Diethyldithiocarbamate Potentiates the Neurotoxicity of In vivo 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine and of In vitro 1-Methyl-4-Phenylpyridinium

摘要

Diethyldithiocarbamic acid (DDC), a dithiocarbamate, potentiates theneurotoxicity of 1-methyl-r-pheny-1,2,3,6-tetrahydropyridine (MPTP) in vivo and of its major metabolite, 1-methyl-4-phenylpyridinium (MPP+), in bovine adrenal medullary (BAM) cells maintained in culture. Male C57B1/6 mice were given 2 or 5 injections of MPTP (30mg/kg, i.p.) preceded 0.5 hy by DDC (400 mg/kg, i.p.). The mice were tested for catalepsy, akinesia or motor activity during and after the period of dosing. Systemically administered MPP+ decreased heart NE but did not alter the striatal levels of DA or GRAP & pretreatment with DDC did not alter these effects but did increase lethality. In culture MPP+ (0.3mM) slightly decreased catecholamine levels but had no effect on the tyrosine hydroxylase activity or cellular protein of BAM cells. However, the incubation of these cells with MPP+ and DDC (1.5 or 3.0mM) caused large decreases in all indicators of cell viability. DDC also blocked the uptake of MPP+ into the vesicles of BAM cells. Findings show that DDC increases the neurotoxicity of MPTP in both striatum and hippocampus. One possible explanation for the ability of DDC to potentiate the in vitro effect of MPP+ on BAM cells is that DDC may cause a redistribution of MPP+ at the subcellular level.