In brown Norway rats, MPP+ is accumulated in the nigrostriatal dopaminergic terminals but it is not neurotoxic: a model of natural resistance to MPTP toxicity.
Rats have been described as being insensitive to relatively high doses of systemically administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that in primates induces a neurological syndrome identical to idiopathic Parkinson's disease. The current explanation for the rat resistance is that most of the MPTP is converted into the toxic metabolite 1-methyl-4-phenylpyridium (MPP+) by the MAO-B present in the brain vessel endothelium. Since MPP+ is a polar compound, a very low amount could cross the blood-brain barrier and be present inside the brain. We administered C57 BL mice and Brown Norway rats with either MPTP (30 mg/kg, ip) or the combined treatment MPTP + diethyldithiocarbamate (DDC). In mice, DDC prolonged the striatal exposure to MPP+, potentiated the MPTP-induced acute syndrome, and enhanced the MPTP-induced striatal dopamine depletion. In rats, DDC potentiated the MPTP-induced acute syndrome, but no changes in the striatal dopamine were observed after either MPTP or DDC + MPTP administration. Also in rats, however, high doses of MPP+ were measured in the striatum of MPTP-alone treated rats and DDC delayed the MPP+ elimination from the striatum. When MPTP alone or DDC + MPTP was administered to rats unilaterally lesioned with 6-hydroxy dopamine (6-OH-DA), the levels of MPP+ measured in the intact striatum were significantly higher than those found in the 6-OH-DA-lesioned striatum.(ABSTRACT TRUNCATED AT 250 WORDS)
Zuddas
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Department of Neuroscience, University of Cagliari, Italy.
Fascetti
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Corsini
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GU
Piccardi
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MP
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D004050:Ditiocarb / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D007700:Kinetics; D020267:MPTP Poisoning; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D011914:Rats, Inbred BN; D013045:Species Specificity; D013239:Stereotyped Behavior / Q000187:drug effects*; D013378:Substantia Nigra / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution
D004050:Ditiocarb; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine