Effects of L-dopa and other amino acids against paraquat-induced nigrostriatal degeneration.
Exposure to the herbicide paraquat causes selective nigrostriatal degeneration and aggregation of alpha-synuclein in the mouse brain. The purpose of this study was to assess mechanisms of paraquat entry into the CNS and, in particular, the effects of substrates of the blood-brain barrier (BBB) neutral amino acid transporter (System L carrier) on paraquat accumulation and neurotoxicity. Using a paraquat antibody, robust immunoreactivity was observed in the midbrain of mice injected with the herbicide. This immunoreactivity was abolished by administration of l-valine or l-phenylalanine, two System L substrates, immediately before paraquat exposure. Pre-treatment with these amino acids completely protected against paraquat-induced loss of nigrostriatal dopaminergic cells and formation of thioflavine S-positive intracellular deposits. Interestingly, the anti-parkinsonian drug l-dopa, which is transported across the BBB through the same neutral amino acid carrier, was also neuroprotective when administered 30 min prior to paraquat. In contrast, paraquat-induced toxicity was unaffected if animals (i) were pre-treated with d-valine, the biologically inactive d-isomer of l-valine, or with l-lysine, a substrate of the basic rather than the neutral amino acid carrier, or (ii) were injected with l-dopa 24 h after paraquat exposure. Data are consistent with a critical role of uptake across the BBB in paraquat neurotoxicity, and suggest that dietary elements (e.g. amino acids) or therapeutic agents (e.g. l-dopa) may modify the effects of toxicants targeting the nigrostriatal system.
McCormack
Alison L
AL
The Parkinson's Institute, Sunnyvale, California 94089, USA.
Di Monte
Donato A
DA
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology; D010269:Paraquat / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000517:prevention & control*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis
D000596:Amino Acids; D018696:Neuroprotective Agents; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D010269:Paraquat