Facilitated transport of the neurotoxin, beta-N-methylamino-L-alanine, across the blood-brain barrier.
beta-N-Methylamino-L-alanine (BMAA) is a neurotoxic plant amino acid that has been implicated in the pathogenesis of the high incidence amyotrophic lateral sclerosis and related parkinsonism dementia of the western Pacific. Previous studies have demonstrated that BMAA is taken up into brain following intravenous or oral administration. To examine the kinetics and mechanism of brain transfer, BMAA influx across the blood-brain barrier was measured in rats using an in situ brain perfusion technique. BMAA influx was found to be saturable with a maximal transfer rate (Vmax) of 1.6 +/- 0.3 x 10(-3) mumol/s/g and a half-saturation constant (Km) of 2.9 +/- 0.7 mM based on total perfusate BMAA concentration. Uptake was sodium independent and inhibitable by excess L-leucine, but not by L-lysine, L-glutamate, or methylaminoisobutyric acid, indicative of transfer by the cerebrovascular large neutral amino acid carrier. L-BMAA competitively reduced brain influx of L-[14C]leucine, as expected for cross-inhibition. The results demonstrate that BMAA is taken up into brain by the large neutral amino acid carrier of the blood-brain barrier and suggest that uptake may be sensitive to the same factors that affect neutral amino acid transport, such as diet, metabolism, disease, and age.
Smith
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QR
Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892.
Nagura
H
H
Takada
Y
Y
Duncan
M W
MW
D026905:Amino Acid Transport Systems; D000596:Amino Acids / Q000493:pharmacokinetics; D000599:Amino Acids, Diamino / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D000087522:Cyanobacteria Toxins; D008401:Gas Chromatography-Mass Spectrometry; D007700:Kinetics; D007930:Leucine / Q000493:pharmacokinetics; D008239:Lysine / Q000493:pharmacokinetics; D008297:Male; D009498:Neurotoxins / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000494:pharmacology; D012965:Sodium Chloride / Q000494:pharmacology
D026905:Amino Acid Transport Systems; D000596:Amino Acids; D000599:Amino Acids, Diamino; D002352:Carrier Proteins; D000087522:Cyanobacteria Toxins; D009498:Neurotoxins; C001824:beta-N-methylamino-L-alanine; D012965:Sodium Chloride; D012964:Sodium; D007930:Leucine; D008239:Lysine