Aspartame, Phenylalanine, and Seizures in Experimental Animals

Abstract

An association has recently been proposed between seizure promotion and consumption of the phenylalanine-containing artificial sweetener aspartame. Since consumption of aspartame, unlike dietary protein, can elevate brain phenylalanine, and thus potentially inhibit the synthesis and release of neurotransmitters known to protect against seizure activity, we have studied the effects of aspartame and of its metabolic breakdown products (aspartic acid, methanol, and phenylalanine) on seizure activity, using two well-established experimental models, i.e., pen-tylenetetrazole and fluorothyl-induced seizures. The doses employed were chosen to produce changes in the plasma phenylalanine ratio which would mimic, in the mouse, the changes seen when humans consume moderate amounts of the sweetener. Mice receiving aspartame in doses of 1000 mg/kg or greater exhibited a significant lowering in the threshold to seizures induced by pentylenetetrazole. This response was mimicked by equimolar phenylalanine, but not by equimolar aspartic acid or methanol. Additionally, we tested the ability of tyrosine, a precursor of seizure-protecting catecholamines, to influence pentylenetetrazole-induced seizures. Tyrosine doses of 500 mg/kg or greater significantly elevated the seizure threshold in this model. Coadministration of tyrosine with either phenylalanine or aspartame prevented the deleterious effects of these compounds on the seizure threshold. Similarly, coadministration of the large neutral amino acid valine, which competes with phenylalanine for entry into the brain, also prevented the phenylalanine-induced changes. When phenylalanine or aspartame were administered prior to fluorothyl exposure, a significant decrease in the seizure threshold was also noted. Doses as low as 500 mg/kg were able to potentiate these seizures in immature mice. We conclude that in these commonly employed seizure models, aspartame, via its metabolic breakdown product phenylalanine, is capable of lowering the threshold to seizures. This may bear on the reported association between aspartame and seizures in humans.