You are here:
DIETHYLDITHIOCARBAMATE POTENTIATES THE NEUROTOXICITY OF IN VIVO 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE AND OF IN VITRO 1-METHYL-4-PHENYLPYRIDINIUM
Citation:
Miller, D., J. O'Callaghan, J. Reinhart, AND A. Daniels. DIETHYLDITHIOCARBAMATE POTENTIATES THE NEUROTOXICITY OF IN VIVO 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE AND OF IN VITRO 1-METHYL-4-PHENYLPYRIDINIUM. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-91/199 (NTIS PB91242586).
Description:
Diethyldithiocarbamic acid (DDC), a dithiocarbamate, potentiates the neurotoxicity 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. ale C57B1/6 mice were given 2 or 5 injections of MPTP (30 mg/kg, i.p.) preceded 0.5 by DDC (400 mg/kg, i.p.). he mice were tested for catalepsy, akinesia or motor activity during and after the period of dosing. triatal and hippocampal tissue were obtained at 2 and 7 days following the last injection and evaluated for dopamine (DA) and norepinephrine (NE) levels, respectively. hese same tissues were also analyzed for the levels of glial fibrillary acidic protein (GFAP) an astrocyte-localized protein known to increase in response to neuronal injury. he pretreatment with DDC potentiated the effect of MPTP in striatum and resulted in a substantially greater DA depletion as well as a more pronounced elevation in GFAP. n hippocampus the levels of NE and GFAP levels were not different from controls in mice receiving only MPTP but pretreatment with DDC prior to the MPTP resulted in a depletion of NE and an elevation of GFAP suggesting that damage was extended ot this brain area by the combination. ice receiving MPTP preceded by DDC also demonstrated a more profound but reversible catalepsy and akinesia. ystemically administered MPP+ decreased heart NE but did not alter the striatal levels of DA or GRAP and pretreatment with DDC did not alter these effects but did increase lethality. n culture MPP+ (0.3mM) slightly decreased catecholamine levels but had no effect on the tyrosine hydroxylase activity or cellular protein of BAM cells. owever, the incubation of these cells with MPP+ and DDC (1.5 or 2.)mM) caused large decreases in all indicators of cell viability. DC also blocked the uptake of MPP+ into the vesicles of BAM cells. ur findings show that DDC increases the neurotoxicity of MPTP in both striatum and hippocampus. ne 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.