Diethyldithiocarbamate causes nigral cell loss and dopamine depletion with nontoxic doses of MPTP.
Although nontoxic when administered alone, diethyldithiocarbamate (DDC) is known to enhance the dopamine-depleting effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse striatum. The purpose of the present study was twofold: (i) to carefully characterize the effects of DDC on MPTP-induced degeneration of dopaminergic neurons in substantia nigra pars compacta using unbiased, stereological cell counting techniques and (ii) to determine whether or not DDC can convert a nontoxic dose of MPTP into one which is clearly toxic on dopaminergic neurons in the substantia nigra. A single low dose of MPTP (15 mg/kg intraperitoneally (ip)) was used for these studies, which failed to induce any neurochemical or histological effects on the nigrostriatal system of C57BL/6 mice when administered alone. However, when animals were pretreated with DDC (400 mg/kg ip), the same dose of MPTP resulted in a 50% loss of neurons in the substantia nigra pars compacta, as well as a 70% reduction in striatal dopamine (DA). A 31% reduction of DA in the ventral mesencephalon was also seen. This combined regimen of DDC and MPTP was not significantly different from a maximally tolerated "toxic" dose of MPTP alone (15 mg/kg x 4, 1 h apart, ip). As expected, animals receiving DDC alone did not show any dopamine depletion nor nigral neuronal loss. The present study confirms previous work suggesting that DDC enhances MPTP-induced nigral cell loss and shows for the first time that DDC can "unmask" MPTP toxicity. These observations could have implications for theories on the cause of Parkinson's disease.
Walters
T L
TL
Department of Neuroscience, Doktorsringen 17 Karolinska Institutet, S-17177, Stockholm, Sweden.
Irwin
I
I
Delfani
K
K
Langston
J W
JW
Janson
A M
AM
D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D004050:Ditiocarb / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000633:toxicity*; D004357:Drug Synergism; D007150:Immunohistochemistry; D020267:MPTP Poisoning; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002395:Catecholamines; D015259:Dopamine Agents; D004050:Ditiocarb; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine