Abstract

2-Amino-3-(methylamino)-propanoic acid (BMAA) is a neurotoxic, excitatory amino acid which has been linked through cycad use and consumption with the onset of a variant of amyotrophic lateral sclerosis occurring with high incidence in the western Pacific region. We have studied BMAA pharmacokinetics, oral bioavailability and blood-brain barrier permeability in the rat in an attempt to better define the possible role for BMAA in this disease. To evaluate its kinetics and uptake, BMAA (25-400 mg/kg) was administered to rats, either acutely or chronically, and then plasma and brain concentrations were determined at various times thereafter by combined gas chromatography mass spectrometry. After single dose i.v. injection, BMAA was cleared from plasma in a rapid distribution phase (Vd approximately 16 liters/kg) followed by a slower elimination phase (t1/2 approximately 1 day). Brain uptake was limited by a low blood-brain barrier permeability-surface area product of 2 to 5 x 10(-5) ml/sed/g. Brain BMAA levels peaked within 8 hr after injection, and then declined with a t1/2 similar to that of plasma. After two weeks of continuous infusion (100 mg/kg/day), steady-state brain concentrations equalled 10 to 30 micrograms/g, and only moderately exceeded those in plasma. The results suggest that BMAA may reach potentially toxic levels in brain (i.e., greater than 250 microM) after large doses (greater than 100 mg/kg). However, such doses are orders of magnitude greater than those available from dietary or medicinal use of cycads.