Valerie S. Palmer

Sodium cyanate alters glutathione homeostasis in rodent brain: relationship to neurodegenerative diseases in protein-deficient malnourished populations in Africa

Sodium cyanate, a neurotoxic chemical in rodents, primates and humans, is implicated in neurodegenerative disorders in protein-deficient populations subsisting in parts of Africa on the cyanogenic plant cassava. The molecular and cellular mechanisms of cyanate neurotoxicity are not understood. This study investigates the effect of sodium cyanate on glutathione (GSH) homeostasis in rodent brain and liver in vitro and in vivo. GSH levels in mouse brain were rapidly, time- and dose-dependently decreased following intraperitoneal administration of 100, 200 or 300 mg/kg sodium cyanate. By contrast, GSH disulfide (GSSG) levels were increased and GSH/GSSG ratios were decreased in a dose-dependent manner in rat brain. Sodium cyanate depleted GSH levels in all regions of mouse brain. Brain glutathione reductase activity was dose-dependently inhibited, while glutathione peroxidase activity was not affected by sodium cyanate. The disruption of GSH homeotasis, as evidenced by reduced tissue GSH/GSSG ratios, likely results from cyanate-induced inhibition of glutathione reductase activity. The results of this study suggest that cyanate neurotoxicity, and perhaps cassava-associated neurodegenerative diseases, are mediated in part by disruption of glutathione homeostasis in neural tissue.

The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner

Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of adult C57BL6 wild-type mice treated with a single systemic dose of MAM acetate display DNA damage (O 6-methyldeoxyguanosine lesions, O 6-mG) that remains constant up to 7 days post-treatment. By contrast, MAM-treated mice lacking a functional gene encoding the DNA repair enzyme O 6-mG DNA methyltransferase (MGMT) showed elevated O 6-mG DNA damage starting at 48 hours post-treatment. The DNA damage was linked to changes in the expression of genes in cell-signaling pathways associated with cancer, human neurodegenerative disease, and neurodevelopmental disorders. These data are consistent with the established developmental neurotoxic and carcinogenic properties of MAM in rodents. They also support the hypothesis that early-life exposure to MAM-glucoside (cycasin) has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for food or medicine, or both. These findings suggest environmental genotoxins, specifically MAM, target common pathways involved in neurodegeneration and cancer, the outcome depending on whether the cell can divide (cancer) or not (neurodegeneration). Exposure to MAM-related environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimers disease.

On the decline and etiology of high-incidence motor system disease in West Papua (southwest New Guinea)

The etiology of a high‐incidence focus of amyotrophic lateral sclerosis and parkinsonism–dementia (ALS/P‐D) in south West Papua (Irian Jaya, Indonesia), first described in the 1960s and 1970s, has been attributed to mineral deficiencies, hyperparathyroidism, and metal neurotoxicity arising from reliance on drinking water obtained from springs and shallow wells. More recent visits (1987 and 1990) to the south West Papua focus of neurodegenerative disease cast doubt on this explanation by revealing changes in disease prevalence in communities with an unchanged water supply. These communities have experienced a dramatic decline in ALS and a reversal in the relative prevalence of ALS and parkinsonism. The extrapyramidal disorder can be distinguished from Parkinson disease by pyramidal features (and dementia) reminiscent of Guam P‐D. Topical use of cycad seed (termed kurru) gametophyte to treat large skin lesions is advanced as a plausible but unproven etiologic factor. Medicinal use of untreated cycad seed (Cycas sp.) has also been linked with ALS foci in Japan (oral use) and Guam (topical use), with the additional consumption on Guam of food items prepared from Cycas sp. seed or animals that consume cycad seed components.

INTERRELATIONSHIPS OF UNDERNUTRITION AND NEUROTOXICITY: FOOD FOR THOUGHT AND RESEARCH ATTENTION

The neurotoxic actions of chemical agents on humans and animals are usually studied with little consideration of the subjects nutritional status. States of protein-calorie, vitamin and/or mineral undernutrition are associated with a range of neurodevelopmental, neurological and psychiatric disorders, commonly with involvement of both the central and the peripheral nervous system. Undernutrition can modify risk for certain chemical-induced neurologic diseases, and in some cases undernutrition may be a prerequisite for neurotoxicity to surface. In addition, neurologic disease associated with undernutrition or neurotoxicity may show similarities in clinical and neuropathological expression, especially in the peripheral nervous system. The combined effects of undernutrition and chemical neurotoxicity are most relevant to people with low incomes who experience chronic hunger, parasitism and infectious disease, monotonous diets of plants with neurotoxic potential (notably cassava), environmental pollution from rapid industrial development, chronic alcohol abuse, or prolonged treatment with certain therapeutic drugs. Undernutrition alone or in combination with chemical exposure is also important in high-income societies in the setting of drug and alcohol abuse, old age, food faddism, post-bariatric surgery, and drug treatment for certain medical conditions, including cancer and tuberculosis. The nutritional demands of pregnancy and lactation increase the risk of fetal and infant undernutrition and chemical interactions therewith.

Interprofessional global health education in a cosmopolitan community of North America: the iCHEE experience.

PROBLEM The rapidly diversifying population of North America has disparate health needs that are addressed by creative, community-based training of health professions students. APPROACH The authors report five years (2008-2012) of experience implementing a novel interprofessional Community Health and Education Exchange (iCHEE) elective course for dental, medical, nursing, nutrition, pharmacy, physician assistant, and public health students at Oregon Health & Science University (OHSU). This pioneering interprofessional course was created by the OHSU Global Health Center and is offered in fall, winter, and spring quarters. Students interact with individual clients drawn from community centers supporting refugees, recent immigrants, and other underserved people. In addition to health concerns, clients are encouraged to share backgrounds and experiences with student teams. Clients receive guidance on nutrition, exercise, pharmaceuticals, and accessible health services. Student teams perform a noninvasive health check on clients with the assistance of faculty mentors who, on finding a physical or mental health issue, refer the client from the educational setting to an appropriate health care facility. OUTCOMES In addition to supporting health promotion and early intervention for medically underserved people, students reported gaining valuable cross-cultural knowledge, understanding, and experience from clients. Students also appreciated the value of diverse skills and knowledge available in their multidisciplinary teams. Through the end of 2012, over 300 health professions students worked with approximately 1,200 clients to complete the iCHEE course. NEXT STEPS The iCHEE model should prove helpful in preparing health professions students at other institutions to understand and serve diverse populations.

Probable toxic cause for suspected Lychee-linked viral encephalitis

To the Editor: Paireau et al. (1) reported a spatiotemporal association between unexplained outbreaks of suspected acute encephalitis in children in northern Vietnam and the harvesting of lychee (litchi) fruit. The clinical, biologic, and immunologic characteristics of the patients suggested a viral etiology (1). However, the lychee-associated acute brain disorder, which has also been reported in Bangladesh and India (Bihar and West Bengal), could also result from ingestion of phytotoxins present in lychee fruit, specifically α-(methylenecyclopropyl)glycine (2), the lower homologue of the neurotoxic L-amino acid hypoglycine (3,4).

Nodding syndrome in Kitgum District, Uganda: association with conflict and internal displacement

Objectives To test for any temporal association of Nodding syndrome with wartime conflict, casualties and household displacement in Kitgum District, northern Uganda. Methods Data were obtained from publicly available information reported by the Ugandan Ministry of Health (MOH), the Armed Conflict Location & Event Data (ACLED) Project of the University of Sussex in the UK, peer-reviewed publications in professional journals and other sources. Results Reports of Nodding syndrome began to appear in 1997, with the first recorded cases in Kitgum District in 1998. Cases rapidly increased annually beginning in 2001, with peaks in 2003–2005 and 2008, 5–6 years after peaks in the number of wartime conflicts and deaths. Additionally, peaks of Nodding syndrome cases followed peak influxes 5–7 years earlier of households into internal displacement camps. Conclusions Peaks of Nodding syndrome reported by the MOH are associated with, but temporally displaced from, peaks of wartime conflicts, deaths and household internment, where infectious disease was rampant and food insecurity rife.

Western Pacific ALS-PDC: a prototypical neurodegenerative disorder linked to DNA damage and aberrant proteogenesis?

A commentary on Unraveling 50-year-old clues linking neurodegeneration and cancer to cycad toxins: are microRNAs common mediators? by Spencer, P., Fry, R. C., and Kisby, G. E. (2012). Front. Gene. 3:192. doi: 10.3389/fgene.2012.00192 The Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC) has been described as a Rosetta Stone that bears the essential clue to understanding the etiopathogenesis of related neurodegenerative diseases. The three clinical forms (ALS, atypical parkinsonism with dementia, and dementia alone) have a single pathology (polyproteinopathy, notably tauopathy), just as the Rosetta Stone is inscribed with three distinct scripts bearing a common message. As recently discussed (Kisby and Spencer, 2011), studies of ALS-PDC in the three geographically separate and genetically distinct island populations (Chamorros on Guam; Japanese in Honshu Islands Kii Peninsula; and Papuan New Guineans in Irian Jaya, Indonesia) show: ALS-PDC is primarily if not exclusively an environmental disease: no gene mutations identified in related neurodegenerative disorders are found in Guam and Kii-Japan cases, and disease rates have steadily declined in the three affected populations. Emigrants from Guam may develop ALS-PDC years or decades later, but disease risk is absent in their offspring who were born and live abroad. Conversely, Filipino and other immigrants who adopt the Chamorro lifestyle on Guam may acquire the disease. As ALS-PDC declined during the twentieth century, the disease changed its clinical face from ALS in the first third of life, to PD in the second, and D in the third, a pattern consistent with a dose-related response to an environmental exposure that waned with modernization. With this hypothesis, those with the highest dose of the putative environmental factor develop fatal ALS (with sub-clinical nigrostriatal damage) relatively shortly after exposure; those with intermediate doses survive with amyotrophy long enough to develop atypical parkinsonism; those with low doses reach old age and display dementia, while others with the lowest exposure have subclinical neurofibrillary disease reminiscent of early aging. Other features of ALS-PDC variably include loss of olfaction, retinal pigment epitheliopathy, and atypical skin cytology. The most plausible but unproven trigger decades before the disease surfaces in clinical form is exposure to certain plant-derived neurotoxins in food or medicine, or both. The raw seed of the neurotoxic cycad plant (Cycas spp.) was used to heal skin lesions (Guam, Irian Jaya) and as a tonic (Kii). On Guam, processed cycad seed was a Chamorro staple, and the cycad seed-eating flying fox (Pteropus sp.) that bioaccumulates the cycad-derived neurotoxin β-N-methylamino-L-alanine (L-BMAA) was a delicacy. Among the many bioactive chemicals in cycad seed, two with neurotoxic properties are singled out as potential triggers of ALS-PDC: (a) methylazoxymethanol (MAM), a potent genotoxin, carcinogen and developmental neurotoxin that is stored in the plant as an inactive β-glucoside, the concentration of which in cycad flour correlates significantly with incidence rates for ALS and PD in males and females on Guam, unlike the concentration of (b) L-BMAA, a weak excitotoxic amino acid that is taken up by brain tissue and possibly undergoes proteogenesis, resulting in misfolded proteins; daily oral dosing of macaques with L-BMAA for up to 3 months induces a L-dopa-responsive, non-progressive motorsystem disorder with non-excitotoxic cortical and spinal motor neuron pathology. Both L-BMAA and MAM are metabolized to formaldehyde, an established genotoxic agent and human carcinogen. Whereas, genotoxin-induced DNA damage is rapidly repaired in non-nervous tissue (i.e., cycling cells), this can persist in the brain because some DNA-repair mechanisms are weakly expressed in post-mitotic cells. MAM-induces O6-methylguanine (O6-mG) DNA damage, promutagenic lesions that induce uncontrolled mitoses (tumorigenesis) in mouse epithelial tissues and widespread degeneration in the developing murine brain. O6-mG lesions are clearly responsible for the MAM-induced neuronal loss because the pathology is greater in mice that lack the DNA-repair enzyme O6-mG methyltransferase (Mgmt−/−) and reduced or absent in mice that overexpress MGMT (Kisby and Spencer, 2011). Motor deficits in these mouse mutants are consistent with the extent of DNA damage. In sum, these findings suggest DNA damage is an initial event that leads to brain pathology (Figure ​(Figure11). Figure 1 Proposed common pathway underlying cancer and neurodegenerative disease that is mediated by DNA damage and epigenetic changes (modified from Spencer et al., 2012). MGMT activity is very low in the young adult human brain and may be absent in mature nerve cells. Mgmt−/− mice, an animal model of the young adult human brain, develop persistent brain O6-mG DNA lesions following a single dose of MAM. In the days following MAM treatment, these DNA lesions modulate key brain cell-signaling pathways that are also perturbed in human neurological disease, notably Alzheimers disease, Parkinsons disease, and inherited and sporadic forms of ALS. Pathway analysis of MAM-modulated genes that are anchored to DNA damage reveals links with human cancer, genetic disorders, and skin and hair development (Kisby et al., 2011a). Several of these cell-signaling pathways continued to be modulated in the brain of Mgmt−/− mice 6 months later, with de novo expression changes of numerous genes involving olfaction (Kisby et al., 2011b). These findings emphasize the relationship between acquired brain tissue DNA damage, modulation of cell-signaling pathways, and the induction of early and persistent molecular changes that lead to neuronal demise. They also reveal important relationships between seemingly disparate diseases—cancer and neurodegeneration—the phenotype of MAM-induced DNA damage being determined, respectively, by the presence or absence of the proliferative capacity of target tissues. The genotoxic properties of MAM and formaldehyde, a common metabolite of MAM and L-BMAA, also involve non-coding RNAs with functional roles in both neurodegeneration and cancer (Spencer et al., 2012) (Figure ​(Figure11). While proof is lacking that cycad toxin(s) trigger ALS-PDC, the results of recent biochemical and systems biology studies, coupled with the absence of known mutations in related neurodegenerative disorders, encourage further efforts to examine the molecular and cellular actions of MAM and L-BMAA. These studies not only highlight the response of the brain to unrepaired DNA damage-induced by a genotoxin (e.g., alkylating agent) as a potential initiator of a neurodegenerative process, they also provide a foundation for understanding whether such effects can lead to persistent changes at the protein level (e.g., tau and synuclein), including the erroneous incorporation of foreign amino acids, a subject of recent interest. The ability of MAM to perturb synuclein and several other classes of brain proteins (e.g., calcium homeostasis, mitochondrial and RNA processing) is consistent with this hypothesis (Kisby et al., 2006).

Environmental, dietary and case-control study of Nodding Syndrome in Uganda: A post-measles brain disorder triggered by malnutrition?

Nodding Syndrome (NS) is an epileptic encephalopathy characterized by involuntary vertical head nodding, other types of seizures, and progressive neurological deficits. The etiology of the east African NS epidemic is unknown. In March 2014, we conducted a case-control study of medical, nutritional and other risk factors associated with NS among children (aged 5-18years) of Kitgum District, northern Uganda (Acholiland). Data on food availability, rainfall, and prevalent disease temporally related to the NS epidemic were also analyzed. In NS Cases, the mean age of reported head nodding onset was 7.6years (range 1-17years). The epidemiologic curve of NS incidence spanned 2000-2013, with peaks in 2003 and 2008. Month of onset of head nodding was non-uniform, with all-year-aggregated peaks in April and June when food availability was low. Families with one or more NS Cases had been significantly more dependent on emergency food and, immediately prior to head nodding onset in the child, subsistence on moldy plant materials, specifically moldy maize. Medical history revealed a single significant association with NS, namely prior measles infection. NS is compared with the post-measles disorder subacute sclerosing panencephalitis, with clinical expression triggered by factors associated with poor nutrition.

The enigma of litchi toxicity: an emerging health concern in southern Asia

How is it possible that lychee, a deliciously sweet tropical fruit, could induce a fatal hypoglycemic encephalopathy in children? The answer is straightforward: the edible fruit (aril) of lychee or litchi (Litchi sinensis or Litchi chinensis), and other members of the Soapberry family (Sapindaceae), contains unusual amino acids that disrupt gluconeogenesis and β-oxidation of fatty acids. This is well established in relation to both litchi fruit and, more particularly, fruit of its cousin, the ackee plant (Blighia sapida), a member of the Sapindaceae originating in west Africa and transplanted in the 18th century to the Caribbean. Ingestion of immature ackee fruit has been known for decades in Jamaica to cause a toxic hypoglycaemic encephalopathy (Jamaican vomiting sickness) in children. This knowledge has been slow to reach certain parts of Asia where the so-called mysterious litchi disease has been attributed to various causes (fruit colouring, heat stroke) in Bihar, India, to an unidentifi ed pesticide in northwest Bangladesh and, after an exhaustive negative virological search, to a yet-to-be-discovered neurotropic virus in northeast Vietnam. However, the illness evolves far too quickly to be a viral disorder, with a median time of 20 h from health to death in Bangladeshi children. In The Lancet Global Health, Aakash Shrivastava and colleagues’ study of Indian children with litchi-associated encephalopathy unequivocally pins the blame on the litchi fruit itself, as predicted by previous Indian investigators and by us. Like most, if not all, neurotoxic factors, the separation between chemicalinduced health and illness depends on dosage and individual susceptibility, which in this case translates to the number of litchi fruit consumed and the concentration of hypoglycaemic amino acids, as well as the children’s age and state of nourishment. Shrivastava and colleagues report that, akin to ackee, the unripe fruit of litchi has a higher concentration of hypoglycin A and its lower homologue, α-(methylenecyclopropyl) glycine; the reported absence of a signifi cant diff erence between the two probably arises from the small number of fruit samples tested (n=6 per batch of ripe and unripe fruit). Unfortunately, the study did not compare litchi-associated cases with controls drawn from the community and, strangely, cases were compared with sick controls lacking neurological disease and no history in the previous 3 months of altered mental status or seizures, and admitted to a case-surveillance hospital less than 7 days from admission of the case. That well-established data for Sapindaceae toxicity have long existed from clinical experience in Africa and the Caribbean is an important lesson for global health and neurotoxicology. A worldwide understanding of the adverse eff ects on the nervous system of both naturally occurring as well as synthetic chemicals will speed diagnosis and treatment of other mysterious epidemics of environmental brain disease. The Indian subcontinent is no stranger to the neurological eff ects of toxins in plants—eg, food dependency on the grass pea or cassava resulting in the spastic parapareses of lathyrism and cassavism, respectively. Unlike these untreatable self-limiting neurological diseases, litchi and ackee encephalopathy can be arrested by restoring serum glucose concentrations. However, some children reportedly are left with cognitive defi cits, muscle weakness, or movement disorder; the causes of which require investigation. Why is seasonal litchi encephalopathy a relatively recent event in India, Bangladesh, and Vietnam? The most plausible explanation is the rapid expansion of commercial litchi production across Asia and beyond. Indian production is second only to China’s, from where Litchi sinensis originates and its potential toxic eff ects are noted in ancient literature. Today, several Asian countries export litchi and other Sapindaceae, including rambutan (Nephelium lappaceum) and longan (Dimocarpus longan) for consumption abroad. In the USA for instance, unlike the regulated importation of canned ackee fruit, which must be screened for hypoglycin content, there are no restrictions on other members of the Soapberry family, including litchi. Fortunately, the high cost of these imported fruits and the likelihood that would be eaten in small quantities by well-nourished consumers, suggests there is little reason for concern in the USA. There is, however, cause for major concern that litchi-induced seasonal toxic hypoglycaemic Lancet Glob Health 2017