The effect of dithiocarbamates on neurotoxic action of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and on mitochondrial respiration chain.
The neurotoxin MPTP induces in human and in some laboratory animals parkinsonism-like neurological disorder, biochemically characterized by selective and irreversible decrease of dopamine content in striatum. The terminal step in the mechanism of neurotoxic action of MPTP is the inhibition of mitochondrial respiratory chain by pyridinium metabolite (MPP+) resulting in energy depletion and nervous cells death. Earlier it was shown that some chemical compounds, in particular diethyldithiocarbamate (DTC), can potentiate MPTP neurotoxicity. In the present work we have studied the influence of DTC derivatives on MPTP neurotoxic effect in vivo and on MPP+ inhibition of mitochondrial respiration (both on intact mitochondria and on submitochondrial particles) in vitro. It was revealed that DTC alone change mitochondrial membrane state by respiratory chain uncoupling and inhibition. DTC and MPP+ mutually potentiate inhibition of electron transport as well. The combined effect of DTC plus MPP+ action on mitochondria respiration reflects the sum of reciprocally leveling and potentiating factors and can explain the order of efficacy of MPTP-neurotoxicity potentiation in vivo in series of close DTC derivatives.
Bachurin
S O
SO
Laboratory of Neurochemistry, Institute of Physiologically Active Substances, Chernogolovka, Moscow Region, Russia.
Shevtzova
E P
EP
Lermontova
N N
NN
Serkova
T P
TP
Ramsay
R R
RR
D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects*; D020267:MPTP Poisoning; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D013859:Thiocarbamates / Q000494:pharmacology*
D002219:Carbamates; D009498:Neurotoxins; D013859:Thiocarbamates