Guam Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Linked to a Plant Excitant Neurotoxin

Abstract

The decline in the high incidence of amyotrophic lateral sclerosis, parkinsonism, and Alzheimer-type dementia among the Chamorro population of the western Pacific islands of Guam and Rota, coupled with the absence of demonstrable viral and hereditable factors in this disease, suggests the gradual disappearance of an environmental factor selectively associated with this culture. One candidate is seed of the neurotoxic plant Cycas circinalis L., a traditional source of food and medicine which has been used less with the Americanization of the Chamorro people after World War II. Macaques were fed the Cycas amino acid beta-N-methylamino-L-alanine, a low-potency convulsant that has excitotoxic activity in mouse brain, which is attenuated by N-methyl-D-aspartate receptor antagonists. These animals developed corticomoto-neuronal dysfunction, parkinsonian features, and behavioral anomalies, with chromatolytic and degenerative changes of motor neurons in cerebral cortex and spinal cord. In concert with existing epidemiological and animal data, these findings support the hypothesis that cycad exposure plays an important role in the etiology of the Guam disease.

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

“…NMDA receptor-mediated processes are potential factors in the mechanism underlying both Parkinson's disease and MPTP-induced parkinsonism. It has been shown, for example, that the unusual amino acid fl-N-methylamino-L-alanine, probably responsible for the amyotrophic lateral sclerosisparkinsonism-dementia complex of Guam (Spencer et al 1987), activates glutamate receptors.…”

Cycads: evolutionary innovations and the role of plant-derived neurotoxins

“…On primates, BMAA causes convulsions and neurodegeneration [50]. However, this response is immediate, whereas Guam's dementia is a latent disease, appearing many years after exposure.…”

The relationship between excitotoxicity and oxidative stress in the central nervous system

“…However a correlation of extended dietary ingestion of a glutaminergic agonist, 13-methylamino-L-alanine, with a delayed occurrence of a neurological complex (Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia) has been claimed. 84 In addition, application of excitotoxins to the brain can both selectively destroy cholinergic neurons, and effect late-occurring neuropathological changes resembling neuritic plaques and neurofibrillary tangles. 85 …”