Cycads and their association with certain neurodegenerative diseases.

INTRODUCTION: Cycads are ornamental plants that in some parts of the world are used as fresh food or raw material for producing flour with a high nutritional value. However, they also contain active compounds, including methylazoxymethanol, ß-methylamino-L-alanine, ß-alanine-L-oxalylamino and cycasin, which may produce neurotoxic effects. Some studies have associated consuming cycads and their derivatives with neurodegenerative diseases such as amyotrophic lateral sclerosis/Parkinsonism dementia complex, and other diseases characterised by motor impairment. Therefore, we must not forget that any product, no matter how natural, may present health risks or benefits depending on the chemical compounds it contains and the susceptibility of those who consume it. DEVELOPMENT: We completed a literature analysis to evaluate the neurotoxic properties of cycads and their association with neurological diseases in order to provide structured scientific information that may contribute to preventing health problems in people who use these plants. CONCLUSION: Cycads contain neurotoxic compounds that may contribute to the development of neurological diseases when ingested improperly. We must be mindful of the fact that while some plants have a high nutritional value and may fill the food gap for vulnerable populations, they can also be toxic and have a negative impact on health.

Grass pea and neurolathyrism: farmers' perception on its consumption and protective measure in North Shewa, Ethiopia.

Neurolathyrism in Ethiopia is caused by food dependency on grass pea (Lathyrus sativus L.). In the study area, a large proportion of the farmers are growing grass pea since it can withstand harsh environments. Socio-economic factors (poverty; lack of money to buy other food legumes) and environmental problems (such as water logging and frost hazards) influence consumption of grass pea. Most of the respondents have the idea that some chemical contained in grass pea causes a health problem. Different processing and preparation methods are used to prepare grass pea into different food forms. The major processing methods include washing and soaking, as the farmers apply these methods mainly because they assume that the chemical that causes lathyrism, scientifically known as ß-ODAP (ß-N-oxalyl-L-α,ß-diaminopropionic acid) is reduced through washing and soaking. The farmers adopt different strategies to avoid the problem of lathyrism such as avoiding consumption of grass pea in the form that they suspect to cause the problem, blending/mixing with other crops, applying different processing/detoxification methods. Since grass pea is consumed with a fear of lathyrism, future research should concentrate either on developing grass pea varieties with safe level of ß-ODAP content or improving the traditional/indigenous processing methods.

Brain glutathione as a target for aetiological factors in neurolathyrism and konzo.

Both neurolathyrism and konzo are associated with the nutritional dependence of human populations on a single plant food. These diseases express themselves as chronic disorders of upper motor neurones, leading to signs and symptoms that characterise amyotrophic lateral sclerosis (motor neurone disease). The plant food associated with neurolathyrism is grass pea, which contains the neurotoxic ß-N-oxalyl-α,ß-diaminopropionic acid (ß-ODAP). The plant food associated with konzo is cassava, which may contain significant concentrations of cyanogenic glycosides and their degradation products. A monotonous diet of grass pea is likely to generate nutritional deficiencies; it is proposed that one of these, plasma methionine deficiency, may predispose neurones to the neurotoxic effects of ß-ODAP. Subjects suffering from konzo also have low concentrations of plasma methionine as a result of a dietary deficiency of this amino acid. However, the plasma cystine concentration is also compromised because cyanide released from cyanogenic glycosides in cassava probably reacts with plasma cystine non-enzymatically. The product of this reaction is 2-imino-4-thiazolidine carboxylic acid. Since both plasma methionine and cystine are used for glutathione synthesis it seems likely that one common feature that leads to motor neurone death in neurolathyrism and konzo is the depletion of glutathione in the central nervous system.

Unraveling the mechanism of ß-N-oxalyl-α,ß-diaminopropionic acid (ß-ODAP) induced excitotoxicity and oxidative stress, relevance for neurolathyrism prevention.

ß-N-Oxalyl-α,ß-diaminopropionic acid (ß-ODAP) is a plant metabolite present in Lathyrus sativus (L. Sativus) seeds that is proposed to be responsible for the neurodegenerative disease neurolathyrism. This excitatory amino acid binds to α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and several lines of evidence indicate that ß-ODAP triggers motor neuron degeneration by inducing excitotoxic cell death and increasing oxidative stress. In addition, this toxin is known to disturb the mitochondrial respiration chain and recent data indicate that ß-ODAP may inhibit the uptake of cystine thereby compromising the cells' abilities to cope with oxidative stress. Recent work from our group furthermore suggests that ß-ODAP disturbs the cellular Ca(2+) homeostasis machinery with increased Ca(2+) loading in the endoplasmic reticulum (ER)-mitochondrial axis. In this review, we aim to integrate the various mechanistic levels of ß-ODAP toxicity into a consistent pathophysiological picture. Interestingly, the proposed cascade contains several aspects that are common with other neurodegenerative diseases, for example amyotrophic lateral sclerosis (ALS). Based on these mechanistic insights, we conclude that dietary supplementation with methionine (Met) and cysteine (Cys) may significantly lower the risk for neurolathyrism and can thus be considered, in line with epidemiological data, as a preventive measure for neurolathyrism.

Factors affecting ß-ODAP content in Lathyrus sativus and their possible physiological mechanisms.

A neuroexcitatory non-protein amino acid, ß-N-oxalyl-L-α,ß-diaminopropionic acid (ß-ODAP), present in the seeds of the hardy legume crop grass pea (Lathyrus sativus L.), was considered responsible for human lathyrism. The levels of ß-ODAP were reported to vary in different tissues during plant development, and to be affected by a wide range of environmental stresses. In this paper, dynamic changes in ß-ODAP level at specific stages of plant development as well as the influences of various environmental factors, including nutrient deficiency, drought, salinity, toxic heavy metals, and Rhizobium symbiosis on ß-ODAP levels were analyzed, highlighting the relationship between changes in ß-ODAP concentrations and Rhizobium growth. Possible mechanisms underlying ß-ODAP accumulation are proposed and future research is suggested.

Assessing diet in populations at risk for konzo and neurolathyrism.

Although both konzo and neurolathyrism are diseases associated with diet, we know surprising little about the diets of the groups at risk. The objective of this paper is to discuss methods for assessing dietary intake in populations at risk for konzo and lathyrism. These methods include weighed food records and interview based techniques like 24-h recalls and food frequency questionnaires (FFQs). Food records have the potential to provide accurate information on food quantities, and are generally the method of choice. Interview based methods provide less precise information on the quantities of foods ingested, and are subject to recall bias, but may be useful in some studies or for surveillance. Sample size needs to be adequate to account for day-to-day and seasonal variability in food intake, and differences between age and sex groups. Adequate data on the composition of foods, as actually consumed, are needed to evaluate the food intake information. This is especially important in the case of cassava and grass pea where the toxins in the diet is a function of processing. Biomarkers for assessing the cyanogen exposure from cassava-based diets are available; biomarkers for the ß-ODAP exposure from grass pea diets need development.

Genetic improvement of grass pea for low neurotoxin (ß-ODAP) content.

Grass pea is a promising crop for adaptation under climate change because of its tolerance to drought, water-logging and salinity, and being almost free from insect-pests and diseases. In spite of such virtues, global area under its cultivation has decreased because of ban on its cultivation in many countries. The ban is imposed due to its association with neurolathyrism, a non-reversible neurological disorder in humans and animals due to presence of neurotoxin, ß-N-oxalyl-L-α,ß-diaminopropionic acid (ß-ODAP) in its seedlings and seeds. The traditional varieties of grass pea contain 0.5-2.5% ß-ODAP. Exploitable genetic variability for ß-ODAP has been observed for development of low ODAP varieties, which along with improved agronomic and detoxification practices can help reduce the risk of lathyrism. Collaborative efforts between ICARDA and NARS have resulted in development of improved varieties such as Wasie in Ethiopia, Ratan, Prateek and Mahateora in India, and BARI Khesari-1 and BARI Khesari-2 in Bangladesh with <0.10% ß-ODAP. Soil application of 15-20 kg ha(-1) zinc sulphate, early planting, and soaking seeds in water have shown significant effects on ß-ODAP. Because of the often cross-pollination nature, the current breeding procedures being followed in grass pea requires paradigm shift in its approach for a possible genetic breakthrough.

Multiple neurotoxic items in the Chamorro diet link BMAA with ALS/PDC.

Beta-methyl-amino-L-alanine, (BMAA), is found in multiple components of the traditional Chamorro diet of Guam and this confounds epidemiological analysis based on a single dietary item. However, using hair as a non-invasive measure of BMAA exposure may help determine risks for developing motor neuron disease. BMAA found in brain tissues of patients with ALS/PDC and not generally in controls suggests that BMAA crosses the blood-brain barrier in patients with disease and is associated with neurodegenerative disease. An examination of frozen versus fixed autopsy tissue from ALS/PDC patients suggests that earlier studies of BMAA in ALS/PDC patients based on fixed tissues may have underestimated the concentration of BMAA in brain tissues. We suggest that the Chamorro people are exposed to chronically low levels of BMAA in the diet and that further research is needed to understand chronic BMAA toxicity.

Consumption of fa cai Nostoc soup: a potential for BMAA exposure from Nostoc cyanobacteria in China?

Grown in arid regions of western China the cyanobacterium Nostoc flagelliforme--called fa cai in Mandarin and fat choy in Cantonese--is wild-harvested and used to make soup consumed during New Year's celebrations. High prices, up to $125 USD/kg, led to overharvesting in Inner Mongolia, Ningxia, Gansu, Qinghai, and Xinjiang. Degradation of arid ecosystems, desertification, and conflicts between Nostoc harvesters and Mongol herdsmen concerned the Chinese environmental authorities, leading to a government ban of Nostoc commerce. This ban stimulated increased marketing of a substitute made from starch. We analysed samples purchased throughout China as well as in Chinese markets in the United States and the United Kingdom. Some were counterfeits consisting of dyed starch noodles. A few samples from California contained Nostoc flagelliforme but were adulterated with starch noodles. Other samples, including those from the United Kingdom, consisted of pure Nostoc flagelliforme. A recent survey of markets in Cheng Du showed no real Nostoc flagelliforme to be marketed. Real and artificial fa cai differ in the presence of beta-N-methylamino-L-alanine (BMAA). Given its status as a high-priced luxury food, the government ban on collection and marketing, and the replacement of real fa cai with starch substitutes consumed only on special occasions, it is anticipated that dietary exposure to BMAA from fa cai will be reduced in the future in China.

Discovery and partial characterization of primate motor-system toxins.

beta-N-Oxalylamino-L-alanine (BOAA) and beta-N-methylamino-L-alanine (BMAA) are chemically related excitant amino acids isolated from the seed of Lathyrus sativus (BOAA) and Cycas circinalis (BMAA), consumption of which has been linked to lathyrism (an upper motor neuron disorder) and Guam amyotrophic lateral sclerosis (ALS), respectively. Both diseases are associated with degeneration of motor neurons. Experimentally, single doses of BOAA or BMAA induce seizures in neonatal mice and postsynaptic neuronal oedema and degeneration in explants of mouse spinal cord and frontal cortex. Preliminary studies show that these behavioural and pathological effects are differentially blocked by glutamate-receptor antagonists. In macaques, several weeks of daily oral doses of BOAA produce clinical and electrophysiological signs of corticospinal dysfunction identical to those seen in comparably well-nourished animals receiving a fortified diet based on seed of Lathyrus sativus. By contrast, comparable oral dosing with BMAA precipitates tremor and weakness, bradykinesia and behavioural changes, with conduction deficits in the principal motor pathway. BOAA and BMAA (or a metabolite thereof) are the first members of the excitotoxin family to have been shown to possess chronic motor-system toxic potential. These observations provide a rational basis for searching for comparable endogenous neurotoxins in sporadic and inherited forms of human motor neuron disease.