RESUMEN
Benzylpiperazine has been designated as Schedule I substance under the Controlled Substances Act by Drug Enforcement Administration. Benzylpiperazine is a piperazine derivative, elevates both dopamine and serotonin extracellular levels producing stimulatory and hallucinogenic effects, respectively, similar to methylenedioxymethamphetamine (MDMA). However, the comparative neurotoxic effects of Piperazine derivatives (benzylpiperazine and benzoylpiperazine) have not been elucidated. Here, piperazine derivatives (benzylpiperazine and benzoylpiperazine) were synthesized in our lab and the mechanisms of cellular-based neurotoxicity were elucidated in a dopaminergic human neuroblastoma cell line (SH-SY5Y). We evaluated the in vitro effects of benzylpiperazine and benzoylpiperazine on the generation of reactive oxygen species, lipid peroxidation, mitochondrial complex-I activity, catalase activity, superoxide dismutase activity, glutathione content, Bax, caspase-3, Bcl-2 and tyrosine hydroxylase expression. Benzylpiperazine and benzoylpiperazine induced oxidative stress, inhibited mitochondrial functions and stimulated apoptosis. This study provides a germinal assessment of the neurotoxic mechanisms induced by piperazine derivatives that lead to neuronal cell death.
Asunto(s)
Apoptosis/efectos de los fármacos , Agonistas de Dopamina/toxicidad , Neuronas Dopaminérgicas/efectos de los fármacos , Alucinógenos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Piperazinas/toxicidad , Proteínas Reguladoras de la Apoptosis/agonistas , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Proteínas Reguladoras de la Apoptosis/metabolismo , Biomarcadores/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Drogas de Diseño/química , Drogas de Diseño/toxicidad , Agonistas de Dopamina/química , Neuronas Dopaminérgicas/citología , Neuronas Dopaminérgicas/metabolismo , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Complejo I de Transporte de Electrón/metabolismo , Alucinógenos/química , Humanos , Peroxidación de Lípido/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Mitocondrias/metabolismo , Estructura Molecular , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Concentración Osmolar , Piperazinas/química , Especies Reactivas de Oxígeno/agonistas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The birth of the twenty first century has provoked a substantial rise in the use of designer drugs, such as synthetic cathinones, because of a decrease in the availability and purity of other drugs of abuse. The khat plant or Catha edulis, contains cathinone, the parent compound. Synthetic cathinones are sold under the name "bath salts" as a ploy to circumvent legislation from banning their use. Constant modification of the chemical structure by covert laboratories allows manufacturers to stay one step ahead of the legal process. Currently, the widespread distribution of "bath salts" has negative consequences for law enforcement officials and public health resources. Comparable mechanisms of action, between the synthetic cathinones and amphetamine, cocaine, and MDMA are attributed to the similarities in their chemical structures. Synthetic cathinone's potent stimulatory effects, coupled with their high abuse potential, and propensity for addiction demands additional pharmacological and toxicological evaluations for these existing and new designer drugs of abuse. If these drugs are designed carefully, they might also have a significant therapeutic value.