RESUMEN
BACKGROUND: Ecstasy (Ec) use produces hyperthermia, excessive sweating, intense thirst, an inappropriate antidiuretic hormone secretion (SIADH) and a multisystemic toxicity due to oxidative stress (OS). Intense thirst induces high intake of pure water, which associated with SIADH, usually develops into acute hyponatremia (Hn). As Hn is induced rapidly, experiments to check if Ec acted directly on the Inner Medullary Collecting Ducts (IMCD) of rats were conducted. Rhabdomyolysis and OS were also studied because Ec is known to induce Reactive Oxygen Species (ROS) and tissue damage. To decrease OS, the antioxidant inhibitors N-acetylcysteine (NAC) and Allopurinol (Allo) were used. METHODS: Rats were maintained on a lithium (Li) diet to block the Vasopressin action before Ec innoculation. AQP2 (Aquaporin 2), ENaC (Epitheliun Sodium Channel) and NKCC2 (Sodium, Potassium, 2 Chloride) expression were determined by Western Blot in isolated IMCDs. The TBARS (thiobarbituric acid reactive substances) and GSH (reduced form of Glutathione) were determined in the Ec group (6 rats injected with Ec-10mg/kg), in Ec+NAC groups (NAC 100mg/Kg/bw i.p.) and in Allo+Ec groups (Allo 50mg/Kg/i.p.). RESULTS: Enhanced AQP2 expression revealed that Ec increased water transporter expression, decreased by Li diet, but the expression of the tubular transporters did not change. The Ec, Ec+NAC and Allo+Ec results showed that Ec increased TBARS and decreased GSH, showing evidence of ROS occurrence, which was protected by NAC and Allo. Rhabdomyolysis was only protected by Allo. CONCLUSION: Results showed that Ec induced an increase in AQP2 expression, evidencing another mechanism that might contribute to cause rapid hyponatremia. In addition, they showed that NAC and Allo protected against OS, but only Allo decreased rhabdomyolysis and hyperthermia.
Asunto(s)
Depuradores de Radicales Libres/farmacología , Riñón/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Rabdomiólisis/inducido químicamente , Acetilcisteína/farmacología , Alopurinol/farmacología , Animales , Acuaporina 2/metabolismo , Western Blotting , Canales Epiteliales de Sodio/metabolismo , Glutatión/metabolismo , Alucinógenos/toxicidad , Riñón/metabolismo , Túbulos Renales Colectores/efectos de los fármacos , Túbulos Renales Colectores/metabolismo , Masculino , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Ratas Wistar , Rabdomiólisis/prevención & control , Miembro 1 de la Familia de Transportadores de Soluto 12/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Agua/metabolismoRESUMEN
This work reports the multimiligram separation of 3,4-methylenedioxy-methamphetamine (MDMA) enantiomers using batch chromatography with peak shaving recycling. The effect of both enantiomers compared to the racemic mixture was examined on the oxidative stress status of rat liver. The enantiomeric purification was performed using a based cyclodextrin chiral selector and methanol:ammonium acetate buffer (pH 6.0, 100mM) (30:70, v/v) as mobile phase. The average mass rate obtained was 40.0mg/day, providing 45.0mg of the (R)-(-)-MDMA (e.r. 99.0%) and 75.0mg (e.r. 96.0%) of (S)-(+)-MDMA. Racemic MDMA and both enantiomers were administered per orally to Wistar rats and oxidative stress status parameters, as liver total glutathione levels and malondialdehyde (MDA) production in liver were evaluated. There was a significant decrease in hepatic glutathione content in the racemic MDMA and the (R)-(-)-MDMA-treated rats when compared to the control and to (S)-(+)-MDMA. These results demonstrate that the R-enantiomer is the enantiomer that contributes to the depletion of hepatic glutathione induced by the racemic mixture. The high reactivity of the R-enantiomer of MDMA in the liver can also be observed in animals treated with (R)-(-)-MDMA. The production of malondialdehyde (MDA) by (R)-(-)-MDMA was significantly higher when compared to the other treated groups and control.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Drogas Ilícitas/aislamiento & purificación , Hígado/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/aislamiento & purificación , Estrés Oxidativo/efectos de los fármacos , Animales , Glutatión/metabolismo , Ensayos Analíticos de Alto Rendimiento , Drogas Ilícitas/química , Drogas Ilícitas/toxicidad , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Masculino , Malondialdehído/metabolismo , N-Metil-3,4-metilenodioxianfetamina/química , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Ratas , Ratas Wistar , EstereoisomerismoRESUMEN
OBJECTIVE: 3,4-Methylenedioxymethamphetamine (MDMA), or ecstasy, is a synthetic drug used recreationally, mainly by young people. It has been suggested that MDMA has a Th cell skewing effect, in which Th1 cell activity is suppressed and Th2 cell activity is increased. Experimental allergic airway inflammation in ovalbumin (OVA)-sensitized rodents is a useful model to study Th2 response; therefore, based on the Th2 skewing effect of MDMA, we studied MDMA in a model of allergic lung inflammation in OVA-sensitized mice. METHODS: We evaluated cell trafficking in the bronchoalveolar lavage fluid, blood and bone marrow; cytokine production; L-selectin expression and lung histology. We also investigated the effects of MDMA on tracheal reactivity in vitro and mast cell degranulation. RESULTS: We found that MDMA given prior to OVA challenge in OVA-sensitized mice decreased leukocyte migration into the lung, as revealed by a lower cell count in the bronchoalveolar lavage fluid and lung histologic analysis. We also showed that MDMA decreased expression of both Th2-like cytokines (IL-4, IL-5 and IL-10) and adhesion molecules (L-selectin). Moreover, we showed that the hypothalamus-pituitary-adrenal axis is partially involved in the MDMA-induced reduction in leukocyte migration into the lung. Finally, we showed that MDMA decreased tracheal reactivity to methacholine as well as mast cell degranulation in situ. CONCLUSIONS: Thus, we report here that MDMA given prior to OVA challenge in OVA-sensitized allergic mice is able to decrease lung inflammation and airway reactivity and that hypothalamus-pituitary-adrenal axis activation is partially involved. Together, the data strongly suggest an involvement of a neuroimmune mechanism in the effects of MDMA on lung inflammatory response and cell recruitment to the lungs of allergic animals.
Asunto(s)
Asma/inmunología , Inflamación/inmunología , Leucocitos/efectos de los fármacos , Pulmón/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Células Th2/efectos de los fármacos , Animales , Células de la Médula Ósea , Líquido del Lavado Bronquioalveolar/citología , Movimiento Celular/efectos de los fármacos , Citocinas/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Recuento de Leucocitos , Pulmón/citología , Masculino , Mastocitos/efectos de los fármacos , Ratones , N-Metil-3,4-metilenodioxianfetamina/inmunología , Células Th2/fisiología , Tráquea/efectos de los fármacosRESUMEN
OBJECTIVE: Looking for possible neuroimmune relationships, we analyzed the effects of methylenedioxymethamphetamine (MDMA) administration on neuroendocrine, neutrophil activity and leukocyte distribution in mice. METHODS: Five experiments were performed. In the first, mice were treated with MDMA (10 mg/kg) 30, 60 min and 24 h prior to blood sample collection for neutrophil activity analysis. In the second experiment, the blood of naïve mice was collected and incubated with MDMA for neutrophil activity in vitro analysis. In the third and fourth experiments, mice were injected with MDMA (10 mg/kg) and 60 min later, blood and brain were collected to analyze corticosterone serum levels and hypothalamic noradrenaline (NA) levels and turnover. In the last experiment, mice were injected with MDMA 10 mg/kg and 60 min later, blood, bone marrow and spleen were collected for leukocyte distribution analysis. RESULTS: Results showed an increase in hypothalamic NA turnover and corticosterone serum levels 60 min after MDMA (10 mg/kg) administration, a decrease in peripheral blood neutrophil oxidative burst and a decrease in the percentage and intensity of neutrophil phagocytosis. It was further found that MDMA (10 mg/kg) treatment also altered leukocyte distribution in blood, bone marrow and spleen. In addition, no effects were observed for MDMA after in vitro exposure both in neutrophil oxidative burst and phagocytosis. CONCLUSION: The effects of MDMA administration (10 mg/kg) on neutrophil activity and leukocyte distribution might have been induced indirectly through noradrenergic neurons and/or hypothalamic-pituitary-adrenal axis activations.