the toxicity of lathyrus species and malnutrition 2011 fct5728

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The nutritive value of grasspea (Lathyrus sativus) and allied species, their toxicity

to animals and the role of malnutrition in neurolathyrism

Dirk Enneking ⇑

Kangaroo Inn Area School, Department of Education and Children’s Services, South Australia, Australia

a r t i c l e i n f o

Article history:

Available online 26 November 2010

Keywords:

NeurolathyrismMalnutritionNutritive ValueNeurovascular connectionFood securityBlood brain barrier

a b s t r a c t

The safe use of grasspea (Lathyrus sativus) and allied species (L. cicera, L. clymenum and L. ochrus) requiresa better understanding of the factors that are involved in the development of neurolathyrism. A suitableanimal model is needed. The nutritional quality, seed chemical composition, the role of malnutrition, syn-ergistic action of antinutritional factors, the toxicity of both seed and forage to animals, metabolism andtissue distribution of the toxic amino acid beta-N-oxalyl-alpha,beta-L -diaminopropionic acid (ODAP) inmammals are reviewed. Malnutrition is not necessary for the development of neurolathyrism, however,the supply of sulfur amino acids by Lathyrus spp. is limited by the combined action of several antinutri-tional factors and the low inherent levels in the seeds. Metabolism or excretion of ODAP and clearancefrom the central nervous system appear to function well under normal circumstances, while species dif-ferences exist. Interruptions to these processes and excessive concurrent demands for reduced sulfuramino acids are likely to be conducive to the onset of neurotoxicity.

Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.

1. Introduction

Neurolathyrism, a spastic paraparesis related to upper motor-neuron dysfunction is intricately linked to poverty, malnutritionand periods of famine (due to drought, floods or conflict) duringwhich people are forced to subsist on diets consisting to a largepart of grasspea (Lathyrus sativus L.), red chickling vetch (L. cicera L.)or purple Spanish vetchling (L. clymenum L.) (Schuchardt, 1887;Cornevin, 1893; Moya et al., 1967; Mitchell, 1971; Spencer, 1995;Tshala-Katumbay and Spencer, 2007). In historic epidemics andcases of lathyrism in France, Algeria and Syria, L. cicera andL. clymenum have been implicated, less frequently L. sativus,although there has been some taxonomic confusion in severalcases (Chevallier, 1841; Hamelin, 1882; Schuchardt, 1887; Cornevin,1893). The recently revived cultivation and human consumptionof L. clymenum on the Greek island of Santorini (Koutsika-Sotiriouet al., 2010) has a long tradition (Sarpaki and Jones, 1990). L. ochrus

is also known as a food legume from Greece ( Jones, 1992) andCyprus (Bevan, 1919; Anonymous, 1959; Christodoulou, 1959and Italy (Schuchardt, 1887) but there do not seem to be any

reports about its consumption causing health problems despiteits high seed neurotoxin content [vide infra].

Kirk (1861) suggested that since grasspea was only consumedin the poorest villages, its quantities at local markets could be usedas an indicator of poverty: ‘‘its abundance indicates wretchedness’’.Mitchell (1971) delineated Uttar Pradesh, Madhya Pradesh andBihar as areas of India with endemic lathyrism. These states areinhabited by nearly half of India’s poor and one third of its humanpopulation (Kapur Mehta and Shah, 2001). Grasspea is also animportant crop in Bangladesh, Pakistan and Nepal (Campbell,1997) with documented widespread current human consumptionin India (Dixit et al., 2008) and the highlands of Ethiopia (Guinand,1999; Dadi, 2003) where it remains an important staple and emer-gency food crop.

In the wake of the recent floods in Pakistan, the fact that grass-pea is a traditional crop in heavily flooded areas such as upperSindh and Punjab (Khawaja et al., 1995; Haqqani and Arshad,1996) is of concern. Chaudhuri et al. (1963) reported on the crip-pling effect of grasspea seeds harvested from crops that grew lux-uriantly after floods, in fields covered with thick deposits of silt andsand. The mud from the floods prevented the seeding of other foodcrops, so people adapted by subsisting on grasspea with devastat-ing results.

While the link between excessive consumption of grasspea con-taining diets and neurolathyrism is well documented, the condi-tions for the onset and development of the disease are stillobscure (Spencer, 1995). Buchanan (1904) in his survey of the

0278-6915/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.fct.2010.11.029

Abbreviations: BBB, blood brain barrier; CNS, central nervous system; d.o., dayold; GSH, reduced glutathione; GSSH, oxidised glutathione; HCA, homocysteic acid;i.p., intraperitoneal; NMDA, N-methyl-D-aspartate; ODAP, beta-N-oxalyl-L -alpha,beta-diaminopropionic acid; PPT, protein precipitable tannins.⇑ Address: 4 Mullins Street, Millicent SA 5280, South Australia, Australia. Tel.: +61

8 87332084.E-mail address: [email protected]

Food and Chemical Toxicology 49 (2011) 694–709

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disease in the Central Provinces of India defined the cause of neu-rolathyrism as a function of the quantity and duration of grasspeaconsumption and reported that diets containing >50% grasspeawere dangerous. It appears that a large number of people can usegrasspea without showing any adverse effects. Indeed, Pratap

Rudra et al. (2004) provided convincing evidence that the neuro-toxin beta-N-oxalyl-L -alpha,beta-diaminopropionic acid (ODAP)from the seeds of L. sativus is metabolised in humans and theyadvocate large scale screening of human populations to identifyindividuals who are deficient in this capacity and hence at risk of contracting neurolathyrism.

Dixit et al. (2008) are more cautious about grasspea toxicity andwarn about the extensive adulteration of food in India by admix-ture with grasspea. Cases of lathyrism appeared within 15–20 daysof consuming large quantities of grasspea (Dwivedi and Mishra,1975; cited by Dwivedi, 1989), 25 days (Trabaud et al., 1932) orafter one month (Ganapathy and Dwivedi, 1961; Attal et al.,1978; both cited by Tekle Haimanot, 1996). Consumption of dietsconsisting of 30% grasspea for 3 months or more is generally con-

sidered to lead to the development of neurolathyrism (TekleHaimanot, 2009). One hundred gram grasspea headÀ1 dayÀ1

consumed by children 7, 10 and 14 years old caused lathyrism( Jiménez Díaz et al., 1943). To resolve the question of a safe levelof grasspea consumption and also to unravel the sequelae that leadto the development of neurolathyrism, a reliable bioassay isneeded (Yan et al., 2006; Tshala-Katumbay and Spencer, 2007).This paper explores the nutritional qualities of grasspea and re-lated species, assesses the role of malnutrition as a factor in neurol-athyrism and explores avenues to develop an animal model for theonset of permanent paralysis in neurolathyrism.

2. Famine and malnutrition

Rodríguez-Salinas and Amador, 2008 described the scale of theglobal food deficiency crisis, they cite UN figures showing thatacute and chronic lack of food affects one in five people in develop-ing countries. Protein-energy malnutrition affects 192 million chil-dren while 2000 million people experience micronutrientdeficiencies (iron, zinc, iodine, vitamin A). Vegetarians are at riskof vitamin B12 deficiency and homocystinuria which elevates theirrisk for stroke, dementia and polyneuropathies. Primary effects of undernutrition can lead to secondary effects such as loweredimmunity and malabsorption. Fat soluble vitamins may not get ab-sorbed due to impeded transport across the intestinal epitheliumor intraluminal problems.

Nutritional neuropathies caused by deficiencies of thiamine(B1), Niacin (B3), pyridoxine (B6), cobalamin (B12), zinc, magne-

sium, iodine, copper, folate, vitamins A and E, have been well doc-umented (Spillane and Scott, 1945; Smith, 1946; Walters, 1966;Román, 1994; Sewell and Recht, 2002; Rodríguez-Salinas and Ama-dor, 2008).

Starvation can be seen as occurring in well defined stagesaccording to the changes in metabolism that take place (Scrim-shaw, 1987; Wang et al., 2006; Hoffer, 2006; Blackburn, 2001 ).Phase 1 begins with a cessation of feed intake (fasting). During thisphase the body utilises glucose stored as glycogen in the liver, italso releases some fatty acids into the blood to spare glycogenstores in muscle (Wang et al., 2006). Phase 2 commences oncethe liver has run out of glycogen. Glucose is now made from aminoacids (gluconeogenesis) since the brain requires it for its energyconsuming functions. Initially muscle protein serves as substrate

for gluconeogenesis, however fat reserves are increasingly beingmobilised, thus saving protein. Ketone bodies and glycerol fromfat breakdown are now used as major fuel sources. The body hasadapted to starvation and can continue in this mode until it runs

out of fat. Stage 3 follows and now only protein is left as a fuelto maintain vital body functions. This stage ends with death inthe worst scenario. Endothermic animals such as humans also needenergy to maintain body temperature while ectothermic animalscan last longer with equivalent energy reserves. Body mass is pos-

itively correlated with the time to death (Wang et al., 2006).During starvation there is a slowing down of basic metabolicrate and the digestive system changes in morphology and function,reducing intestinal mass as well as reducing the size of absorptivestructures such as the intestinal villi. Upon refeeding there is a ra-pid restoration of function. Similar changes take place in other gas-trointestinal organs (Wang et al., 2006; Hoffer, 2006). A tendencyto gorge (gluttony) is one of the adaptive behaviours observed dur-ing famines (Prentice, 2005). In a protein malnutrition experimentwith rats, the liver and kidney progressively decreased in weight.After 25 days the weight of kidneys stabilised while the liver con-tinued to decrease in weight (Castro Mendoza et al., 1942), this ispart of an adaptation to starvation when central functions and or-gans such as the brain are spared while peripheral tissues provide

the required proteins (Hoffer, 2006; Wang et al., 2006). The liversof mice fed for three weeks on a protein deficient diet showed a80% lower reduced glutathione (GSH) to oxidised glutathione ratio(GSSG) (Li et al., 2002). GSH deficiency is characteristic of severeedematous protein-energy malnutrition in children (Reid et al.,2000). Nutritional deficiency reduces GSH dependent detoxifica-tion processes in the liver (Godin and Wohaieb, 1988) and thismay be highly relevant to the metabolism of ODAP and hence tothe problem of neurolathyrism.

3. Nutritional status of neurolathyrism victims

Due to poverty, the diet of lathyrism victims lacked foods rich invitamin A such as milk, butter and green vegetables (McCombieYoung, 1927). Jiménez Díaz et al. (1943) reported that out of 549lathyrism victims only two were malnourished and the majorityof patients were considered well fed due to the nutritive valueand high intake of grasspea, particularly by landless labourers.Spencer et al. (1986) reporting on 30 cases of neurolathyrism foundno signs of malnutrition. Likewise, Buchanan (1904) observed pa-tients with the disease who appeared well nourished, noting thatit appears to strike the strongest and most hard working. LópezAydillo and Toledano Jiménez Castellanos (1968) while generallyconfirming the notion that absence of a varied diet is associatedwith neurolathyrism, also cite cases contrary to a deficiencyhypothesis, namely some familial cases in which not all membersof a family on the identical restrictive diets contracted neurolathy-

rism (Miguel and Galiacho, 1942; Romero and Fernández Marcos,1962), People on mixed diets were also affected (ZubizarretaAramburu, 1944; Romero and Fernández Marcos, 1962; TorresCañamares and Vergara Olivas, 1943). Similar observations on bet-ter fed prisoners were made by Kessler (1947) although the major-ity of his patients were clearly subsisting on a highly restrictivegrass pea dominated diet. Rizzotti (1952) reported a case of lathy-rism that occurred despite a diet rich in proteins and vitamins. Incontrast, subsistence on a varied diet containing grasspea is appar-ently harmless, particularly when such a diet includes animalproducts ( Jiménez Díaz et al., 1943; Moya et al., 1967). Based ondetailed dietary composition data from Spanish prison labour itwas estimated that a protein poor diet (2000 kcal dayÀ1) and anaverage 70 g dayÀ1 L. sativus [as 150–300 g dayÀ1 rations] do not

produce lathyrism. Up to 300 g dayÀ

1 of L. sativus can be consumedin the presence of protecting factors derived from better qualityfood (meat, cheese, milk) without provoking lathyrism. A higherdose of L. sativus (up to 1 kg dayÀ1) lead to the development of

D. Enneking/ Food and Chemical Toxicology 49 (2011) 694–709 695




neurolathyrism [1/200] even in the presence of protecting factors[abundant milk] (Ortiz de Landazuri, 1944).

Kessler (1947) estimated that a diet consisting of 50% grasspeaat 400 g dayÀ1 leads to the onset of lathyrism, with undernutrition,hard labour as well as chronic diseases such as tuberculosis and

diabetes affecting the onset and course of the disease. Jahan andAhmad (1993) observed that vitamin C levels in families with neu-rolathyrism were lower (0.430 ± 0.18 mg dlÀ1 serum) than in fam-ilies without the disease (0.647 ± 0.168 mg dlÀ1 serum).

While the above citations are not all that are available on thesubject, it is clear that a balanced diet has benefits but also somedefinite limits with respect to protection against neurolathyrism.Subsistence on grasspea dominant diets keeps humans alive. Theymay even appear well nourished and thus would not be noticed byneed assessments during modern famine relief operations.

4. Nutritional value of grasspea

The nutritional value of grasspea is determined by its content of biologically available nutrients and the effects of its antinutrients.The seeds of L. sativus were found to be deficient in methionine, ly-sine, isoleucine, vitamins C, D, E and B1, lipids, sodium chloride, co-balt, flourine, iodine, phosphorus and sulphur (López Aydillo andToledano Jiménez Castellanos, 1968). More recent chemical analy-ses for L. sativus and L. cicera seed indicate a content of protein,starch, fat, minerals, metabolisable energy and digestibility (ca14 MJ digestible energy (DE) kgÀ1 varying with species) similarto peas (Pisum sativum L.) and faba beans (Vicia faba L.). Methionineand cystine are deficient, while lysine and phytate are high in bothLathyrus species. ODAP levels are lower in L. cicera (mean 0.16%)than in L. sativus mean (0.46%). Tryptophane and homoargininewere not included in the review (Hanbury et al., 2000; Mullanet al., 2009). Tryptophane and sulphur amino acid levels are lowin the seeds of L. clymenum (Pastor-Cavada et al., 2010) andL. sativus (Smulikowska et al., 2008). Eichinger et al. (2000) confirmthat seed ODAP levels are lowest in L. cicera, followed by L. sativus,L. ochrus and maximum in L. clymenum, while L. cicera stands outwith high mean levels of homoarginine. Lectins (proteins that bindspecific sugars and sugar residues on glycoproteins) and proteina-ceous inhibitors of starch digestion (amylase) and high levels of protease inhibitors (including trypsin and chymotrypsin inhibi-tors) are present in the seeds of L. sativus (Ayyagari et al., 1989;Deshpande and Campbell, 1992; Aletor et al., 1994; Wang et al.,1998a). Lectins have also been isolated from L. cicera (Cavada,1987). Lectins interfere with nutrient absorption by binding toendothelial glycoproteins in the small intestine (Lajolo and Genov-ese, 2002). In addition, condensed polyphenols are present in

most seed samples tested which correlate with seed coat colour(Deshpande and Campbell, 1992). Aletor et al. (1994) detectedprotein precipitable tannins (PPT) in only half of the L. sativus

accessions screened, while for L. ochrus there was only one acces-sion free of PPT. Unfortunately, L. clymenum was not included intheir study. Saponins are present in the seeds of L. sativus (Sharma,1987) while little attention has been given to their presence in theseeds of the Lathyrus species discussed here.

Phytate in legumes reduces the bioavailability of otherwisequite high contents of minerals, particularly the absorption of Feand Zn from legume diets is low, while vitamin C improves Fe up-take in the presence of phytate (Sandberg, 2002).

The lipid content of Lathyrus seed is low (<2%), already noted byBuchanan (1904) but the profile of constituent fatty acids is nutri-

tionally valuable with major proportions of palmitic and linoleicacids and smaller quantities of oleic, linolenic and arachidonic acids(Hanbury et al., 2000; Chinnasamy et al., 2005; Pastor-Cavada et al.,2009; Grela et al., 2010). Pastor-Cavada et al. (2009) found L. sativus

to stand out with a high (13.8) x6/x3 ratio, although this ratio canvarywith different genotypes (Swarup and Lal, 2000).The ratio mayaffect the vascular system since x3 fatty acids have an importantrole in endothelial function and influence blood flow to the centralnervous system (Yehuda et al., 2005; Sinn and Howe, 2008).

Malnourished humans may not be able to absorb all the lipids froma grasspea diet since lipid digestion and uptake can be impaired. Anessential fatty acid deficiency in turn has an influence on protein –energy metabolism through impaired nutrient uptake and utilisa-tion (Smit et al., 2004). Yehuda et al. (2005) citing Yehuda et al.(1998) draws attention to a link between x3 fatty acid deficiencyand dopamine vesicle density in the cortex associated with mal-function of the dopaminergic mesocorticolimbic pathway.

Grela and Günter (1995) reported for L. sativus seed a Vitamin Econtent of 40 IU kgÀ1.

To supplement the available data on chemical composition of Lathyrus species, a useful review of minor constituents of food le-gumes is provided by Campos-Vega et al. (2010) which shows thatseeds of related species such as lentils (Lens culinaris) and faba

beans (Vicia faba) are well endowed with thiamine, riboflavin, nia-cin, pyridoxamine, pyridoxal and pyridoxine vitamins.Generally, there are no overt symptoms of the classic vitamin

deficiencies associated with neurolathyrism, it is not a vitamin Adeficiency and there are clear differences to B complex deficiencies,for example an absence of cardiac symptoms and oedema as seenin beri beri, nor are there skin lesions as in pellagra ( Jiménez Díaz,1941; del Cura and Huertas, 2009). In a detailed analysis, deficien-cies of vitamin A, B1, B2, B3, B6, E, were excluded as factors in neu-rolathyrism ( Jiménez Díaz et al., 1943).

Rudra and Bhattacharya (1946) surveyed lathyrism patients forVitamin B1 (thiamine) deficiency and found that the diets of somepatients were balanced for this nutrient. Blood and urine levelswere found to be within normal limits. To assess physiological thi-amine activity they measured serum alkaline phosphatase andfound that it was elevated (>200%) in lathyrism patients. In factit correlated with the severity of symptoms, while serum phos-phate levels in these patients were also high.

Overt vitamin deficiency symptoms were not observed exceptfor 14% of lathyrism patients with B complex deficiency. Treatmentof patients with vitamins gave no response. A latent vitamin defi-ciency favouring toxicity was not ruled out ( Jacoby, 1947).

The B vitamins are important in the regulation of mitochondrialenzymes and mitochondrial integrity and are hence closely linkedto energy metabolism (Depeint et al., 2006a) and sulphur aminoacid metabolism (Depeint et al., 2006b). Deficiencies of Riboflavinand B6 are associated with collagen disorders (Merrill andHenderson, 1987 and references therein). The digestion of folate,cobalamins and riboflavin depends on the activity of stomach acids

and proteases since they are bound to proteins in food. Vitamin B6is an important co-factor in amino acid metabolism. Its require-ments increase with higher protein intake. B6 deficiency can leadto increased excretion of oxalate and accumulation of calcium oxa-late in kidneys contributing to their failure (Depeint et al., 2006b).A marginal thiamine deficiency combined with oxidative stressand high postprandial glucose levels can lead to neurodegenera-tion (Zimitat and Nixon, 1999; cited by Depeint et al., 2006a).Chronic liver failure leads to thiamine deficiency and neuraldamage (Butterworth, 2009).

Several studies have shown that a depletion of vitamin C in gui-nea pigs and primates makes them susceptible to grasspea toxicity.The guinea pig, like all primates, depends on external sources of vitamin C which makes it a suitable model for neurolathyrism

and this also explains why earlier studies obtained mixed resultswith vitamin C ( Jahan and Ahmad, 1993; Dunham et al., 1995).Ascorbate depleted guinea pigs exhibited early signs of scurvy suchas punctate to massive leakage of lymph into cell tissues. A vitamin

696 D. Enneking / Food and Chemical Toxicology 49 (2011) 694–709




C fortified diet protected the animals from the toxic effects of anintraperitoneal (i.p.) injection of L. sativus extract, while some of the ascorbate depleted animals treated similarly showed symp-toms of spastic paralysis. Vitamin C may play an important rolein maintaining the integrity of the blood brain barrier. The study

also highlighted the need for increased vitamin C consumptionfor people subsisting on grasspea diets (Dunham et al., 1995).Interestingly, Vitamin C is also needed for collagen synthesis andfor norepinephrine conversion from dopamine (Li and Schellhorn,2007). One simple method to provide vitamin C is to sprout legumeseeds as advocated by the international red cross during foodemergencies (Mourey, 2008). Since germination of ODAP synthe-sizing Lathyrus species increases their seedling concentration of ODAP and the osteolathyrogen beta-isoxazolin-5-one-propionitrile(Lambein et al., 1993; Addis and Narayan, 1994; Bell, 2003;Chowdhury et al., 2001a), a simple method to extract vitamin Cfrom Lathyrus sprouts to avoid undesirable and additional toxicitywould be useful.

Considerable losses of vitamins and minerals occur during food

processing (Schroeder, 1971). Foods heated for a long time or athigh temperature are low in thiamin and deficient diets can be pre-pared by autoclaving (Depeint et al., 2006a). Furthermore, vegetar-ian diets provide a whole range of heat stable thiamine antagonistssuch as polyphenols and flavonoids (Herrmann and Geisel, 2002).Thiamine deficiency has recently been implicated as a causal factorin Konzo, a spastic paraparesis very similar to neurolathyrismcaused by excessive consumption of incompletely processed cas-sava (Adamolekun, 2010). While Lathyrus seeds can be expectedto provide thiamine the actual levels absorbed during digestionare not known. Erythrocyte transketolase activity is a reliable mea-sure of plasma thiamine status (Depeint et al., 2006a).

Vitamin B12 cannot be provided by plant foods (Herbert, 1988)and hence is deficient in vegetarians (Herrmann and Geisel, 2002;Yajnik et al., 2006). Its deficiency affects glial cells, myelin andinterstitial tissue and therefore it may be important for the integ-rity of the blood brain barrier (Scalabrino, 2009). Elevated plasmahomocysteine is an indicator of either folate or B12 deficiency(Stipanuk, 2004). Microorganisms are a source of Vitamin B12but it does not get absorbed from the human hindgut, however alack of hygiene can contribute to adequate dietary intake, whilefermented soy products do not necessarily provide adequate levels(Herbert, 1988). Coprophagy by animals such as mice, rats and pigscould therefore provide a source of vitamin B12.

Contrary to this idea, Depeint et al. (Depeint et al., 2006b) whilenoting that deficiencies are difficult to induce in animals, cited astudy by Ebara et al. (2003) where vitamin B12 deficient rats devel-oped methylmalonic aciduria and neuropathy, though they did notdevelop a megaloblastic anemia which is otherwise characteristic

for this deficiency. Perhaps their study conditions were exception-ally hygienic?

Together the findings from these reports suggest that an in-creased dietary reliance on either L. sativus, L. cicera or L. clymenum

for food provides energy, protein, minerals, lipids and vitamins forsurvival and maintenance but over time this would lead to severalnutrient deficiencies, particularly lipids, sulphur amino acids, vit. C,B12 and, depending on the methods used for food preparation, alsominerals and water soluble vitamins.

5. Animal feeding trials

The growth and reproductive performance of animals feeding

on diets containing grasspea and similar species is a useful indica-tion of their nutritional qualities.

Canadian work with poultry and pigs highlighted the significantantinutritional effects of protease inhibitors as a major impedi-

ment to utilisation of grasspea for monogastric animal production.L. sativus was evaluated as pig feed at up to 40% of diets with highand low ODAP genotypes. Methionine was evaluated as a supple-ment and found to contribute little to alleviating the observed anti-nutritional effects at dietary inclusion of L. sativus above 10%. It

was concluded that it was not ODAP but protease inhibitors thatreduced the nutritional quality (Castell et al., 1994). A pig produc-tion trial with extruded or raw grasspea as the main source of pro-tein found no adverse effects on fatty acid composition of adductorand longissimus dorsi muscles or meat sensory quality, concludingthat grasspea is suitable as a economic substitute for soybean orrapeseed meal (Winiarska-Mieczan, 2010). Pig diets containing10% or 15% raw grasspea with 0.01% or 0.02% ODAP, respectively,were found suitable for meat production (Winiarska-Mieczan andKwiecien, 2010).

Rotter et al. (1991) fed experimental diets containing L. sativus

to chicks and found that seeds containing low (0.13%) to mediumlevels (0.33%) of ODAP made no difference to growth performance.They fed grasspea up to 80% of the diet and besides reduced growth

performance at such high levels observed none of the typicalsymptoms of neurolathyrism. Rotter et al. (1990) demonstratedthe benefit of heat treatments to improve the nutritional qualityof L. sativus seed for chicks. Low et al. (1990) observed that supple-mentation of L. sativus containing diets with methionine andtryptophane improved chick growth performance, however,methionine additions alone do not necessarily improve chickenlaying performance (Chowdhury et al., 2005). Interestingly, theseauthors chose grasspea with acceptable flavour and colour (0.42%ODAP) for their feeding studies and their birds showed highest gainon a 20% grasspea diet, while at 15% no deleterious effect on eggproduction was noticeable. Smulikowska et al. (2008) noted symp-toms of osteolathyrism (bone and joint deformations) in broilerchicken fed with 10% diet of L. sativus cv. Krab. They determinedthe metabolisable energy for several grasspea genotypes to rangefrom 7.2–9.8 MJ kgÀ1 DM, and considered the estimates of Hanbury et al. (2000) too high. The very high trypsin inhibitorlevels measured in the grasspea seeds 58–72 mg gÀ1 crude protein,comparable to raw soybeans, correlated with enlarged pancreasesin all birds fed with 10% grasspea diets (0.1–0.15% ODAP) while areduction of liver size was noted for several varieties.

The late Chowdhury et al. (2001b) published the results of aninteresting poultry feeding experiment with combinations of Vicia

sativa and L. cicera seeds. L. cicera is very low in ODAP (max in thespecies 0.2%). ‘‘Feeding a high quantity of L. cicera did not affectgrowth, unless Lathyrus was combined with V. sativa. This impliesa negative synergism between the antinutritional factors inL. cicera and V. sativa.’’

IfODAPisverylow,isthereanothertoxicfactorin L. cicera,ordoes

the sulphur amino acid depletingeffect of Vicia sativa (Lambein et al.2009) potentiate the activity of the low levels of ODAP?

Female pigs (16 kg) fed diets containing up to 30% L. cicera seedmeal showed normal weight gains and no adverse effects on liveror kidney mass (Mullan et al., 1999). A feeding trial with male wea-ner piglets found that 15% is the upper inclusion level for L. cicera

(0.09% ODAP) for such young animals (Trezona et al., 2000; Mullanet al., 2009).

Fingerlings of the Rohu fish (Labeo rohita) grew well on a dietcontaining 40% fermented L. sativus, despite ODAP levels remaininghigh (0.97%) after processing with an amylolytic, cellulolytic, lipo-lytic and proteolytic Bacillus strain (Ramachandran et al., 2005).

Agricultural feed evaluation studies are designed to optimiseanimal production through the design of well balanced diets by

additions of minerals, vitamins and amino acids to avoid detrimen-tal effects of nutrient deficiencies and antinutritional factors. Sim-ilar feeding studies using high ODAP feeds such as L. ochrus orL. clymenum seed meal in unsupplemented diets are likely to lead





to less desirable results but may help in the development of an ani-mal model for neurolathyrism.

6. Toxicological feeding experiments

Extended feeding experiments with rats, rabbits, dogs and amonkey did not produce lathyrism symptoms but led to the obser-vation that the growth of rats is retarded when fed for 10 monthson exclusive grasspea diets ( Jiménez Díaz and Vivanco, 1942a).This growth could be restored with addition of animal protein ora heat labile factor from liver extract that was not one of theknown vitamins. Cysteine supplementation reduced alopecia inthree of four cases ( Jiménez Díaz and Vivanco, 1942b).

Spencer et al. (1986) have demonstrated that ODAP adminis-tered orally in high doses to well nourished macacque monkeyscan elicit typical neurological symptoms involving the pyramidalcorticospinal tracts.

López Aydillo and Toledano Jiménez Castellanos (1968) tested

the hypothesis that nutritional deficits caused neurolathyrism bytesting grasspea diets in combination with supplements. They re-ported that even their most balanced grasspea containing diet pro-duced neuropathological symptoms in white mice. Survival rates(%) (male/female, n = 15) for grasspea diets total adjusted (40/80)or deficient in: olive oil (0/0), salts (20/0), vitamins (40/00), casein(0/40), amino acids (40/80). Histochemical analysis of mousebrains revealed extensive and steady subarachnoid, pial and sub-pial hemorrhages. These are structures associated with the bloodbrain barrier. They also found demyelination at the corpus callosum

and the white matter of the small cerebellar lobes, amoeboid typesof gliosis, changes in the Ammon’s horn area (Fascia dentata) andthe pyramidal stratum. They considered the observed hemorrhagesimilar to human internal hemorrhagic pachymeningitis. The mag-nitude and extent of histopathological symptoms increased byomission of either of the following: mineral salts (no effect), vita-mins (least), amino acids, fats (olive oil) and casein (most), thushighlighting some essential neuroprotective nutrient requirementsin the presence of grasspea. They found no symptoms related tonutritional neuropathies thus supporting a toxic etiology for neu-rolathyrism. Curiously this study is not cited in the literature anddespite its promising approach has not yet been repeated.

Rats 40–45 d.o. fed on grasspea (0.1–0.2% ODAP) seeds for8 months were found to show transient changes in behaviour (in-creased locomotion and defecation) but developed no neurologicallesions (La Bella et al., 2007).

Guinea pigs and rats were fed for 3 months with vitamin supple-mented diets containing 50% of either low (0. 09% ODAP) or high(0.6% ODAP) toxin grasspea seed meal (Amba et al., 2002). While

the rats remained normal, the locomotor activity of the guinea pigschanged. An inclined plane test proved useful to quantitate thisbehaviour. Guinea pigs were also fed for 3 months on cooked andvitamin supplementeddietscontaining10%, 50%and 80%of thehightoxin variety. These levels were chosen to represent common expo-sures to grasspea encountered in India i.e. 10%casual contaminationof Bengal gram (Cicer arietinum), 50% intentional adulteration and80% to model famine conditions! Biochemical examination of braintissue revealed an increase of intracellular calcium and fluidity of membranes in both animal species. Binding studies providedevidence for the neurotoxic involvement of NMDA, Non-NMDAand cholinergic receptors in both species on grasspea diets, whilecerebellar benzodiazepine receptors were only inhibited in guineapigs. This study showed the utility of the guinea pig as an animal

model to study grasspea toxicity.This suggestion was followed up quickly by a study on the inter-

action of grasspea with manganese (Kumar et al., 2003). Guineapigs were fed with an 80% grasspea (0.6% ODAP) diet ±4 mg kgÀ1

Mn for 3 months. Mn alone had a pronounced inhibitory effecton gamma-glutamyl transferase from intestinal brush bordermembranes while grasspea alone decreased the activities of intes-tinal glutathione-S-transferase by 22% and alkaline phosphatase by28%, Additionally, the combined effects of grasspea and Mn de-

pressed sucrase and Ca2+

Mg2+

ATPase. Mn clearly potentiates theintestinal toxicity of grasspea diets.Male mice fed for 4 or 12 weeks on diets containing either 30%

grasspea (1.05% ODAP) or grasspea detoxified by leaching (0.15%ODAP) providing ODAP at an estimated daily dose of 525 mg kgÀ1

and 75 mg kgÀ1, respectively (Shinomol and Muralidhara, 2007).Brain tissues (cortex and cerebellum) were analysed for markersof oxidative stress. While cholinergic function was altered at bothtoxin concentrations, enhanced signs of oxidative stress werefound in brains of animals feeding on the higher dose, including in-creased lipid oxidation, reactive oxygen species, protein oxidation,changes in activities of antioxidant enzymes and anticholinester-ase activity. Marked increases of malondialdehyde levels were no-ticed in the cerebellum after 12 weeks on the high dose while GSH

depletion was more pronounced in the cortex. This study providedin vivo evidence for the occurrence of oxidative stress followingconsumption of diets containing high levels of grasspea kgÀ1 liveweight, with the lower inclusion level approximately equating toa human grasspea intake of 400 g dayÀ1 (Kessler, 1947) or 84 mgODAP kgÀ1 live weight.

7. Antinutritional factors act in concert to decrease sulphur

amino acid availability

Aletor et al. (1994), echoing Liener (1962) pointed out that thecombined effect of proteinaceous and polyphenolic enzyme inhib-itors contribute to the loss of sulphur amino acids through the for-mation of enzyme-inhibitor complexes that are lost through thefaeces and thus add to an already sulphur amino acid deficientnutritional situation. Bowman-Birk type protease inhibitors arepresent in L. sativus seed (Campbell, 1997). They have a molecularmass of 8–10 kDa and seven disulphide bridges (14 cysteines). Theproteases which they interact with are also stabilised by disulphidebridges for optimal function in an extracellular environment. Tryp-sin inhibitors in lima and navy beans make up 2.5% of the total pro-tein, however, they contain 32–40% of the total seed cystine (Lajoloand Genovese, 2002). Increased biosynthesis of proteases by thepancreas leads to pancreatic hypertrophy. This results in a deple-tion of sulphur amino acids and other amino acids (Liener, 1983),so a significant portion of sulphur amino acids provided by a grass-pea diet are not digested while their endogenous depletion is en-hanced. Since the trypsin inhibitor activity of grasspea seed is

high [vide supra] and a 200 g of raw legume seed can inhibit aday’s worth of human protease production (Lajolo and Genovese,2002), the impact on amino acid and vitamin absorption could alsobe significant.

Patients eating L. sativus had a lower urinary excretion of methi-onine (84 ± 47 mg dayÀ1) than those who had stopped eating it.Once patients were feeding on other pulses instead methionineexcretion rose immediately (379 ± 106 mg dayÀ1) and normal con-trols excreted 447 ± 120 mg dayÀ1 (Rudra and Chowdhury, 1952),however, these values exceed currently accepted values. Renalreabsorption of sulphur amino acids is very high (P94%), so thatvery little methionine is excreted (3.3–6.1 mg dayÀ1) (Stipanuk,2004).

ODAP also depletes reduced thiols through oxidative stress

causing mitochondrial dysfunction in the motor cortex and lumbarspinal cord of mice (Ravindranath, 2002) and thereby interruptsenergy supplies. In addition it inhibits tyrosine amino transferasewhich leads to an increase in L -3,4-dihydroxyphenylalanine





(L -DOPA) (Vardhan et al., 1997). Regulation of L -DOPA and its met-abolic products is by O-methylation which requires S-adenosylme-thionine thus drawing on methionine (Axelrod and Lerner, 1963),or through an oxidative pathway involving sulphotransferase andGSH (Smythies and Galzigna, 1998). Raised levels of tyrosine in

rat brains deplete reduced thiols and can lead to lipid and proteinoxidation (Sgaravatti et al., 2009). Diwakar and Ravindranath(2007) found that ODAP inhibits cystathionine-c-lyase. Diwakaret al. (2007) reported that glutaredoxin plays a prominent role inthiol homeostasis and that ovariectomised female rats lost theirprotection against the toxic effects of ODAP, since estrogen upreg-ulates the expression of glutaredoxin in the central nervoussystem.

ODAP accumulates intracellularly in neuronal cells via the sys-tem xÀc glutamate/cysteine transporter (Warren et al. 2004). In thepresence of cysteine its uptake is inhibited and apoptotic cell deathin a ventral spinal cord cell line is prevented. Theoretically, evenvery small doses of ODAP may accumulate over time ( La Bellaet al. 1996). Curiously, ODAP as well as homocysteic acid (HCA)

sensitize CA1 pyramidal neurons in hippocampal slices to cystinetoxicity which is related to the affinity of these substances for sys-tem xÀc . ODAP or homocysteic acid accumulate in glial cells. Cystinetriggers their release leading to activation of non-NMDA receptorsfor ODAP or NMDA receptors for HCA (Chase et al., 2007), so suffi-cient cysteine in the extracellular fluid may be required to preventuptake of ODAP or HCA through system xÀc . The expression of thisglutamate/cysteine antiporter in neurons, astrocytes and fibro-blasts increases during development and reaches a maximum withage, suggesting that it has a key role in the balance of oxidativestress during adulthood (La Bella et al. 2007).

8. A lack of reduced thiols predisposes to lathyrism

The above leads to the hypothesis that a lack of reduced thiolspredisposes to lathyrism. This is caused through a low intake of sulphur amino acids, depletion by antinutrients, interference withcystine transport, increased metabolic demand through oxidativestress and the excretion of sulphated detoxification products. Lam-bein et al. (2009) developed this idea, based on epidemiologicaland biochemical studies, as a theme for legume defence in general.Supplementation with additional sources of sulphur amino acids,or thiol antioxidants such as alpha-lipoic acid or N-acetyl-cysteine,could act as antidotes and enhance the nutritive value of otherwiseunwholesome diets. The hypothesis that a deficiency of methio-nine is involved in neurolathyrism (Rudra and Kant, 1950) was al-ready tested more than 50 years ago when lathyrism patients weretreated with methionine and two out five showed improvements

(Rudra et al., 1952), unfortunately, the role of sulphur amino acidsin the prevention of neurolathyrism was not investigated. Fikreet al. (2010) have just demonstrated the validity of this conceptby showing that supplementation of grasspea containing dietswith methionine reduces their toxicity, particularly to youngchicks.

From the available nutritional information it is clear that grass-pea can provide energy and a fair portion of essential nutrients butit clearly has a fine tuned capacity to induce sulphur amino aciddeficiencies.

9. Sulphur amino acid metabolism

The liver is the major source of extracellular GSH (Godin and

Wohaieb, 1988). It is an important organ for the regulation, storageand metabolism of sulphur amino acids. Conversion of cysteineto taurine and sulphate is irreversible and thus depletes thethiol sulphur amino acid pool. There is also a role for H 2S in

neuromodulation. Little is known about cysteine metabolism inthe kidney which contains high concentrations of the compoundand has a high GSH turnover. Betaine and choline may serve asmethylatingagentsin methionine or folatedeficientdiets (Stipanuk,2004). Dietarysulphate canhave a sulphur amino acid sparing effect

(Nimni et al., 2007).Rats deprived of food for 48 h maintained GSH levels in thebrain while liver stores reduced by 30%. Older rats had 50% lowerlevels in the cerebral cortex, while liver taurine levels were lowerin younger animals (Benuck et al., 1995). Prenatal protein malnu-trition leads to reduced brain GSH content but this recovers rapidlydespite continued protein deficiency (Feoli et al., 2006). Mild pro-tein deficiency for 6 weeks did not affect brain GSH levels. L -2-oxothiazolidone-4-carboxylate restored liver GSH levels withoutincreasing concentrations in the brain above normal levels (Zhanget al., 2002). Supplementing diets of protein-malnourished micewith cysteine precursors restored GSH in liver, lung, heart andspleen, but not in the colon. Brain levels of GSH and GSSG werenot affected by the precursors (Li et al., 2002). For a review on

GSH in the brain based on cell culture studies see Dringen(2000). Neurons and glial cells co-operate in the metabolism of taurine, a cell osmolite and volume regulator, GSH, a major antiox-idant and S-adenosylmethionine, the major methyl group donor(Banerjee et al., 2008). Poultry studies have shown that supple-mental cysteine can be used to minimise Cu toxicity, however itcan also increase the toxicity of As by reducing pentavalent As tothe 100 times more toxic trivalent form (Baker, 2009 and refer-ences therein), so caution is needed for using cysteine supplemen-tation in areas where As in drinking water drawn from deep wellsis a serious problem, for example Bangladesh and West Bengal,India, (Harvey et al., 2005; Das et al., 2009).

Longer lived animals such as the horse and cow have a lowerheart muscle methionine content (Pamplona and Barja, 2006), sug-gesting that reserves of sulphur amino acids required to counteroxidative stress during exercise (Rankin et al., 2006) may not beas abundant as in mice or rats, however cysteine was not mea-sured. The tight regulation of brain sulphur amino acid metabolismeven during nutritional stress at the expense of other tissues in thebody appears to help prevent the negative effects of Lathyrus tox-icity. To provoke the development of neurolathyrism in an animalmodel it may be necessary to interfere with it. Secondly, the regen-eration of GSH and replenishment of brain cysteine levels may notkeep pace with demand during periods of multiple oxidative stress.

10. Energy requirements and oxidative stress

Episodes of cold, hard work and other stressors are frequently

reported as triggers for the onset of neurolathyrism (Spencer,1995). Cahill (1976) provides a simple calculation of energyrequirements drawing on a store of ca 420–630 MJ available from12 kg of adipose tissue. 6.2–7.5 MJ dayÀ1 are required by a normaladult for basic metabolism. Cold episodes double this requirementwhile hard work can increase the demand to 21–25 MJ dayÀ1.

While 300–600 g grasspea dayÀ1 can provide the energy for ba-sal metabolism, 1.5–1.8 kg would be needed for hard work (basedon a generous 14 MJ digestible energy (DE) kgÀ1). ODAP disturbsmitochondrial function (Sriram et al., 1998; Ravindranath, 2002)and thereby interferes with energy metabolism. It also reducesthe in vitro activity of high affinity transporters for aspartate andglutamate in synaptic regions from rat cerebral cortex and spinalcord. Depolarisation of membranes and increased membrane per-

meability caused by excitotoxins such as ODAP can be expectedto lead to a high energy demand to restore ionic balance in neu-rons, a failure resulting in cell breakdown (Ross et al. 1985). There-fore, people subsisting on grasspea diets, who are meeting





increased energy demands through higher food intake also in-crease the ingested dose of its toxins while exacerbating nutri-tional imbalances.

There are many sources of additional oxidative stress that maybe important in individual circumstances (Lees, 1993; Migliore and

Coppede, 2009; Franco et al. 2009). Even the blood glucose load fol-lowing a meal is a stressor (O’Keefe et al. 2008), however there isalso a plethora of counteracting nutrients (Blaylock, 1998; Fanget al. 2002).

A high physiological demand for energy and a concurrentdestruction of the capacity to provide it, is clearly a deleteriouscombination and may be exploited for the development of an ani-mal model of neurolathyrism.

11. The role of hormones in neurolathyrism

One striking feature of neurolathyrism epidemics is the high ra-tio of males to females 8:1–10:1 affected. Only prepubertal girlsand amenorrheagic women are affected (Dwivedi, 1989). Lower ra-

tios 2.6:1 (Tekle Haimanot et al., 1993) and 4.8:1 are reported fromEthiopia (Getahun and Tekle Haimanot, 1998) which appears toindicate a higher grasspea intake and more extreme nutritionalstress. In Punjab Shah (Shah, 1939) observed a ratio of 1.5:1 andattributed the cause to Vicia sativa.

Male Swiss albino mice were susceptible to ODAP at 10 mg kgÀ1

while the females were resistant. Ovariectomy led to decreasedGSH and the activities of glutaredoxin and complex I in mitochon-dria from the lumbar spinal cord of mice injected with 10 mg kgÀ1

ODAP. Using antisense nucleotides glutaredoxin activity in thelumbosacral cord was regulated down by 28% and made femalemice susceptible to ODAP toxicity. This study shows the impor-tance of glutaredoxin in maintaining mitochondrial function inthe presence of neurotoxins and provides evidence for a neuropro-

tective effect of estrogen in neurolathyrism (Diwakar et al., 2007).Estradiol influences the phenylalanine/tyrosine ratio in liver

and urine but not in the kidneys of rats suggesting that there isendocrine control (Presch et al., 1997). It has been suggested thatthe constant stimulation of the mitochondrial respiratory chainfunctions by estradiol and estrogen receptors contributes to aninhibition of programmed cell death (apoptosis) which can leadto the development of carcinogenesis (Chen et al., 2009a) butmay have a beneficial effect for grasspea consumers. Estrogens alsoinfluence energy metabolism (glycolysis, mitochondrial biogenesis,fatty acid beta-oxidation) with dominant effects in the liver (Chenet al., 2009b). Legumes are known to produce isoflavones withestrogenic activity (Campos-Vega et al., 2010). It should be infor-mative to assess their levels and genetic variation in the seeds of

Lathyrus species with a view towards utilising their protective ef-fects, while genotypes with low levels may be useful for an animalmodel of neurolathyrism.

12. Neurolathyrism in animals

Reports on accidental poisonings of animals by Lathyrus speciesare numerous (Table 1) and appear to be associated with recentintroductions of these crop into new areas where farmers werenot entirely familiar with their potential toxicity (Chevallier,1841). It is not always clear which species caused an intoxication.The french name Jarosse refers to different species in different re-gions (L. cicera, L. sativus, V. ervilia and V. articulata Hornem.), whilesome authors confuse chickling vetch (L. cicera) with chickpea

(Cicer arietinum) (Hamelin, 1882; Cornevin 1893).The harmful effect of Lathyrus species is due to their almost

exclusive and in all cases prolonged use as a feed (Cornevin,1893). In France L. cicera was more frequently implicated and

considered more toxic than L. sativus (Hamelin, 1882; Cornevin,1893). The toxicity of L. cicera is discussed in detail by Cornevin(1893) who positively identifies this species by its red flower col-our. In Spain and Italy it was used as food and feed while in Franceit was exclusively cultivated for animals, except for some localities

in the South. In its vegetative stage and until flowering it is notconsidered dangerous. Given to sheep and cattle as a green fodderthe animals are keen to eat it. From seed formation onwards it isdangerous. The process of toxin formation seems to parallel theformation of its grain, so it is important for farmers to cut the plantbefore it bears seed. From this moment on the seed, either entire oras flour is the most toxic part, but stems, leaves and pods withoutseeds are also harmful to health. Desiccation does not influence itstoxicity. Toxicity is leached with water. Cooking and baking doesnot destroy it. Fed in flour form toxic symptoms appear more rap-idly. Apparently, the blood of animals fed L. cicera coagulates morerapidly (pousse au sang) but other legumes can also cause this ef-fect. High doses cause toxicity so rapidly that lesions do notdevelop.

Lathyrism in the horse has received much attention by veteri-narians due to the importance of this species for military and civil-ian transport up until the mid 20th century. No symptoms are seenwhile the animals are resting. During walking a weakness and clearstiffness of the hindquarter is noticeable. After a short trot or gal-lop, wheezing or heavy breathing commences. This is due to aparalysis of the larynx. Hind leg paralysis can also develop. Animalsat rest may appear normal, exercise provokes the onset of roaringand animals may fall during work. Death occurs due to asphyxia-tion (Delafond, 1833; Fröhner, 1910; Fumarola and Zanelli(1914); Maleval, 1927; Jiménez Díaz et al., 1943).

Autopsy showed atrophy of the recurrent laryngeal nerve andanterior horn cells and pyramidal sclerosis in the upper part of the spinal cord, resembling amyotrophic lateral sclerosis (Barronrelated by Althaus, 1885). In addition there is thrombosis of thesmall arteries and thickening of capillary walls in the grey matter(Leather and sons, 1885; McCall, 1890; both cited by Allbutt,1897; see also Stockman, 1917; Bruyn and Poser, 2003). Maleval(1926) found no neurological lesions. Curiously, mules, the infertilehybrids between horse and donkey are more susceptible thaneither species to feeding on a mixture containing 2.6 kg L. sativus

and 1 kg Vicia ervilia Willd. for 97 days, with symptoms appearingweeks to months after cessation of feeding on the toxic mixture.Cessation of feeding may even help to trigger the onset (Ortiz deLandazuri and Galdo Seco, 1949). Maleval (1926) reports that race,sex or age had no influence on the appearance of the disease butthe morbidity of mules was higher (29%) compared to 10% inhorses, however, in general a much greater proportion of animalsis resistant than susceptible. Garcia Izcaria (1927) remarks that

cases of horses requiring treatment by tracheotomy were less fre-quent in Spain than in England. The few cases that required thistreatment were descendent from British breeds. He also notes thathorses cannot breathe through their throat and rely on air passagethrough their nostrils.

Horses fed for 10 days on an exclusive diet of L. cicera developedlathyrism symptoms. 1–2 L of grain together with unlimited oats,hay and straw led to symptoms after 3 months (Cornevin, 1893).

Two to three months on an exclusive diet of L. sativus leads tothe development of lathyrism in horses and numerous cases wereobserved in Spain ( Jiménez Díaz et al., 1943).

Horses (n = 2) feeding on L. sativus forage lost condition aftertwo weeks, followed by diarrhoea, dirty brown conjunctiva a weeklater and in the fourth one horse developed progressive paralysis.

Post Mortem: Abrasions on all prominent parts of the carcass; in-tense general icterus; hyperaemia of the lungs; subepicardialhaemorrhages; pigmentation and degenerative changes in theliver; blood not coagulated and tarry in consistence; gastrophilus





Table 1

Neurolathyrism in animals.

Animal species Lathyrus species Clinical symptoms Time Reference

Dogs L. sativus Pronounced unfocussed pathological alterations of the gray matter inthe spinal cord

Spirtoff (1903) cited byFiliminoff (1926)

Horse n = 1 230 kg L. sativus flour ca2.3 kg d-1 Increased pulse frequency after 14 days. After 30 days increasedirritability, hindlegs stiff and muscles twitching (croupe, shoulder).Hindquarter showed a low grade dorsal weakness. Tail trembling andmoving incessantly. Swaying in the lower back followed a few days later.No roaring. Recovery after removing Lathyrus from the diet

2 months Agonigi (1900) cited byFröhner (1910)

Horses n = 45 L. cicera 1.5–2 kg dÀ1 29 fell ill, neurolathyrism and dyspnoea. Nine die. First symptoms at75 days, last cases 84 days after cessation of diet.

103 days Verrier (1868) cited bySchuchardt (1887)

Horses L. cicera seed 1-2 L dÀ1 Neurolathyrism and dyspnoea 3 months Cornevin (1893)Horses L. sativus Neurolathyrism and dyspnoea Leather and sons (1885)Horses L. sativus Neurolathyrism and dyspnoea McCall (1890)Horses Lathyrus sp. 4 kg dÀ1 Neurolathyrism and dyspnoea, 70% morbidity 3 months Lenglen (1860) cited by

Maleval (1926)Horses Lathyrus sp. In 1894, 769 horses were affected by lathyrism, most of 407 recovered

from roaring after six monthsLavalard, cited by Maleval(1926) [nodetails]

Horses L. sativus exclusivediet

Lathyrism in horses and numerous cases were observed in Spain 2–3 months

Jiménez Díaz et al. (1943)

Horses n = 2 L. cicera straw + seed

8 kg dÀ13 developed dyspnoea 2 months Delafond (1833)

Horses n = 2 L. sativus forage One animal: progressive paralysis and death, the other normal 4–5 weeks Steyn (1933)Horses, donkeys L. sativus, split seeds Neurotoxic symptoms 1–3 years Tekle Haimanot et al. (1997)Mules L. sativus 2.6 kg + 1 kg

Vicia ervilia Willd. dÀ1More susceptible than horse or donkey. Symptoms appeared weeks tomonths after cessation of feeding on the toxic mixture. Cessation of feeding may even help to trigger the onset

97 days Ortiz de Landazuri andGaldo Seco (1949)

Pigs Lathyrus sp. forage Paraplegia of hind legs Ferraresi; cited bySchuchardt (1887)

Pigs Lathyrus sp.forage Death Zurcher; cited bySchuchardt (1887)

Bonnet + Rhesusmonkeys Macaca

radiata, M. rhesus

L. sativus Cooked 100–200 g dÀ1

Weight loss, paresis of motor nerves, respiratory failure; in someanimals muscle wasting leading to death by respiratory paralysis. Pareticsymptoms more pronounced 2 h after a meal

4–755 days

Stockman (1917)

Cynomolgusmonkeys M.

fasicularis n = 2

L. sativus

extract + ODAP oral(0.6–0.9 g kgÀ1 dÀ1)

Neurological symptoms involving the pyramidal corticospinal tracts 4–6 weeks Spencer et al. (1986)

Cynomolgusmonkeys n = 2

ODAP oral (0.3–0.6 g kgÀ1 dÀ1)

Neurological symptoms involving the pyramidal corticospinal tracts 2–4 weeks Spencer et al. (1986)

Cynomolgusmonkeys n = 6

L. sativus + ODAP oral(1.1–1.4 g total ODAPkgÀ1 dÀ1)

Neurological symptoms involving the pyramidal corticospinal tracts 3–10 months

Spencer et al. (1986)

Guinea pigs L. sativus 50% (0.09%or 0.6% ODAP)

Locomotor activity, increase of brain intracellular Ca, membrane fluidity;neurotoxic involvement of NMDA, Non-NMDA and cholinergicreceptors; cerebellar benzodiazepine receptors

3 months Amba et al. (2002)

Guinea pigs L. sativus 80% flour(0.6% ODAP) ± Mn(4 mg kgÀ1)

Reduced activities of intestinal gamma-glutamyl transferaseglutathione-S-transferase, alkaline phosphatase, sucrase, Ca2+ Mg2+

ATPase. Mn increases grasspea toxicity

3 months Kumar et al. (2003)

Guinea pigs, rabbits Lathyrus sp. flour Neurodegenerative changes in cortex and spinal cord, varicose atrophyof dendrites

Mirto (1897a); citedFiliminoff (1926)

Mice white 16–22 g LW bothsexes

L. sativus + various

deficient diets

Extensive and steady subarachnoid, pial and subpial hemorrhages.Neuronal changes in the Fascia dentata, Stratum pyramidale. 100% deathafter 14–21 days on olive oil deficient diets

14–189 days

López Aydillo and Toledano Jiménez Castellanos (1968)

Mice, male L. sativus 30% flour(1.05% ODAP)

Brain cholinergic function altered; oxidative stress; GSH depletion incortex

4–12 weeks

Shinomol and Muralidhara(2007)

Mice, Swiss albino 1-

3 mo old

ODAP at 10 mg kgÀ1

injected subcutaneous

Males susceptible while females were resistant. Ovariectomy led to

decreased GSH and the activities of glutaredoxin and complex I inmitochondria from the lumbar spinal cord

0.5–24 h Diwakar et al. (2007)

Rabbits Lathyrus sp Spastic paraplegia but no significant anatomical lesions 1 month Mingazzini and Buglioni(1896)

Rats L. sativus Growth retarded, alopecia, megacolon, paraphimosis, diarrhoea,dermatitis

10 months Jiménez Díaz and Vivanco(1942a)

Rats L. sativus Animal protein or liver extract restore growth 12 weeks Jiménez Díaz and Vivanco(1942b)

Rats 40-45 d.o. L. sativus (0.1–0.2%ODAP)

Transient increases in locomotion and defecation 8 months LaBella et al. (1997)

Rats L. sativus 50% flour(0.09% or 0.6% ODAP)

No symptoms; increase of brain intracellular Ca, membrane fluidity;neurotoxic involvement of NMDA, Non-NMDA and cholinergic receptors

3 months Amba et al. (2002)

Cattle L. clymenum + Vicia

sativa forage

Reduced lactation and feed intake, later inability to stand up, death;internal hemorrhages (digestive and central nervous systems)

17 days Boissiere (1926)

Cattle L. clymenum forageexclusively

Neurolathyrism, death after one week, hyperaemia, inflammatoryinfiltrations of spinal cord, no roaring; some cases 14 weeks aftercessation of feeding

1 months Perrussel (1896); cited byFröhner (1910)

Cows L. clymenum 5 of 16 fell ill. Lethargy, Paralysis, blindness, anesthesia Lucet (1898); cited byFröhner (1910)

Cows n = 7 L. clymenum + L. alatus Motoric and sensory paralysis of hind legs, incapable of standing up, Alessandro (1892); cited

(continued on next page)





larvae in the stomach; impaction of caecum, which contained alarge amount of grit; chronic enteritis. Histology: no specificchanges in the organs. Liver and kidney showed hyperaemia. Deathoccurred in one horse after 35 days and ingestion of 114 kg of theforage (fresh weight). The other horse was fed for 55 days consum-ing 212 kg fresh forage before developing similar symptoms. Lackof further L. sativus feed prompted discontinuation of the experi-ment and the animal recovered (Steyn, 1933).

Lathyrism in horses is similar to stringhalt (Spencer, 1995)

which is a distal axonopathy (Slocombe et al., 1992). Using metab-onomics in combination with nuclear magnetic resonance imaging,a mouse model for this disease was used to identify possible toxins(Domange et al., 2008). Such an approach may also be useful forthe study of neurolathyrism.

Among pigs, death by asphyxiation is also the most commoncause of death (Cornevin, 1893), presumably, while feeding onthe forage (Schuchardt, 1887).

While accidental poisoning has affected a whole range of ani-mals, numerous feeding studies with Lathyrus species to a varietyof animals have produced mixed results (Fumarola and Zanelli,1914; Stockman, 1917; Spencer, 1995; Hugon et al., 2000).

Filiminoff (1926) extracted some useful anatomical informa-tion. Rabbits after one month of feeding on Lathyrus sp. developed

spastic paraplegia but no significant anatomical lesions, suggestinga toxic irritation of the terminal ramifications of the corticospinalneurons in the lumbar spinal cord (Mingazzini and Buglioni,1896). Experiments with guinea pigs and rabbits fed with Lathyrus

sp. flour caused acute toxicity. Histology revealed changes in gan-glial cells, atrophy of many pyramidal cells in the cortex (Biels-chowski silver stain) and perinuclear chromatolysis (Nissl stainfor ribonucleic acid). In the spinal cord there were varicose atro-phies of dendrites, frequently extending to cell body and some-times spread to the axon, with chromatolysis more pronouncedthan in the cortex. It started more frequently from the peripherythan from around the nucleus (Mirto, 1897a; cited by Filiminoff,1926). Other work by Mirto (1897b, 1898) was not consulted.

L. sylvestris, L. sativus, L. clymenum and L. cicera were fed to dogs.

L. sylvestris gives rapid toxic results, affecting cerebral grey matterand particularly the cortex (Spirtoff, 1903; cited by Filiminoff,1926), caused by diaminobutyric acid (Ressler et al., 1961), a toxinaffecting ornithine transcarbamylase (O’Neal et al., 1968) (for a re-view see Foster, 1990). In contrast, L. sativus causes in dogs pro-nounced pathological alterations of the gray matter in the spinalcord. These alterations do not have any foci. Instead they are dif-fusing and only in some places more pronounced (Spirtoff, 1903;cited by Filiminoff, 1926).

Horses appear to be the most susceptible animal to diets con-taining the seed of L. sativus or L. cicera seed while the forage canalso induce toxicity but the roaring or dyspnoea complicates theirsymptoms.

13. Ruminants

The green forage of Lathyrus sativus and other ODAP synthesiz-ing species is a principal fodder for ruminants (Cornevin, 1893;

Schuchardt, 1887; Stockman, 1917; Mukerjee, 1924; Stockman,1931). Reports of cattle or buffaloes being poisoned by Lathyrus

sativus are hard to find. Most references trace back to a statementabout local beliefs made by Sleeman (1844). Irving (1860) notesthat ‘‘one man said one thing, the other said the reverse’’ andHendley (1903) mentions that some veterinarians had noticedthe effects of L. sativus in cattle, leaving Buchanan (1904) not quiteconvinced that cattle are poisoned by the crop. On the whole theforage appears to be wholesome for cattle and buffaloes. Bashir

(1989) reports that during his 1988 survey in Pakistan few inci-dents of human neurolathyrism were reported by Lathyrus farmersbut the disease was common among buffaloes fed with the seed.

All clear cases of lathyrism in cattle are related to animals graz-ing the forage of L. clymenum (Fröhner, 1910; see also Schribaux,1895 [not consulted]). Boissiere (1926) reported lathyrism in cattleafter foraging on a mixture of Vicia sativa and L. clymenum. (seeTable 1 for further details).

One hundred and twenty five lambs were poisoned by being fedexclusively for 2 months with ripe and unthreshed L. cicera. At5 months old they were unable to stand on their front legs, forcingthem to crawl on their knees while the hind legs were not affected.The animals recovered after feed was withdrawn (Dus, 1875; citedby Cornevin, 1893).

Newborn sheep and goats fed with split seeds of L. sativus sup-plemented with hay developed neurotoxic symptoms after one tothree months which did not resemble those of human neurolathy-rism, initial signs were hind leg weakness, followed by generalweakness, lethargy and eventual death. Signs of degeneration of the pyramidal tracts of upper and lower spinal cord were observed.Prolonged feeding of horses and donkeys for 1–3 years apparentlyalso led to toxic symptoms. The goat was considered to be the mostsuitable species as a model for neurolathyrism (Tekle Haimanotet al. 1997).

It is clear that ruminants can get poisoned by Lathyrus specieswhich produce ODAP. The forage of L. clymenum when eaten exclu-sively appears to be the most toxic.

14. Toxicity of forage

Several cases of poisoning have been due to ruminant andmonogastric animals grazing the forage of L. cicera, L. sativus orL. clymenum (Cornevin, 1893; Fröhner, 1910; Stockman, 1917;Boissiere, 1926; Spencer, 1995 and references therein). The oftencited cases of pigs being poisoned by Lathyrus (Ferraresi [withparaplegia of hind legs], Zurcher [death]) are due to the animalsgrazing on green Lathyrus sp. (Cicerchie; Gardner and Sakiewicz,1963 interpret L. cicera), while those of Bourlier and Gauthierappear to be due to Vicia ervilia seed (Schuchardt, 1887).

The toxicity of the plants increases with the onset of flowering(Cornevin, 1893). Prakash et al. (1977) using paper chromatogra-phy found ODAP in vegetative tissue (leaf, root, stem) with high

levels (0.35%) in young leaves of field grown L. sativus, and foundvarietal differences in the decrease of ODAP levels in older leaves.Developing pods and seeds showed an increase, suggesting trans-location or dilution by growth. Addis and Narayan (1994) could

Table 1 (continued)

Animal species Lathyrus species Clinical symptoms Time Reference

forage (ad lib) tonic-clonic cramps. Appetite normal, no fever. Fröhner (1910)Lambs 3 months old L. cicera ripe and

unthreshed125 lambs at 5 months old, unable to stand on front legs, forcing them tocrawl on their knees, hind legs not affected. Recovery after Lathyrus feed

removal

2 months Dus (1875); cited byCornevin (1893)

Lambs, goatsnewborn

L. sativus, split seeds Neurotoxic symptoms after one to three months. Initial signs were hindleg weakness, followed by general weakness, lethargy and eventualdeath. Signs of degeneration of the pyramidal tracts of upper and lowerspinal cord were observed

3 months Tekle Haimanot et al. (1997)





not detect ODAP in short term glasshouse grown plants but wereable to confirm high levels during seedling and reproductivestages. Przybylska and Rymowicz (1965) using paper electrophore-sis also found ODAP in leaves, stems and flowers of several Lathyrus

species of concern to the present discussion. Denekew and Tsega

(2009) reported the level of ODAP in dry matter of forage (0.19–0.34%), seed (0.2–0.45%) and straw (0.13–0.21%) in several acces-sions of grasspea. High forage and straw levels correlated with highconcentrations of ODAP in the seeds. A preliminary trial with ges-tating female sheep (ewes) feeding on L. sativus cv. AC-Greenfix, orMedicago sativa hay found both to be of comparable nutritional va-lue (Poland et al. 2003).

15. Distribution of ODAP in animal tissues

Lakshmanan and Padmanaban (1977) injected 10 d.o. ratsintraperioneally with radioactive 3H-ODAP (250 mg kg–1) and ob-served convulsions within 5–10 mins. After 10 mins the highest

level of ODAP was found in the kidney (660 ± 73 lg g–1

tissue),followed by liver (193 ± 34 lg g–1 tissue) and brain (45 ± 12 lg g–1

tissue). After 24 h ODAP levels in the brain had not diminishedmuch while liver and kidney levels had decreased below those inthe brain. A small amount of radioactivity was detected in a ketoacid fraction in the kidney after 10 mins and in liver and kidneyafter 24 h, which they interpreted as a beta-N-oxaly-alpha-keto-beta-amino pyruvic acid, the deamination product of ODAP. Mon-keys (unspecified) injected intrathecally with the compound(10 mg kgÀ1) developed hind leg paralysis 6–24 h later. ODAP wasfound predominantly in the brain stem and spinal cord. Subcellularfractionation indicated that high levels of ODAP on a protein basiswerepresent in the synaptosomesin ratsand monkeys. The authorssuggested that ODAP may have blocked glutamate transport intosynaptosomes.

Mehta et al (1976) pretreated adult squirrel monkeys with sub-cutaneous injections of 450 mg kg–1 day–1 [14C oxalyl] ODAP for6 days, followed by 250 lg kgÀ1 or 500 lg lg kgÀ1 injected i.p..Most of the radioactivity was found as unchanged ODAP in the ur-ine and abdominal organs. Less than 0.25% of the injected radioac-tivity was found in the CNS, with 75% of it in the cerebralhemispheres, while the highest concentration was found in thelumbosacral cord. Approximately 5% of ODAP was hydrolysed inthe stomach (10% trichloroacetic acid extract) and no radioactiveCO2 was detected in exhaled air. This study suggests that ODAPcan enter the central nervous system in adult primates reachinghigh concentrations in the lumbosacral cord. The authors suggestthat the lack of degradation and metabolism of ODAP in the brainmay be an important feature of its neurotoxicity.

Cheema et al (1971) injected 12 d.o. rats i.p. with 250 mg kgÀ1

radioactive [14C oxalyl] ODAP. 60 mins later they found the highestconcentration of radioactivity in blood, spleen, heart and kidneys.

Rao (1978) found a significantly higher concentration of radio-active 3H-ODAP (g/wet weight tissue) in the lower third of thespinal cord when compared to other regions of the CNS in rhesusmonkeys injected intravenously with 105 mg kgÀ1 ODAP or i.p.with 120 mg kgÀ1 ODAP. Administration by i.p. route led to a great-er concentration in the CNS, however these animals also receivedthe slightly higher dose and were killed 15 mins later (75 mins)than their comparators. Acidotic monkeys had a 2.5 times higherblood level of ODAP but this did not affect CNS levels (0.12–0.22% of injected dose). Fifty percentage of ODAP and radioactivitywas found in the urine while the kidneys were the tissue with the

highest concentration of the toxin. Experiments with d.o. chicksand adult rats injected i.p. with 375 mg kgÀ1 and 460 mg kgÀ1,respectively, showed similarly high levels of ODAP in the kidneysafter 90 mins and interestingly, revealed 1.5–2 times higher levels

in brain and spinal cord after 24 h, while concentrations in othertissues decreased. This study showed that ODAP enters the brainregardless of the susceptibility of an animal and can accumulatethere as a function of time rather than concentration. The observa-tion that ODAP concentrations in the chick CNS during expression

of neurotoxic symptoms was much lower than during recovery ledto the suggestion that the onset of symptoms is related to ahomeostatic disturbance caused by ODAP rather than its mere con-centrated presence. The presence of ODAP in the brain of rat andmonkey in the absence of neurotoxic symptoms could not be ex-plained. A focus on identification of species differences in suscep-tibility was advocated for future studies.

Mehta et al. (1980) found that ODAP injected i.p. in doses rang-ing from 0.32–0.66 mg kgÀ1 into squirrel monkeys (Saimiri

sciureus) resulted in its retention in the cerebellum where its con-centration increased during a 72 h period. They measured 20–95%of the injected dose of ODAP in the urine and 3–30% in faeces.

Rao et al (1967) injected adult rats either i.p. or intravenouslywith ODAP 1 mg/g body weight but saw no toxic symptoms. The

same results was obtained with i.p. injections of the same dosein mice while 25 lg injected intracisternally produced convulsions.To increase toxin concentrations in the CNS they injected adult Ma-caque monkeys (Macaca radiata) intrathecally by the lumbar routewith increasing doses of ODAP, resulting in three cases of flaccidand two cases of spastic initially transient and eventual permanentparaplegia at higher accumulative doses (10–20 mg). Transientweakness was prolonged at increasing doses. Anatomically theyfound destruction of grey matter nerve cells in the spinal cordand a proliferation of microglial cells in their vicinity.

Layer hens feeding for 32 weeks on a low ODAP L. cicera cultivarChalus accumulate 0.4–0.7 mg kg–1 ODAP in their brains, irrespec-tive of the level of Chalus feed inclusion level (5–30%). ODAP couldalso be detected in egg yolk (0.1–0.7 mg kgÀ1) but not egg white(Hanbury and Hughes, 2003).

Olney et al. (1976) observed that convulsive doses of ODAP(350 mg kgÀ1) administered i.p. to 1 week old albino mice causeda pattern of damage spreading from the margins of the area pos-trema in the brain stem caudally down the spinal cord.

Kusama-Eguchi et al. (2005) injected newborn rats subcutane-ously with 400 mg kgÀ1 ODAP or repeated doses of 200 mg kgÀ1

ODAP. After 15 mins the highest concentration of ODAP withinthe CNS was found in the lower spinal cord, followed by upperspinal cord and medulla.

These observations document that ODAP when injected intorats or monkeys is rapidly eliminated in urine and faeces. The dataalso suggest that low levels of ODAP are tolerated in the centralnervous system of different animal species. The concentration gra-dient of ODAP within the CNS, with highest levels measured by

several studies in the lower lumbar region point is striking.Filiminoff’s observations on alterations of the gray commissure

and the most recent report by Kusama-Eguchi et al. (2010) of hem-orrhages along the lower spinal cord of lathyritic neonate rats, sug-gest that there may be a problem with either the clearing of ODAPfrom the lower spinal cord or its facile entry due to vascularalterations.

16. Vascular lesions

The blood brain barrier (BBB) is made up of tightly joined endo-thelial cells that are enveloped by nerve cells such as pericytes,astrocyte cell projections, microglia and neurons. These cells con-

stitute the neurovascular unit. There is a functional interdepen-dence between the nerve and blood vessel cells to regulate bloodflow and the movement of metabolites (Wang and Bordey, 2008;Segura et al., 2009). Besides this vascular BBB there is also the





choroid plexus which interfaces the blood with the cerebrospinalfluid (CSF) (Banks, 2009). The BBB and its neurovascular unit ac-tively eliminate amino acids into the blood stream to maintainconcentrations in the CSF below those in the blood and to regulatepotentially neurotoxic concentrations inside the CNS (Hawkins

et al., 2006). Rather than thinking about toxins such as ODAP enter-ing a leaky BBB it might be useful to consider a possible inhibitionof transport processes that are involved in eliminating this toxinfrom inside the CNS.

In a 90 day feeding study with guinea pigs, diets consisting of 80% grasspea (0.6% ODAP) plus Mn (4 ppm) caused significantalterations to the permeability of the blood brain barrier and se-vere hair loss. There was a marked increase in lipid peroxidationand reduction in catalase activity, there were less pronounced ef-fects on increased glutathione peroxidase activity and decrease inGSH. Mn by itself reduced the neuronal activity of glutathioneS-transferase. Pretreatment of animals with Mn 15 mg kgÀ1,followed after 24 h by oral administration of ODAP 240 mg kgÀ1

resulted in a massive increase of brain ODAP another 24 h later.

Neural damage (neural vacuolisations and chromatolysis, isolateddegenerated neurons) was observed in the lumbar spinal cord.Mn clearly potentiates grasspea toxicity (Mishra et al., 2009).

Based on the autopsies of lathyritic horses [Leather, McCall],Allbutt (1897) suggested that neurolathyrism may be the conse-quence of vascular lesions. Acton (1922) thought that the neurola-thyritic corticospinal lesion in humans is below the second lumbarroot. This is a region anatomically predisposed for trouble due to apoor blood supply, particularly, the lateral and anterior columns. Aminor and even temporary interruption of blood flow, caused by athrombosis or arterial spasm which conceivably could be triggeredby starvation induced low blood pressure in conjunction with acold chill would explain the sudden onset of symptoms. More re-cently Bruyn and Poser (2003) suggested that a lack of attentionto vascular components has hindered progress with the develop-ment of an animal model for neurolathyrism.

Filiminoff (1926) dissected the spinal cord of a man who hadcontracted neurolathyrism some 30 years earlier. In the gray com-missure (lamina X) (commissura grisea anterior medullae spinalis), athin strip of gray matter surrounding the central canal of the spinalcord that, together with the anterior white commissure, joins thetwo halves of the spinal cord. He found curious vascular altera-tions, a superfluous number of vessels, a possible proliferation of vessels that accompanied repair processes of the gray matter as asequel to damage caused by grasspea toxicity or residual leftoversof a proliferative leptomeningitis that could have led to an invagi-nation of the pia in the region of the commissure in the onset of neurolathyrism.

Support for a vascular hypothesis comes also from the study of

Kusama-Eguchi et al. (2010) who injected neonatal rats after 6 hfasting with consecutive subcutaneous doses of ODAP. Parapareticrats dissected within the first week showed severe hemorrhageexclusively in the lower spinal cord, localised in the ventral paren-chyma and in several cases all the ‘‘subpial parenchyma of the cau-dal spinal cord’’ and were able to link these hemorrhagicsymptoms to a reduction in the expression of vascular endothelialgrowth factor receptor 2 (VEGFR 2). The hemorrhage was a tran-sient event, as postulated by Acton (1922). They also found a de-crease in the size and number of motor neurons in the lowerspinal cord 3–9 months after treatment and evidence for degener-ation of upper motor neurons.

In this context the observation by Sigler et al. (2007) on a case of quinine induced thrombocytopenia in a patient who had 50 years

earlier been diagnosed with mild lathyrism (Kessler, 1947) maybe of interest.

The anatomy of the corticospinal vascular system has recentlybeen reviewed and referenced to magnetic resonance imaging

(Tatu et al., 2008), showing the delicate nature of the anteriorspinal artery that Acton (1922) referred to, with the Arteria radic-ularis magna (of Adamkiewicz) constituting a major supply route.Temporal surgical interruption of the arterial or venal vascular sys-tem or manipulation of its function by inhibitors in this part of the

spinal cord in the presence of circulating ODAP might contribute tothe testing of Allbutt and Acton’s ideas mentioned above. Is ODAPsuch an inhibitor?

17. Homoarginine

Homoarginine (Bell, 1965) is a factor which is frequently ne-glected in studies of grasspea toxicity (Rao, 2010). While a thor-ough examination of its biochemistry, for example in the contextof hyperargininemia and hyperhomoargininemia, is beyond thescope of the present discussion, the compound is a substrate for ni-tric oxide synthesis and hence can have an effect on vascular reg-ulation (Raghavan and Dikshit, 2004). It has also been found tohave an effect on pancreatic activity in rats (Hira et al., 2003), while

Hiramatsu (2003) provides evidence that it and other guanidinocompounds cause convulsions when injected intracisternally intorats, rabbits and cats. It should also be noted that birds excrete ex-cess nitrogen as uric acid since they do not have a fully functionalurea cycle (Urich, 1994; Baker, 2009), so homoarginine has differ-ent metabolic effects in poultry than in mammals.

18. Metabolism of ODAP

While animals seem to eliminate the bulk of injected or in-gested ODAP via the kidneys and urine, human grasspea consum-ers appear to be metabolising >99% of ingested toxin. Instead of ODAP an increased level of oxalic acid is detected in human urine,corresponding to an estimated 25% of ingested toxin. The remain-der is still unaccounted for. Breakdown of ODAP in the gastrointes-tinal tract is one possibility. An animal species that can metaboliseODAP similar to humans would be ideal for further biochemicalstudies, while wide scale screening of urine from human grasspeaconsumers would help to ascertain whether there is genetic varia-tion within populations for the capacity to metabolise ODAP andthus may lead to the identification of lathyrism susceptible indi-viduals (Pratap Rudra et al., 2004).

In a comparison of mice, rats and chicks, using 1,2,3-14C-ODAPand 4,5-14C-ODAP given either orally or i.p., interesting species dif-ferences were found in the extent that ODAP was metabolised toCO2 and a hitherto unidentified metabolite or unchanged ODAPwas excreted in the urine. It was established that the CO 2 arisesfrom the diaminopropionic acid moiety of ODAP. I.p. administra-

tion resulted in a five fold higher clearance of radioactivity within8 h in the rat while mice did not show any difference, compared tooral intake. It also resulted in more unchanged ODAP in rats andmice. Rats metabolised more ODAP into oxalate and metabolite1. The chick does not metabolise ODAP to CO2 Surprisingly, neitheroxalate nor metabolite 1 could be detected in either liver or kidney( Jyothi et al., 1998).

Parker et al. (1979) were surprised to observe that an i.p. injected dose of 0.75 g kgÀ1 ODAP produced convulsive seizures ina young squirrel monkey. During autopsy they found that the sin-gle animal susceptible to this dose had a fatty liver. This observa-tion was exceptional since five other animals injected with thesame dose developed only mild neurological symptoms. Theyfound that a dose of 2 g kgÀ1 ODAP administered by the same route

is lethal to healthy squirrel monkeys.Some feeding studies have reported increases in the size of kid-

ney and liver following the feeding of pigs on diets containing rawL. sativus seed meal (Castell et al., 1994; Grela, 1998) although





Winiarska-Mieczan and Kwiecien (2010) did not observe thiseffect.

Curiously, blood bypassing the liver can cause the developmentof a spastic paraparesis with symptoms closely resembling thoseseen in cases of neurolathyrism (Conn et al., 2006).

Since ODAP inhibits tyrosine aminotransferase (Vardhan et al.,1997) it is also worth noting that an excess of metabolic tyrosine(tyrosinemia) is related to liver, kidney and peripheral nerve dys-functions (Russo et al., 2001).

The gastrointestinal tract, kidney and liver (splanchic organs)play an important role in ODAP uptake, metabolism and excretion,so their role in neurolathyrism should be examined more closely.

19. Conclusion

Grasspea seed has a high nutritional value. Consumers of grass-pea generally appear well nourished and it has been observed thatneurolathyrism can strike the strongest young men. People in suchcondition are easily overlooked by conventional malnutrition sur-

veys during food shortage crises. It is also evident from the litera-ture on malnutrition, that the human or animal body can live off itsreserves. Hence, it is conceivable that a diet deficient in somenutrients as is the case for a monotonous diet of grasspea is com-pensated for by reserves from peripheral parts of the body. Oncethis store of critical nutrients is depleted, detoxification andhomeostasis processes begin to fail and a crisis is triggered.

The supply of sulphur amino acids is limited by the combinedaction of several antinutritional factors and the low inherent levelsprovided by a leguminous diet.

Considering the importance of reduced thiols to maintain func-tion in the CNS (Nunn et al., 2010) and the ability of this system tomarshal the resources of peripheral tissues, the onset of neurolog-ical damage would be favoured by an interruption of these vital

supplies.L. clymenum, L. ochrus and L. cicera may be useful in experimen-

tal studies with animals because they allow an increased dose of ODAP ± homoarginine to be fed while metabolisable energy is keptconstant. Not only the seed but also the green plants can induceneurotoxic symptoms with the forage of L. clymenum capable of producing neurotoxicity in cattle. It would also be advisable tochoose genotypes with high levels of other antinutritional factorssuch as tannins, enzyme inhibitors, lectins, etc.

The d.o. chick bioassay appears to be a simple and effectivemethod to test the toxicity of grasspea (Sharma et al., 2003). Newlydeveloped Lathyrus cultivars destined for human consumptioncould be easily tested to assess their in vivo neurotoxicity.

A closer examination of ingestion, excretion and metabolism of

ODAP in animals may lead to methods to inhibit these processes sothat their involvement in neurolathyrism can be assessed.The liver and the kidney appear to play important roles in the

supply of GSH, ODAP detoxification and excretion.The vascular supply to brain and spinal cord and clearance of

toxins from the CNS appear to play a critical role inneurolathyrism.

Conflict of Interest

The authors declare that there are no conflicts of interest.

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