RESUMO
Studies have suggested that the neuroprotective actions of alpha7 nicotinic agonists arise from activation of receptors and not from the extensive desensitization which rapidly follows activation. Here, we report that the alpha7-selective nicotinic antagonist, methyllycaconitine (MLA), protects against beta-amyloid-induced neurotoxicity; whereas the alpha4beta2-selective antagonist, dihydro-beta-erythroidine, does not. These findings suggest that neuroprotective actions of alpha7-acting agents arise from receptor inhibition/desensitization and that alpha7 antagonists may be useful neuroprotective agents.
Assuntos
Aconitina/análogos & derivados , Peptídeos beta-Amiloides/toxicidade , Neurônios/efeitos dos fármacos , Antagonistas Nicotínicos/farmacologia , Fragmentos de Peptídeos/toxicidade , Receptores Nicotínicos/metabolismo , Aconitina/antagonistas & inibidores , Aconitina/farmacologia , Animais , Animais Recém-Nascidos , Encéfalo/citologia , Morte Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Interações Medicamentosas , Camundongos , Sais de Tetrazólio , Tiazóis , Receptor Nicotínico de Acetilcolina alfa7RESUMO
The abuse of gamma-hydroxybutyrate (GHB) and two of its precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are recognized as a public health concern. Here, we report dose-response and time-course analyses for effects of GBL and 1,4-BD on locomotor activity and body temperature in Swiss-Webster mice. Locomotor activity was measured for 2 h following a single injection of one of four doses of each agent plus a saline vehicle control. At 50 mg/kg, GBL produced an initial depression of locomotor activity which was followed by stimulation of locomotor activity. In contrast, 1,4-BD at 50 mg/kg stimulated locomotor activity without producing any depression of activity. At higher doses, GBL produced primarily a dose-dependent decrease in locomotor activity that returned to baseline within 50 min. In contrast, 1,4-BD produced an initial depression which was followed by stimulation of activity. Body temperature was measured rectally across a 2.5-h time course following injection with either agent. Both drugs produced hypothermia with peak effects occurring at 20 and 30 min for both drugs for the lower and higher dose, respectively. At 150 mg/kg, GBL produced a greater hypothermic response; however, no differences in hypothermic response were observed at 100 mg/kg. These studies demonstrate that the precursor drugs to GHB have some differential actions from each other.