carvalho
    Abstract:

    Synthetic cathinones (β-keto amphetamines) act as potent CNS stimulants similarly to classical amphetamines, which raise concerns about their potential neurotoxic effects. The present in vitro study aimed to explore and compare the mechanisms underlying the neurotoxicity of two commonly abused cathinone derivatives, 3,4-methylenedioxymethcathinone (Methylone) and 3,4-methylenedioxypyrovalerone (MDPV), with those of 3,4-methylenedioxymethamphetamine (MDMA), using undifferentiated and differentiated SH-SY5Y cells. Following a 24 h exposure period, Methylone and MDPV induced loss of cell viability in a concentration-dependent manner, in the following order of potency: MDPV ≈ MDMA > Methylone. Dopaminergic differentiated cells evidenced higher sensitivity to the neurotoxic effects of both cathinones and MDMA than the undifferentiated ones, but this effect was not inhibited by the DAT inhibitor GBR 12909. Intracellular oxidative stress mediated by Methylone and MDPV was demonstrated by the increase in reactive oxygen and nitrogen species (ROS and RNS) production, depletion of intracellular reduced glutathione and increased oxidized glutathione levels. All three drugs elicited mitochondrial impairment, characterized by the mitochondrial membrane potential (Δψm) dissipation and intracellular ATP depletion. Apoptosis was found to be a common mechanism of cell death induced by Methylone and MDPV, with evident chromatin condensation and formation of pyknotic nuclei, and activation of caspases 3, 8, and 9. In conclusion, the present data shows that oxidative stress and mitochondrial dysfunction play a role in cathinones-induced neuronal damage, ultimately leading to cell death by apoptosis

Marilyn A. Huestis - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats
    Neuropsychopharmacology, 2016
    Co-Authors: Joshua S. Elmore, Kenner C. Rice, Ora Dillon-carter, John S. Partilla, Kayla N. Ellefsen, Marta Concheiro, Masaki Suzuki, Marilyn A. Huestis, Michael H. Baumann
    Abstract:

    3,4-Methylenedioxy-N-methylcathinone (Methylone) is a new psychoactive substance and the β-keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). It is well established that MDMA metabolism produces bioactive metabolites. Here we tested the hypothesis that Methylone metabolism in rats can form bioactive metabolites. First, we examined the pharmacokinetics (PKs) of Methylone and its metabolites after subcutaneous (sc) Methylone administration (3, 6, 12 mg/kg) to male rats fitted with intravenous (iv) catheters for repeated blood sampling. Plasma specimens were assayed by liquid chromatography tandem mass spectrometry to quantify Methylone and its phase I metabolites: 3,4-methylenedioxycathinone (MDC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 4-hydroxy-3-methoxy-N-methylcathinone (HMMC). The biological activity of Methylone and its metabolites was then compared using in vitro transporter assays and in vivo microdialysis in rat nucleus accumbens. For the PK study, we found that Methylone and MDC peaked early (Tmax=15-45 min) and were short lived (t1/2=60–90 min), while HHMC and HMMC peaked later (Tmax=60-120 min) and persisted (t1/2=120–180 min). Area-under-the-curve values for Methylone and MDC were greater than dose-proportional, suggesting non-linear accumulation. Methylone produced significant locomotor activation, which was correlated with plasma Methylone, MDC, and HHMC concentrations. Methylone, MDC, and HHMC were substrate-type releasers at monoamine transporters as determined in vitro, but only Methylone and MDC (1, 3 mg/kg, iv) produced significant elevations in brain extracellular dopamine and 5-HT in vivo. Our findings demonstrate that Methylone is extensively metabolized in rats, but MDC is the only centrally active metabolite that could contribute to overall effects of the drug in vivo.

  • Quantification of Methylone and metabolites in rat and human plasma by liquid chromatography-tandem mass spectrometry
    Forensic Toxicology, 2015
    Co-Authors: Kayla N. Ellefsen, Kenner C. Rice, Joshua S. Elmore, Marta Concheiro, Masaki Suzuki, Michael H. Baumann, Marilyn A. Huestis
    Abstract:

    Methylone is a commonly abused synthetic cathinone derivative marketed as a “legal” alternative to “ecstasy” or cocaine. Previous studies examined the metabolism of Methylone in vitro and in vivo; 4-hydroxy-3-methoxymethcathinone (HMMC) was identified as the primary metabolite, with other reported minor metabolites, 3,4-methylenedioxycathinone (MDC) and 3,4-dihydroxymethcathinone (HHMC). However, limited information is known about Methylone and its metabolites’ pharmacokinetics. We developed and fully validated a method for the simultaneous quantification of Methylone, HMMC, MDC and HHMC by liquid chromatography-tandem mass spectrometry in 100 µl rat and human plasma. β-Glucuronidase was utilized for plasma hydrolysis, followed by perchloric acid protein precipitation and solid-phase extraction utilizing cation exchange columns. Chromatographic separation was performed with a Synergi Polar column in gradient mode, and analytes were determined by two multiple reaction monitoring (MRM) transitions. Linear ranges of 0.5–1,000 µg/l (Methylone, HMMC and MDC) and 10–1,000 µg/l (HHMC) were achieved. Bias and imprecision were generally acceptable, although quantification of HHMC exhibited variability (16.2–37 %). Extraction efficiencies and ion suppression were 89.9–104 % (for HHMC, 15.9–16.2 %) and < 11.4 %, respectively. Methylone and metabolites were stable in plasma for 24 h at room temperature, 72 h at 4 °C, and after three freeze–thaw cycles (except for a 60 % HMMC increase). Human and rat plasma were cross-validated, documenting that rat plasma quality control samples were accurately quantified against a human plasma calibration curve (−23.8 to 12 % bias). As proof of method, rat plasma specimens were analyzed pre-injection and after subcutaneous administration of Methylone at 6 mg/kg from 15 to 480 min post-dosing. Methylone, HMMC, MDC and HHMC concentrations ranged from 1.1 to 1,310, 11.2 to 194, 1.9 to 152 and 24.7 to 188 µg/l, respectively.

Michael H. Baumann - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats
    Neuropsychopharmacology, 2016
    Co-Authors: Joshua S. Elmore, Kenner C. Rice, Ora Dillon-carter, John S. Partilla, Kayla N. Ellefsen, Marta Concheiro, Masaki Suzuki, Marilyn A. Huestis, Michael H. Baumann
    Abstract:

    3,4-Methylenedioxy-N-methylcathinone (Methylone) is a new psychoactive substance and the β-keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). It is well established that MDMA metabolism produces bioactive metabolites. Here we tested the hypothesis that Methylone metabolism in rats can form bioactive metabolites. First, we examined the pharmacokinetics (PKs) of Methylone and its metabolites after subcutaneous (sc) Methylone administration (3, 6, 12 mg/kg) to male rats fitted with intravenous (iv) catheters for repeated blood sampling. Plasma specimens were assayed by liquid chromatography tandem mass spectrometry to quantify Methylone and its phase I metabolites: 3,4-methylenedioxycathinone (MDC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 4-hydroxy-3-methoxy-N-methylcathinone (HMMC). The biological activity of Methylone and its metabolites was then compared using in vitro transporter assays and in vivo microdialysis in rat nucleus accumbens. For the PK study, we found that Methylone and MDC peaked early (Tmax=15-45 min) and were short lived (t1/2=60–90 min), while HHMC and HMMC peaked later (Tmax=60-120 min) and persisted (t1/2=120–180 min). Area-under-the-curve values for Methylone and MDC were greater than dose-proportional, suggesting non-linear accumulation. Methylone produced significant locomotor activation, which was correlated with plasma Methylone, MDC, and HHMC concentrations. Methylone, MDC, and HHMC were substrate-type releasers at monoamine transporters as determined in vitro, but only Methylone and MDC (1, 3 mg/kg, iv) produced significant elevations in brain extracellular dopamine and 5-HT in vivo. Our findings demonstrate that Methylone is extensively metabolized in rats, but MDC is the only centrally active metabolite that could contribute to overall effects of the drug in vivo.

  • Reinforcing and neurochemical effects of the “bath salts” constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (Methylone) in male rats
    Psychopharmacology, 2015
    Co-Authors: Charles W. Schindler, Nicholas V. Cozzi, Eric B. Thorndike, Steven R. Goldberg, Kurt R. Lehner, Simon D. Brandt, Michael H. Baumann
    Abstract:

    Rationale 3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (Methylone) are synthetic drugs found in so-called “bath salts” products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while Methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT).

  • Quantification of Methylone and metabolites in rat and human plasma by liquid chromatography-tandem mass spectrometry
    Forensic Toxicology, 2015
    Co-Authors: Kayla N. Ellefsen, Kenner C. Rice, Joshua S. Elmore, Marta Concheiro, Masaki Suzuki, Michael H. Baumann, Marilyn A. Huestis
    Abstract:

    Methylone is a commonly abused synthetic cathinone derivative marketed as a “legal” alternative to “ecstasy” or cocaine. Previous studies examined the metabolism of Methylone in vitro and in vivo; 4-hydroxy-3-methoxymethcathinone (HMMC) was identified as the primary metabolite, with other reported minor metabolites, 3,4-methylenedioxycathinone (MDC) and 3,4-dihydroxymethcathinone (HHMC). However, limited information is known about Methylone and its metabolites’ pharmacokinetics. We developed and fully validated a method for the simultaneous quantification of Methylone, HMMC, MDC and HHMC by liquid chromatography-tandem mass spectrometry in 100 µl rat and human plasma. β-Glucuronidase was utilized for plasma hydrolysis, followed by perchloric acid protein precipitation and solid-phase extraction utilizing cation exchange columns. Chromatographic separation was performed with a Synergi Polar column in gradient mode, and analytes were determined by two multiple reaction monitoring (MRM) transitions. Linear ranges of 0.5–1,000 µg/l (Methylone, HMMC and MDC) and 10–1,000 µg/l (HHMC) were achieved. Bias and imprecision were generally acceptable, although quantification of HHMC exhibited variability (16.2–37 %). Extraction efficiencies and ion suppression were 89.9–104 % (for HHMC, 15.9–16.2 %) and < 11.4 %, respectively. Methylone and metabolites were stable in plasma for 24 h at room temperature, 72 h at 4 °C, and after three freeze–thaw cycles (except for a 60 % HMMC increase). Human and rat plasma were cross-validated, documenting that rat plasma quality control samples were accurately quantified against a human plasma calibration curve (−23.8 to 12 % bias). As proof of method, rat plasma specimens were analyzed pre-injection and after subcutaneous administration of Methylone at 6 mg/kg from 15 to 480 min post-dosing. Methylone, HMMC, MDC and HHMC concentrations ranged from 1.1 to 1,310, 11.2 to 194, 1.9 to 152 and 24.7 to 188 µg/l, respectively.

  • Effects of Social Interaction and Warm Ambient Temperature on Brain Hyperthermia Induced by the Designer Drugs Methylone and MDPV
    Neuropsychopharmacology, 2014
    Co-Authors: Eugene A. Kiyatkin, Michael H. Baumann, Albert H. Kim, Ken T. Wakabayashi, Yavin Shaham
    Abstract:

    3,4-Methylenedioxymethcathinone (Methylone) and 3,4-methylenedioxypyrovalerone (MDPV) are new drugs of abuse that have gained worldwide popularity. These drugs are structurally similar to 3,4-methylenedioxymethamphetamine (MDMA) and share many of its physiological and behavioral effects in humans, including the development of hyperthermia during acute intoxication. Here, we examined the effects of Methylone (1–9 mg/kg, s.c.) or MDPV (0.1–1.0 mg/kg, s.c.) on brain temperature homeostasis in rats maintained in a standard laboratory environment (single-housed in a quiet rest at 22 °C) and under conditions that model human drug use (social interaction and 29 °C ambient temperature). By simultaneously monitoring temperatures in the nucleus accumbens, temporal muscle, and facial skin, we assessed the effects of Methylone and MDPV on intra-brain heat production and cutaneous vascular tone, two critical factors that control brain temperature responses. Both Methylone and MDPV dose-dependently increased brain temperature, but even at high doses that induced robust locomotor activation, hyperthermia was modest in magnitude (up to ∼2 °C). Both drugs also induced dose-dependent peripheral vasoconstriction, which appears to be a primary mechanism determining the brain hyperthermic responses. In contrast to the powerful potentiation of MDMA-induced hyperthermia by social interaction and warm ambient temperature, such potentiation was absent for Methylone and minimal for MDPV. Taken together, despite structural similarities to MDMA, exposure to Methylone or MDPV under conditions commonly associated with human drug use does not lead to profound elevations in brain temperature and sustained vasoconstriction, two critical factors associated with MDMA toxicity.

Maria De Lourdes Bastos - One of the best experts on this subject based on the ideXlab platform.

  • Metabolic signature of Methylone in primary mouse hepatocytes, at subtoxic concentrations.
    Archives of Toxicology, 2019
    Co-Authors: Ana Margarida Araújo, Félix Carvalho, Márcia Carvalho, Maria De Lourdes Bastos, Paula Guedes De Pinho
    Abstract:

    Methylone (3,4-methylenedioxymethcathinone) is one of the most popular new psychoactive drugs worldwide. Although advertised as a safe drug, its use has been associated to several cases of liver damage. In this work, a metabolomics approach based on gas chromatography-mass spectrometry (GC-MS) combined with chemometric analyses was used to characterize the disturbances occurring in the intra- and extracellular metabolome of primary mouse hepatocytes exposed to two subtoxic concentrations (LC01 and LC10) of Methylone to better understand the early hepatotoxic events. Results showed a characteristic metabolic fingerprint for Methylone, where aspartate, cysteine, 2-methyl-1-pentanol, 4-methylheptane, dodecane, 2,4-dimethyl-1-heptene, 1,3-di-tert-butylbenzene, acetophenone, formaldehyde and glyoxal levels were significantly changed at both concentrations tested. Furthermore, subtoxic concentrations of Methylone caused profound changes in several biochemical pathways, suggesting adaptations in energy production processes (TCA cycle, amino acids metabolism and pyruvate metabolism), cellular antioxidant defenses (glutamate, cysteine and glutathione metabolism) and hepatic enzymes (associated to hydrocarbons, alcohols, aldehydes and ketones metabolism). This metabolic response to the initial Methylone challenge most probably reflects the activation of protective mechanisms to restore cellular homeostasis. Overall, this study highlights the potential of untargeted metabolomic analysis to reveal the hepatic metabolic signature of Methylone at subtoxic concentrations, and also provides clues to clarify the early mechanisms underlying the toxicity triggered by this new psychoactive substance, opening a new perspective for the study of toxicity mechanisms of new xenobiotics.

  • neurotoxicity of β keto amphetamines deathly mechanisms elicited by Methylone and mdpv in human dopaminergic sh sy5y cells
    ACS Chemical Neuroscience, 2017
    Co-Authors: Maria Joao Valente, Félix Carvalho, Maria De Lourdes Bastos, Paula Guedes De Pinho, Eduarda Fernandes, Márcia Carvalho
    Abstract:

    Synthetic cathinones (β-keto amphetamines) act as potent CNS stimulants similarly to classical amphetamines, which raise concerns about their potential neurotoxic effects. The present in vitro study aimed to explore and compare the mechanisms underlying the neurotoxicity of two commonly abused cathinone derivatives, 3,4-methylenedioxymethcathinone (Methylone) and 3,4-methylenedioxypyrovalerone (MDPV), with those of 3,4-methylenedioxymethamphetamine (MDMA), using undifferentiated and differentiated SH-SY5Y cells. Following a 24 h exposure period, Methylone and MDPV induced loss of cell viability in a concentration-dependent manner, in the following order of potency: MDPV ≈ MDMA > Methylone. Dopaminergic differentiated cells evidenced higher sensitivity to the neurotoxic effects of both cathinones and MDMA than the undifferentiated ones, but this effect was not inhibited by the DAT inhibitor GBR 12909. Intracellular oxidative stress mediated by Methylone and MDPV was demonstrated by the increase in reactive...

  • Neurotoxicity of β‑Keto Amphetamines: Deathly Mechanisms Elicited by Methylone and MDPV in Human Dopaminergic SH-SY5Y Cells
    2017
    Co-Authors: Maria João Valente, Maria De Lourdes Bastos, Paula Guedes De Pinho, Eduarda Fernandes, Félix Carvalho, Márcia Carvalho
    Abstract:

    Synthetic cathinones (β-keto amphetamines) act as potent CNS stimulants similarly to classical amphetamines, which raise concerns about their potential neurotoxic effects. The present in vitro study aimed to explore and compare the mechanisms underlying the neurotoxicity of two commonly abused cathinone derivatives, 3,4-methylenedioxymethcathinone (Methylone) and 3,4-methylenedioxypyrovalerone (MDPV), with those of 3,4-methylenedioxymethamphetamine (MDMA), using undifferentiated and differentiated SH-SY5Y cells. Following a 24 h exposure period, Methylone and MDPV induced loss of cell viability in a concentration-dependent manner, in the following order of potency: MDPV ≈ MDMA > Methylone. Dopaminergic differentiated cells evidenced higher sensitivity to the neurotoxic effects of both cathinones and MDMA than the undifferentiated ones, but this effect was not inhibited by the DAT inhibitor GBR 12909. Intracellular oxidative stress mediated by Methylone and MDPV was demonstrated by the increase in reactive oxygen and nitrogen species (ROS and RNS) production, depletion of intracellular reduced glutathione and increased oxidized glutathione levels. All three drugs elicited mitochondrial impairment, characterized by the mitochondrial membrane potential (Δψm) dissipation and intracellular ATP depletion. Apoptosis was found to be a common mechanism of cell death induced by Methylone and MDPV, with evident chromatin condensation and formation of pyknotic nuclei, and activation of caspases 3, 8, and 9. In conclusion, the present data shows that oxidative stress and mitochondrial dysfunction play a role in cathinones-induced neuronal damage, ultimately leading to cell death by apoptosis