The Experts below are selected from a list of 7521 Experts worldwide ranked by ideXlab platform
Pannghill Suh - One of the best experts on this subject based on the ideXlab platform.
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thiram and ziram stimulate non selective cation channel and induce apoptosis in pc12 cells
Neurotoxicology, 2003Co-Authors: Myoung Sook Han, Kum Joo Shin, Yunhee Kim, Sunhee Kim, Taehoon Lee, Euikyung Kim, Sung Ho Ryu, Pannghill SuhAbstract:Abstract The Neurotoxicity of dithiocarbamates has been previously reported, however, the detailed Mechanism underlying the Neurotoxicity is still not fully understood. Among the dithiocarbamates, we investigated thiram and ziram in a neuronal-like pheochromocytoma (PC12) cells. Thiram and ziram strongly induced cell death in both dose- and time-dependent manners with the LC 50 of 0.3 and 2 μM, respectively. The cell death showed typical apoptotic features, such as DNA fragmentation and an increase of subdiploidy nuclei. Interestingly, both thiram and ziram induced rapid and sustained increases of intracellular Ca 2+ in PC12 cells, which were almost completely blocked by flufenamic acid (FFA), an inhibitor of non-selective cation channel. BAPTA-AM, an intracellular Ca 2+ chelator, inhibited the thiram- and ziram-induced apoptotic cell death. These results suggest that thiram and ziram induce apoptotic neuronal cell death by Ca 2+ influx through non-selective cation channels. The present study may provide a clue for understanding the Mechanism of Neurotoxicity of thiram and ziram.
Myoung Sook Han - One of the best experts on this subject based on the ideXlab platform.
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thiram and ziram stimulate non selective cation channel and induce apoptosis in pc12 cells
Neurotoxicology, 2003Co-Authors: Myoung Sook Han, Kum Joo Shin, Yunhee Kim, Sunhee Kim, Taehoon Lee, Euikyung Kim, Sung Ho Ryu, Pannghill SuhAbstract:Abstract The Neurotoxicity of dithiocarbamates has been previously reported, however, the detailed Mechanism underlying the Neurotoxicity is still not fully understood. Among the dithiocarbamates, we investigated thiram and ziram in a neuronal-like pheochromocytoma (PC12) cells. Thiram and ziram strongly induced cell death in both dose- and time-dependent manners with the LC 50 of 0.3 and 2 μM, respectively. The cell death showed typical apoptotic features, such as DNA fragmentation and an increase of subdiploidy nuclei. Interestingly, both thiram and ziram induced rapid and sustained increases of intracellular Ca 2+ in PC12 cells, which were almost completely blocked by flufenamic acid (FFA), an inhibitor of non-selective cation channel. BAPTA-AM, an intracellular Ca 2+ chelator, inhibited the thiram- and ziram-induced apoptotic cell death. These results suggest that thiram and ziram induce apoptotic neuronal cell death by Ca 2+ influx through non-selective cation channels. The present study may provide a clue for understanding the Mechanism of Neurotoxicity of thiram and ziram.
Carlo Santini - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the profile and Mechanism of Neurotoxicity of water soluble cu p 4 pf6 and au p 4 pf6 p thp or pta anticancer complexes
Neurotoxicity Research, 2018Co-Authors: C Ceresa, Gabriella Nicolini, S Semperboni, Valentina Gandin, M Monfrini, F Avezza, P Alberti, A Bravin, Maura Pellei, Carlo SantiniAbstract:[Cu(thp)4]PF6, [Cu(PTA)4]PF6, [Au(thp)4]PF6 and [Au(PTA)4]PF6 are phosphane (thp = tris(hydroxymethyl)phosphane; PTA = 1,3,5-triaza-7-phosphaadamantane) copper(I) and gold(I) water-soluble complexes characterized by high anticancer activity in a wide range of solid tumors, often able to overcome drug resistance of platinum-based compounds. For these reasons, they have been proposed as a valid alternative to platinum-based chemotherapeutic drugs (e.g., cisplatin and oxaliplatin). In vitro experiments performed on organotypic cultures of dorsal root ganglia (DRG) from 15-day-old rat embryos revealed that copper-based compounds were not neurotoxic even at concentrations higher than the IC50 obtained in human cancer cells while [Au(PTA)4]PF6 was neurotoxic at lower concentration than IC50 in cancer cell lines. The ability of these compounds to hinder the proteasome machinery in DRG neurons was tested by fluorimetric assay showing that the non-neurotoxic copper-based complexes do not inhibit proteasome activity in DRG primary neuron cultures. On the contrary, the neurotoxic complex [Au(PTA)4]PF6, induced a significant inhibition of proteasome activity even at concentrations lower than the IC50 in cancer cells. The proteasome inhibition induced by [Au(PTA)4]PF6 was associated with a significant increase in α-tubulin polymerization that was not observed following the treatment with copper-based compounds. Uptake experiments performed by atomic absorption spectrometry showed that both copper-based complexes and [Au(PTA)4]PF6 are internalized in neuron cultures. In vitro and in vivo preliminary data confirmed copper-based complexes as the most promising compounds, not only for their anticancer activity but also concerning the peripheral Neurotoxicity profile.
Bradley T Hyman - One of the best experts on this subject based on the ideXlab platform.
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blockade of 1 methyl 4 phenylpyridinium ion mpp nigral toxicity in the rat by prior decortication or mk 801 treatment a stereological estimate of neuronal loss
Neurobiology of Aging, 1993Co-Authors: Rachana Srivastava, Emmanuel Brouillet, Flint M Beal, Elsdon Storey, Bradley T HymanAbstract:1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, (MPTP), produces a parkinsonian syndrome both in man and in experimental animals. Its toxicity is mediated by a metabolite, the 1-methyl-4-phenylpyridinium ion (MPP+). When injected into the striatum, MPP+ is accumulated by dopaminergic nerve terminals and retrogradely transported to the substantia nigra pars compacta (SNc) where it causes neuronal degeneration. MPP+ accumulates in mitochondria and blocks complex 1 of the electron transport chain. A proposed Mechanism of Neurotoxicity isexcitotoxic neuronal degeneration induced by this energy depletion. We examined whether either prior decortication or administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) could prevent or diminish the selective nigral neuronal degeneration that follows unilateral intrastriatal injection of MPP+. We quantified the extent of neuronal death in the SNc ipsilateral and contralateral to the injections on Nissl-stained sections with unbiased stereological techniques. One week after injection of MPP+, approximately 75% of the SNc neurons were lost on the side of the injection. The loss was a consequence of the reduction in both SNc volume and neuronal density. Both prior decortication or the administration of MK-801 for 2 days nearly completely prevented MPP+-induced neuronal loss in the ipsilateral SNc. These results are consistent with an NMDA receptor mediated excitotoxic Mechanism for MPP+-induced nigral toxicity.
Perfetti Ximena - One of the best experts on this subject based on the ideXlab platform.
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Desarrollo de biomarcadores del grado de exposición y activación para la evaluación de la neurotoxicidad de la MDMA en humanos
2009Co-Authors: Perfetti XimenaAbstract:La 3,4-Metilendioximetanfetamina (MDMA, éxtasis) es un derivado anfetamínico sintético ampliamente usado como droga recreativa, que produce neurotoxicidad serotonérgica en animales y posiblemente también en humanos. El mecanismo subyacente de neurotoxicidad, incluye la formación de especies reactivas de oxigeno (ROS), pero la fuente de generación de estos es un punto de controversia. Se postula que la neurotoxicidad inducida por la MDMA es mediada por la formación de metabolitos bioreactivos. Específicamente, los metabolitos primarios de tipo catecol, la 3,4- dihidroximetanfetamina (HHMA) y la 3,4-dihidroxianfetamina (HHA), que luego dan lugar a la formación de conjugados con el glutatión y la N-acetilcisteína, y que conservan la capacidad de entrar en el ciclo redox y presentan neurotoxicidad serotonérgica en ratas. Aunque la presencia de dichos metabolitos se demostró recientemente en microdialisados de cerebros de ratas, su formación en humanos no se ha reportado aun. Este trabajo describe la detección de N-acetil-cisteína-HHMA (NAC-HHMA) y N-acetil-cisteína-HHA (NAC-HHA) en orina humana de 15 consumidores recreacionales de MDMA (1.5 mg/kg) en un entorno controlado. Los resultados revelan que en las primeras 4 horas después del consumo de MDMA aproximadamente el 0.002% de la dosis administrada es recuperada como aductos tioéter. Los polimorfismos genéticos en la expresión de las enzimas CYP2D6 y COMT, que en conjunto son las principales determinantes de los niveles estables de HHMA y HHA, posiblemente expliquen la variabilidad interindividual observada en la recuperación de la NAC-HHMA y la NAC-HHA en orina. Resumiendo, por primera vez se demuestra la formación de aductos tioéteres neurotóxicos de la MDMA en humanos. Estos resultados apoyan la hipótesis de que la bioactivación de la MDMA a metabolitos neurotóxicos es el mecanismo relevante para la generación de la neurotoxicidad en humanos.3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a widely misused synthetic amphetamine derivative, and a serotonergic neurotoxicant in animal models and possibly humans. The underlying Mechanism of Neurotoxicity involves the formation of reactive oxygen species (ROS) although their source remains unclear. It has been postulated that MDMA induced Neurotoxicity is mediated via the formation of bioreactive metabolites. Specifically, the primary catechol metabolites, 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), subsequently give rise to the formation of glutathione and N-acetylcysteine conjugates, in which retain the ability to redox cycle, and are serotonergic neurotoxicants in rats. Although the presence of such metabolites has been recently demonstrated in rat brain microdialysate, their formation in humans has not been reported. The present study describes the detection of N-acetyl-5-cysteinyl-HHMA (NAC-HHMA) and N-acetyl-5-cysteinyl-HHA (NAC-HHA) in human urine of fifteen recreational users of MDMA (1.5 mg/kg) in a controlled setting. The results reveal that in the first 4 hours after MDMA ingestion ~0.002% of the administered dose was recovered as thioether adducts. Genetic polymorphisms in CYP2D6 and COMT expression, the combination of which are major determinants of steady state levels of HHMA and HMA, likely explain the inter-individual variability seen in the recovery of NAC-HHMA and NAC-HHA. In summary, the formation of neurotoxic thioether adducts of MDMA has been demonstrated for the first time in humans. The findings lend weight to the hypothesis that the bioactivation of MDMA to neurotoxic metabolites is a relevant pathway to Neurotoxicity in humans
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Neurotoxic thioether adducts of 3,4-methylenedioxymethamphetamine identified in human urine after ecstasy ingestion
'American Society for Pharmacology & Experimental Therapeutics (ASPET)', 2009Co-Authors: Perfetti Ximena, O'mathúna Brian, Pizarro Nieves, Cuyàs Elisabet, Khymenets Olha, Almeida Bruno, Pellegrini Manuela, Pichini Simona, Lau, Serrine S., Monks, Terrence J.Abstract:8 pages, 5 figures, 2 tables.-- PMID: 19349378 [PubMed].-- PMCID: PMC2698942.-- Supporting information available at: http://intl-dmd.aspetjournals.org/content/37/7/1448/suppl/DC13,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely misused synthetic amphetamine derivative and a serotonergic neurotoxicant in animal models and possibly humans. The underlying Mechanism of Neurotoxicity involves the formation of reactive oxygen species although their source remains unclear. It has been postulated that MDMA-induced Neurotoxicity is mediated via the formation of bioreactive metabolites. In particular, the primary catechol metabolites, 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), subsequently cause the formation of glutathione and N-acetylcysteine conjugates, which retain the ability to redox cycle and are serotonergic neurotoxicants in rats. Although the presence of such metabolites has been recently demonstrated in rat brain microdialysate, their formation in humans has not been reported. The present study describes the detection of 5-(N-acetylcystein-S-yl)-3,4-dihydroxymethamphetamine (N-Ac-5-Cys-HHMA) and 5-(N-acetylcystein-S-yl)-3,4-dihydroxyamphetamine (N-Ac-5-Cys-HHA) in human urine of 15 recreational users of MDMA (1.5 mg/kg) in a controlled setting. The results reveal that in the first 4 h after MDMA ingestion approximately 0.002% of the administered dose was recovered as thioether adducts. Genetic polymorphisms in CYP2D6 and catechol-O-methyltransferase expression, the combination of which are major determinants of steady-state levels of HHMA and 4-hydroxy-3-methoxyamphetamine, probably explain the interindividual variability seen in the recovery of N-Ac-5-Cys-HHMA and N-Ac-5-Cys-HHA. In summary, the formation of neurotoxic thioether adducts of MDMA has been demonstrated for the first time in humans. The findings lend weight to the hypothesis that the bioactivation of MDMA to neurotoxic metabolites is a relevant pathway to Neurotoxicity in humans.This work was supported in part by the National Institutes of Health National Institute on Drug Abuse [Grant 1R0-1DA017987-10A2]; a postdoctoral grant by the Secretaria de Estado de Universidades e Investigación del Ministerio de Educación y Ciencia, Spain (to N.P.); a de Gestió d’Ajuts Universitaris i de Recerca predoctoral fellowship Generalitat de Catalunya, Spain (to X.P.); Ministerio de Educación y Ciencia (Spain) [Grant SAF2005-0189]; and Generalitat de Catalunya (Spain) [Grant 2005SGR00032]. We acknowledge assistance from the National Institute of Environmental Health Sciences-supported Southwest Environmental Health Sciences Center [Grant P30-ES06694] at the University of Arizona.Peer reviewe
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Neurotoxic Thioether Adducts of 3,4-Methylenedioxymethamphetamine Identified in Human Urine After Ecstasy IngestionS⃞
American Society for Pharmacology and Experimental Therapeutics, 2026Co-Authors: Perfetti Ximena, O'mathúna Brian, Pizarro Nieves, Cuyàs Elisabet, Khymenets Olha, Almeida Bruno, Pellegrini Manuela, Pichini Simona, Lau, Serrine S., Monks, Terrence J.Abstract:3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely misused synthetic amphetamine derivative and a serotonergic neurotoxicant in animal models and possibly humans. The underlying Mechanism of Neurotoxicity involves the formation of reactive oxygen species although their source remains unclear. It has been postulated that MDMA-induced Neurotoxicity is mediated via the formation of bioreactive metabolites. In particular, the primary catechol metabolites, 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), subsequently cause the formation of glutathione and N-acetylcysteine conjugates, which retain the ability to redox cycle and are serotonergic neurotoxicants in rats. Although the presence of such metabolites has been recently demonstrated in rat brain microdialysate, their formation in humans has not been reported. The present study describes the detection of 5-(N-acetylcystein-S-yl)-3,4-dihydroxymethamphetamine (N-Ac-5-Cys-HHMA) and 5-(N-acetylcystein-S-yl)-3,4-dihydroxyamphetamine (N-Ac-5-Cys-HHA) in human urine of 15 recreational users of MDMA (1.5 mg/kg) in a controlled setting. The results reveal that in the first 4 h after MDMA ingestion ∼0.002% of the administered dose was recovered as thioether adducts. Genetic polymorphisms in CYP2D6 and catechol-O-methyltransferase expression, the combination of which are major determinants of steady-state levels of HHMA and 4-hydroxy-3-methoxyamphetamine, probably explain the interindividual variability seen in the recovery of N-Ac-5-Cys-HHMA and N-Ac-5-Cys-HHA. In summary, the formation of neurotoxic thioether adducts of MDMA has been demonstrated for the first time in humans. The findings lend weight to the hypothesis that the bioactivation of MDMA to neurotoxic metabolites is a relevant pathway to Neurotoxicity in humans