Behavioral Measures of Neurotoxicity (1990) / Chapter Skim
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Are Neurotoxins Driving Us Crazy? Planetary Observations on the Causes of Neurodegenerative Diseases of Old Age
Are Neurotoxins Driving Us Crazy? Planetary Observations on the Causes of Neurodegenerative Diseases of Old Age
Pages 11-36
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From page 11... ...
Indeed, one would posit that a knowledgeable extraterrestrial investigator, charged with the task of identifying causes of the great neurodegenerative diseases of Homo sapiens on planet Earth, would be unlikely to begin by researching elderly populations in Canberra, London, or New York; rather, the hunt for causation would probably commence in places such as Guam or Irian Jaya where, in certain spots, incidence rates for such diseases have exceeded worldwide statistics by more than one to three orders of magnitude. If the etiologic search can be likened to the proverbial hunt for a needle in a haystack, why not maximize chances of success by focusing 11
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From page 12... ...
was also etiologically linked to Guam ALS. My conjecture was that detailed study of the neurotoxic factors in these plants might lead to a precise understanding of the chemical triggers of lathyrism and western Pacific ALS/P-D, information that could then be applied to search for the etiology of related neurodegenerative diseases worldwide.
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From page 13... ...
The underlying damage to the nervous system consists of progressive degenerative changes and loss of nerve cells in the motor cortex (upper motor neurons) and of lower motor neurons in spinal cord (anterior horn cells)
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From page 14... ...
Some patients with slowly evolving motor neuron disease later developed parkinsonism or P-D; in others, the appearance of P-D was followed by amyotrophy and spasticity, whereas in yet others, there was a more or less simultaneous onset of both ALS and P-D. Similarly, among Japanese residents of the Hobara region in the Kii peninsula focus of ALS/P-D, ALS incidence rates for the period 1946 to 1965 exceeded the average for Japan by more than 100 times.
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From page 15... ...
Because the incidence of motor neuron disease is declining in all three zones, and inherited and viral factors have been virtually ruled out, the search for etiology has focused on nontransmissible environmental factors that are disappearing as the susceptible population groups acculturate to modern ways. Two major etiologic hypothesis have been advanced, neither of which is mutually exclusive: one invokes metal intoxication promoted by a dietary deficiency of calcium, whereas the other implicates the neurotoxic cycad plant used for food and medicine.
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From page 16... ...
Although these data appear to have dislodged the cornerstone (deficient dietary calcium) of the mineral dysmetabolism hypothesis, there is nonetheless concrete evidence of heavy intraneuronal deposition of calcium and aluminum in Guam ALS/P-D.
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From page 17... ...
Cycad seed is often brightly colored (red, brown, green) and has the appearance of an edible fruit, features that have undoubtedly encouraged human contact.
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From page 18... ...
. Individual cases of ALS in these regions have been linked with heavy exposure to Cycas seed kernel used as a topical medicine (Irian Jaya, Guam)
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From page 19... ...
used by aboriginals to "detoxify" the seed. The acute toxic effects of cycads variously exploited In the past to execute criminals (Honduras)
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From page 20... ...
Many other examples of acute cycad poisoning, sometimes with fatal outcome are recorded among early settlers in Australia and elsewhere. Eventually, however, the migrant Europeans learned how to "cletoxify" the cycad.
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From page 21... ...
Although the exposure of seemingly large numbers of people in certain developed countries to small amounts of "detoxified" cycad products may hold more than passing interest, the focus here is on populations that have sustained heavy exposure to patently nondetoxified cycad seed. This takes place when the raw seed is used as a topical or an oral medicine, or when time is too short to complete the lengthy procedure of detoxication by drying, water leaching, or fermentation.
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From page 22... ...
Between 1962 and 1972, six international conferences instigated by the National Institutes of Health in the United States were held to consider the possible relationship between Guam ALS/ P-D and the traditional Chamorro practice of employing cycad seed for food. Only the third (Lyon Arboretum, 1964)
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From page 23... ...
By 1972, the cycad hypothesis for western Pacific ALS had fallen into disfavor for two principal reasons: cycads were reported not to be used for food in either the Kit peninsula or the Irian laya foci of ALS, and nonprimate laboratory animals repeatedly exposed to cycad products failed to develop a paralytic disorder. However, what must remain as a most puzzling oversight was the publication in the third conference of an experimental feeding study in Macaca mulatta which resulted in one of the three tested animals developing unilateral arm weakness, with neuropathological evidence of nonreactive degeneration of motor neurons (possibly the first primate model of ALS, this important experiment was neither confirmed nor refuted)
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From page 24... ...
Severe loss of Betz cells (upper motor neurons) may occur, most noticeably in the upper part of the precentral sulcus and in the paracentral lobule.
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From page 25... ...
Once the primate studies had confirmed BOAA as the culpable agent of lathyrism, my attention turned to the relationship between the acute neurotoxic properties of BOAA and BMAA, and then to the primate toxicity of the latter. Initial studies were performed with mouse spinal cord explants.
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From page 26... ...
These data, reported for the first time in the summer of 1987, demonstrated an intriguing parallelism between chronic BMAA intoxication and human ALS/P-D. However, because the experimental disorder lacked certain important features of the human disease, notably nigral degeneration and plentiful paired helical filaments, clearcut loss of motor neurons, and muscle denervation, it was inappropriate to refer to the primate disorder as a model of ALS/P-D.
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From page 27... ...
The few pathological reports of this condition in cattle described degeneration of long, presumably motor tracts in the lumbar region, with changes in the fasciculus gracilis and dorsal spinocerebellar tracts in the cervical area. Information on the status of motor neurons that innervate the weakened and atrophied limbs of animals with cycadism is unavailable.
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From page 28... ...
Although this medical use of cycad seed kernel was acknowledged by many, all vigorously denied employing any part of the plant for food because it was considered poisonous. Instead, the people relied for food on saga obtained from the stem of the true sago palm (Metroxylon spp.~.
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From page 29... ...
Immediately, the association between cycad exposure and familial ALS became clear. Establishing a link between cycad and ALS in the Kii peninsula focus of neurodegenerative disease was more difficult.
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From page 30... ...
apparently had perfected rather, it was exposure to the untreated cycad seed kernel as medicine. In Guam and in Irian Jaya, this took the form of topical exposure to open wounds (tropical ulcers)
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From page 31... ...
Specifically, heavy exposure may precipitate ALS by lethally damaging motor neurons. The heavily exposed subjects also sustain some damage to the apparently less susceptible nigrostriatal pathway a silent change demonstrable neuropathologically and by fluorodopa positron emission tomography, but because the lesion is insufficient to overcome the large functional reserve of this pathway (thereby permitting the clinical expression of parkinsonism)
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From page 32... ...
Although BMAA is present in low concentrations relative to that of cycasin in cycad seed kernel, what constitutes a significant dose of BMAA has yet to be established.
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From page 33... ...
Other studies show that cycasin in cycad leachate diminishes in concentration prior to BMAA. Thus, individuals ingesting seed kernel that has been soaked in water for only a few days would receive doses of both MAM and BMAA.
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From page 34... ...
Although the different neuronal receptors targeted by BOAA and BMAA may be etiologically linked to the distinct patterns of neuronal vulnerability in human lathyrism (cortical motor neuron) and western Pacific ALS (upper and lower motor neurons, substantia nigra, and hippocampus)
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From page 35... ...
Although BMAA produces an interesting and potentially important constellation of motor neuron, extrapyramidal, and behavioral dysfunction in cynomolgus monkeys repeatedly fed subconvulsive doses of the pure compound, insufficient neuropathological changes have been generated to merit description of the primate response as an animal model of western Pacific ALS/ P-D. The role of BMAA, MAM, and other factors in the etiology of this disease is being studied.
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From page 36... ...
Research of this type should not be restricted to chemical components in plants used for medicine or food but should also take into account the wider potential for chemical factors that might have a role in triggering some forms of motor neuron disease, parkinson~sm, and senile dementia of He Al~he~mer type. By intensive exploration of the chemical exposure cupboards of young-onset patients with neurodegenerative diseases, it may be possible to obtain pertinent leads that can be tested in the laboratory.
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