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Glutamate agonists from marine algae
Journal of Applied Phycology
Abstract
The occurrence of three glutamate agonists — glutamic acid, D-homocysteic acid and kainic acid — in a spontaneous mutant of
Palmaria palmata is reported. Glutamic acid and D-homocysteic acid, but not kainic acid, were found in the wild-type plant. The closely related
glutamate agonist, domoic acid, was found in the red alga Chondria baileyana and in the diatom Nitzschia pungens forma multiseries. In the diatom, domoic acid can build up to high levels in excess of 3% (dry wt.), making N. pungens a potential commercial source of this neuroactive amino acid. Information is also presented on the distribution, chemistry
and biological activity of neuroactive amino acids from algae, and a possible biogenic relationship among kainoid metabolites
is discussed.
... Kainic acid and domoic acid, a marine amino acid, with excitatory activity have been isolated from marine plants ( Figure 30.5) (Laycock, Freitas, and Wright 1989;Moloney 1998). They have been demonstrated to act as a glutamate receptor agonist (Laycock, Freitas, and Wright 1989). ...
... (Laycock, Freitas, and Wright 1989;Moloney 1998). They have been demonstrated to act as a glutamate receptor agonist (Laycock, Freitas, and Wright 1989). The amino acid glutamate is responsible for most of the excitatory neurotransmission in CNS (Vogensen et al. 2011). ...
... Recently, various marine plants and their constituents have been investigated for AChE inhibitory activity (Stirk, Reinecke, and van Staden 2007;Yoon et al. 2008Yoon et al. , 2009Suganthy, Karutha Pandian, AU: The reference citation 'Laycock, 1989' has been changed as 'Laycock, Freitas, and Wright 1989' and Pandima Devi 2010). The AChE inhibitory activity of 27 Korean seaweeds was screened by Yoon et al. (2009). ...
... Production of a glutamate-derived neurotoxin is common among plants, especially the algae (Laycock et al. 1989). Molecules like L-glutamic and Laspartic acid are ubiquitous among algae while γ-amino-n-butyric acid and βalanine are common in algae and higher plants (Curtis & Watkins 1961). ...
... Molecules like L-glutamic and Laspartic acid are ubiquitous among algae while γ-amino-n-butyric acid and βalanine are common in algae and higher plants (Curtis & Watkins 1961). DA is unique in that it is the most potent of the algal derived neurotoxins (Laycock et al. 1989). Another potent neurotoxin produced by a plant is β-methylamino-L-alanine or BMAA (Vega & Bell 1967). ...
... The DA molecule is created from glutamate and an isoprenoid pyrophosphate both originating from acetate, but derived by different pathways ( Fig. 1.3; Laycock et al. 1989, Pan et al. 1998, Ramsey et al. 1998. Research suggests the origin of the isoprenoid pyrophosphate is through the glyceraldehyde 3-phosphate (GAP) -pyruvate pathway while glutamate is a product of the Citric Acid cycle (Lichtenthaler et al. 1997, Ramsey et al. 1998. ...
... DA is a member of the kainoid group of neurologically active nonproteinogenic amino acids, of which kainic acid (KA) is the parent molecule (Lefebvre et al., 2002). With respect to their affinity to target glutamate receptors, kainoids share a 2,3,4trisubstituted pyrollidine core structure (Laycock, de Freitas, and Wright, 1989). ...
... This red macrophyte also produces isodomoic acids A, B, C (Maeda et al., 1986), D (Maeda et al., 1985), G, H (Zaman et al., 1997), and two analogs, domoilactones A and B (Maeda et al., (Table 8.1). Chondria baileyana (Laycock, de Freitas, and Wright, 1989), Alsidium corallinum (Impellizzeri et al., 1975), Amansia glomerata, Digenea simplex and Vidalia obtusiloba, all of which belong to the order Ceramiales, also synthesize DA, often concurrently with KA (Sato et al., 1996). ...
... Although Pseudo-nitzschia multiseries has been reported to contain >3% (dry weight) DA (Laycock, de Freitas, and Wright, 1989), some strains of reputedly toxigenic species may not always test positive for DA (Lelong et al., 2012). The same is true for certain strains of Nitzschia navis-varingica, the other DA-producing species (e.g., Romero et al., 2012). ...
Domoic acid (DA) was of no special scientific interest until a series of case studies revealed its role as the major marine neurotoxin causing amnesic shellfish poisoning (ASP). The analysis, toxicology, synthesis and degradation of the highly polar amino acid DA and its kainoid congeners are discussed in this chapter. Although DA is structurally simple and ubiquitous in contaminated food samples, it was not simple to prove that it was the causative agent of ASP in humans and of DA poisoning in carnivorous birds and mammals. Further-more, its detection and the prevention of ASP requires regular monitoring of seafood using rapid and accurate analyses. The main producers of DA are certain seasonally blooming diatoms of the genus Pseudo-nitzschia, major com-ponents of coastal phytoplankton. Here, details are provided of the species most likely to be involved in food-poisoning episodes, together with a brief account of the molecular mechanisms that underlie DA toxicity, which cause symp-toms of acute and chronic neurotoxicity. DA may attain critically toxic levels within two major food chains involving benthic filter-feeders (e.g., mussels) or planktivorous fish (e.g., anchovies). Preventive measures must be comple-mented by risk assessments of seasonal toxigenic blooms, especially in nutrient-enriched coastal areas. The major chemical and biotic factors that influence diatom bloom formation and toxigenicity are outlined. Genomics of DA production allow the development of novel molecular tools to better understand DA biosynthesis at the gene level, and the evolutionary significance of DA as a metabolite with primary and secondary characteristics.
... Kainoids are pyrrolidine dicarboxylates with excitatory and excitotoxic activities (Carcache et al., 2003). They are unusual amino acids structurally related to, and having similar functions as, glutamic and aspartic acids, both well-known neuronal excitants (agonists) or neurotransmitters (Laycock et al., 1989). Kainoids are important tools in research (Higa & Kuniyoshi, 2000) into neurophysiological disorders such as Alzheimer's and Parkinson's disease and epilepsy (Ben-Ari & Cossart, 2000; Hopkins et al., 2000; Carcache et al., 2003). ...
... Pennate marine diatoms in the genera Nitzschia, Pseudo-nitzschia and Amphora are the best known sources of domoic acid (Figure 2), the compound responsible for amnesic shellfish poisoning (Bates, 1998, 2000). Domoic acid and another kainoid, kainic acid (Figure 2), have also been isolated from the macroalgae Digenea simplex, Chondria armata, Chondria baileyana, Alsidium corallium, Amansia glomerata, Vidalia obtusiloba, Laurencia papillosa and Centroceras clavulatum (Ceramiales) (Takemoto & Daigo, 1958; Impellizzeri et al., 1975; Laycock et al., 1989; Smith & Kitts, 1994; Sato et al., 1996). A related compound, N-methyl-D,L-aspartic acid, occurs in Bryopsis plumosa, Gloiopeltis furcata, Coelothrix charoides, Ahnfeltia paradoxa, Gymnogongrus flabelliformis , Chondrus elatus and Amansia glomerata (Sato et al., 1996). ...
... Kainoids are pyrrolidine dicarboxylates with excitatory and excitotoxic activities (Carcache et al., 2003). They are unusual amino acids structurally related to, and having similar functions as, glutamic and aspartic acids, both well-known neuronal excitants (agonists) or neurotransmitters (Laycock et al., 1989). Kainoids are im-portant tools in research (Higa & Kuniyoshi, 2000) into neurophysiological disorders such as Alzheimer's and Parkinson's disease and epilepsy (Ben-Ari & Cossart, 2000; Hopkins et al., 2000; Carcache et al., 2003). ...
In the last three decades the discovery of metabolites with biological activities from macroalgae has increased significantly. However, despite the intense research effort by academic and corporate institutions, very few products with real potential have been identified or developed. Based on Silverplatter MEDLINE and Aquatic Biology, Aquaculture & Fisheries Resources databases, the literature was searched for natural products from marine macroalgae in the Rhodophyta, Phaeophyta and Chlorophyta with biological and pharmacological activity. Substances that currently receive most attention from pharmaceutical companies for use in drug development, or from researchers in the field of medicine-related research include: sulphated polysaccharides as antiviral substances, halogenated furanones from Delisea pulchra as antifouling compounds, and kahalalide F from a species of Bryopsis as a possible treatment of lung cancer, tumours and AIDS. Other substances such as macroalgal lectins, fucoidans, kainoids and aplysiatoxins are routinely used in biomedical research and a multitude of other substances have known biological activities. The potential pharmaceutical, medicinal and research applications of these compounds are discussed.
... In this chapter we will discuss several broad families of marine-derived iGluR ligands, including peptides isolated from Conus snails that target N-methyl-Daspartate (NMDA) receptors and rigid analogs of the excitatory amino acid L-glutamate that predominantly activate non-NMDA receptors, which consist of (S)-α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) and kainate receptor families. Molecules that target non- NMDA receptors include kainic acid (KA) and domoic acid (DOM), which are algal products collectively referred to as kainoids because they share a 2,3,4-trisubstituted pyrrolidine core structure (Laycock et al. 1989). The terrestrial excitotoxin acromelic acid, from the Japanese mushroom Clitocybe acromelalga, also falls into this structural class. ...
... Aqueous extracts of D. simplex were used as anthelmintics in traditional Chinese and Japanese medicine for many centuries (Nitta et al. 1958 ; Pei-Gen and Lin 1986), but the isolation and structural determination of KA as the vermicidal principle was first achieved by Takemoto in 1953 (Murakami et al. 1953; Takemoto and Daigo 1958). KA has also been isolated from other species of Ceramiales red algae such as Alsidium helmithochorton (Calaf et al. 1989), Caloglossa leprieurii (Pei-Gen and Shan-Lin 1986), Centroceras clavulatum (Impellizzeri et al. 1975), and certain variety of non-Ceramiales red algae Palmaria palmata (Laycock et al. 1989). Tank cultures of a naturally occurring " dwarf " mutant of P. palmata provided a source for isolation of KA and other excitatory amino acids such as D-homocysteic acid and glutamate (Laycock et al. 1989). ...
... KA has also been isolated from other species of Ceramiales red algae such as Alsidium helmithochorton (Calaf et al. 1989), Caloglossa leprieurii (Pei-Gen and Shan-Lin 1986), Centroceras clavulatum (Impellizzeri et al. 1975), and certain variety of non-Ceramiales red algae Palmaria palmata (Laycock et al. 1989). Tank cultures of a naturally occurring " dwarf " mutant of P. palmata provided a source for isolation of KA and other excitatory amino acids such as D-homocysteic acid and glutamate (Laycock et al. 1989). A survey of 46 marine red and green algae found KA or the structural analog domoic acid (DOM) in four and five Rhodomelaceae species, respectively. ...
Marine-derived small molecules and peptides have played a central role in elaborating pharmacological specificities and neuronal functions of mammalian ionotropic glutamate receptors (iGluRs), the primary mediators of excitatory synaptic transmission in the central nervous system (CNS). As well, the pathological sequelae elicited by one class of compounds (the kainoids) constitute a widely-used animal model for human mesial temporal lobe epilepsy (mTLE). New and existing molecules could prove useful as lead compounds for the development of therapeutics for neuropathologies that have aberrant glutamatergic signaling as a central component. In this chapter we discuss natural source origins and pharmacological activities of those marine compounds that target ionotropic glutamate receptors.
... Kainic acid has since been documented in several other seaweeds, which all belong to Rhodophyta. Palmaria palmata, dulse, has also been shown to contain kainic acid, as reported in four published studies [106,124,148,182]. A 2011 report by the National Food Institute of the Technical University of Denmark lists kainic acid as a concern for P. palmata, and points to the lack of information on the concentration of the toxin in dulse from Denmark and abroad [169]. ...
... The highest documented concentration of kainic acid at 10,000 µg g -1 in dried seaweed was found in Canadian dwarf mutant strains [182]. In regular phenotypes, the highest documented concentration was 4,000 µg g -1 in fresh Canadian P. palmata [124]. The wide variability in kainic acid concentrations has been attributed to differential genetic expression by Ramsey et al. [182], and may be influenced by environmental factors. ...
Seaweeds, i.e., marine macroalgae, have gained increasing interest as food in the Nordic countries in recent years. Greenland, geopolitically a part of Europe as a self-governing region within the Kingdom of Denmark, currently imports most if its food. Locally harvested and produced seaweed could contribute to a more sustainable food landscape, and open new possibilities for export. Seaweed is a part of the traditional Greenland Inuit diet, though not widely consumed any more. Furthermore, knowledge on the nutritional composition and possible harmful compounds of Greenlandic seaweeds is scarce.
The overall aim of this PhD study was to characterise seaweed species from Greenland re
garding their potential use as food items. The aim was therefore to determine the nutritional composition, contaminants, and anti-nutritional factors. Furthermore, the influence of anthropogenic microbial and chemical contamination was investigated. The influence of processing in the form of washing and blanching on the shelf-life of fresh seaweed was also studied. Finally, this project aimed to quantify the impact of increased local seaweed harvesting and culture in Greenland within the framework of the United Nations Sustainable Development Goals (SDGs).
The nine brown and one red seaweed species investigated had different nutritional profiles considering elemental composition (As, Ca, Cd, Cr, Cu, Fe, Hg, K, Mg, Mn, Na, Ni, P, Pb, Se and Zn), iodine, proteins, fatty acids, amino acids, antioxidants. However, they shared some similarities within groups: the fucoids (Ascophyllum nodosum, Fucus distichus and Fucus vesiculosus) and the kelps (Hedophyllum nigripes, Laminaria solidungula, Saccharina latissima and Saccharina longicruris), except for the kelp Agarum clathratum, which had a vastly different profile from the other kelps. The red seaweed Palmaria palmata also showed a different profile compared to the brown seaweeds investigated.
High iodine content was identified as an issue in all brown seaweeds, but none of the common contaminants typically associated with seaweed (arsenic, cadmium, lead, and mercury) were at concerning levels. However, due to high potassium concentrations, patients on low potassium diets would obtain a significant part of their recommended daily intake from the consumption of H. nigripes, L. solidungula or S. longicruris. Kainic acid was detected in P. palmata but was not evaluated to be a hazard.
Anthropogenic contamination was both evident in elemental profiles as well as through microbial contamination. Therefore, it is recommended to avoid harvesting close to, and downstream from, wastewater discharge into the sea.
A shelf-life study of Danish S. latissima washed or blanched in either potable or seawater
suggested a maximum refrigerated shelf-life of 7 days, stored at 3 °C. Bacterial spoilage was driven by Pseudomonas spp. and Shewanella spp. Blanching successfully increased some positive odour attributes and changed the colour of the seaweed from brown to green, making it an interesting tool for culinary experiments, and product development.
This study serves as an important contribution to the understanding of food quality and storage life in general and should be repeated with Greenlandic seaweed to validate the findings.
An increased seaweed harvest and cultivation in Greenland would most positively impact
SDGs 8 (Decent work and economic growth), 12 (Responsible consumption) and 14 (Life below water), and most negatively SDG 13 (Climate action). Reducing energy consumption and shifting to renewable energy sources for harvesting, culture and processing could mitigate some of this negative impact.
In summary, the overall evaluation of the chemical, nutritional and microbial assessment
shows that all ten species investigated are suitable for human consumption, when harvested away from contamination sources. It is therefore recommended to promote seaweed consumption through the public health program Inuuneritta III, and the SDG agenda of Greenland. The results from this project can be directly used to inform consumers about the nutritional properties of Greenlandic seaweeds, and as a basis for future research of further interesting components.
... Meanwhile, DA production in red algae is further constrained to just one family, Rhodomelaceae. After the initial discovery of DA in C. armata, further chemical studies identified potential kainoid production in other red algae, including Alsidium corallinum (10,11), Digenea simplex (12), Amansia glomerata (12), Chondria baileyana (13), and Vidalia obtusiloba (12). The ability of diatoms (Bacillariophyta) to produce DA is surprising considering no other taxa has been described to produce the neurotoxin besides Rhodophyta and Bacillariophyta, two significantly divergent clades of algae (Fig. 1A). ...
Significance
Originally isolated from the red alga Chondria armata , domoic acid (DA) is best known as a potent marine neurotoxin produced by oceanic harmful algal blooms of planktonic diatoms. Sequencing efforts to date of kainoid-producing red algae have focused exclusively on a closely related molecule, kainic acid, leaving a gap in the understanding of DA biosynthesis in red algae and its evolutionary linkage to diatoms. Here, we present the phylogenetic and biochemical investigation of DA biosynthesis in C. armata . This work demonstrates the high synteny of DA biosynthetic genes between relatively distant taxonomic groups of algae and suggests a complex evolutionary history for DA biosynthesis involving gene transfer and neofunctionalization.
... Kainate, or Kainic Acid Receptors (KAR) are the third family of ionotropic glutamate receptors, named after the receptor agonist Kainate, a neurotoxin isolated from the red algae Diagenea simplex used in epilepsy research (Laycock et al., 1989). Compared to fast excitatory signaling by AMPARs, synaptic KARs' excitatory post-synaptic currents (EPSC) possess slower decay kinetics, which make them especially well-suited for regulation of metaplasticity (via temporal and amplitude modulation of pre-to post-synaptic firing patterns) (Yang et al., 2007;Sachidhanandam et al., 2009;Castillo et al., 1997). ...
Current models of language processing do not address mechanisms at the neurotransmitter level, nor how pharmacologic agents may improve language function(s) in seemingly disparate disorders. L-Glutamate, the primary excitatory neurotransmitter in the human brain, is extensively involved in various higher cortical functions. We postulate that the physiologic role of L-Glutamate neurotransmission extends to the regulation of language access, comprehension, and production, and that disorders in glutamatergic transmission and circuitry contribute to the pathogenesis of neurodegenerative diseases and sporadic-onset language disorders such as the aphasic stroke syndromes. We start with a review of basic science data pertaining to various glutamate receptors in the CNS and ways that they may influence the physiological processes of language access and comprehension. We then focus on the dysregulation of glutamate neurotransmission in three conditions in which language dysfunction is prominent: Alzheimer’s Disease, Fragile X-associated Tremor/Ataxia Syndrome, and Aphasic Stroke Syndromes. Finally, we review the pharmacologic and electrophysiologic (event related brain potential or ERP) data pertaining to the role glutamate neurotransmission plays in language processing and disorders.
... The Corsican moss Alsidium helminthochorton [12] contains kainic acid (2), allokainic acid (6), and α-kainic acid lactone (7) (Figure 2) along with a peptide of 37 amino acids including two kainic acid residues. A mutant strain of the alga Palmaria palmata was found to produce high levels of kainic acid [13]. Chemical transformation of 2 provided several additional compounds of this series such as isokainic acid (8) [12]. ...
This review considers the results of recent studies on marine excitatory amino acids, including kainic acid, domoic acid, dysiherbaine, and neodysiherbaine A, known as potent agonists of one of subtypes of glutamate receptors, the so-called kainate receptors. Novel information, particularly concerning biosynthesis, environmental roles, biological action, and syntheses of these marine metabolites, obtained mainly in last 10–15 years, is summarized. The goal of the review was not only to discuss recently obtained data, but also to provide a brief introduction to the field of marine excitatory amino acid research.
... Canadian researchers were the first to report the presence of kainic acid ( Figure 1) in P. palmata (Laycock et al. 1989;Ramsey et al. 1994). The reported concentrations of kainic acid varied from below the limit of detection to up to 4000 µg g −1 dry weight (dw). ...
Twenty samples of the seaweed Palmaria palmata (dulse) purchased mainly from commercial internet shops on the European market were analysed by a liquid chromatograph coupled with a tandem mass spectrometer (LC-MS/MS) method for the content of kainic acid, a naturally occurring neurotoxic compound in P. palmata. Kainic acid levels in the samples ranged widely from trace levels to approximately 560 μg g⁻¹ dry weight.
... Nonetheless, P. palmata has not only the characteristic of accumulating beneficial compounds, but as any other seaweed, it can also accumulate unfavourable substances. Some strains of P. palmata also contain kainic acid, a neuroactive amino acid and secondary metabolite (Laycock et al. 1989;Ramsey et al. 1994;L€ uning 2008). Ramsey et al. (1994) found that these strains produced kainic acid in concentrations independent of environmental conditions influencing growth, such as temperature and nitrogen availability. ...
This review summarizes the recent literature on the biology, cultivation techniques and uses of the red seaweed Palmaria palmata ((Linnaeus) Weber & Mohr 1805). The paper covers its distribution, appearance and life cycle, the state of the art cultivation techniques for spore release and seeding, and the culture of meristematic fragments of fronds harvested from natural populations. Furthermore, culture conditions for P. palmata sporelings and gametophytes and set-ups of tank and open sea culture are presented. For tank culture, relatively high irradiance and frequent seawater exchange to supply carbon dioxide and nutrients are the most important parameters. In open sea culture, site selection and system design play an important role. Land-based culture has the advantage that optimum culture conditions can be applied and quality-controlled, whereas nearshore cultivation is less costly and labour intensive. In addition, the bioremediation potential and the use of P. palmata in integrated multitrophic aquaculture (IMTA) are discussed. More research is needed to investigate bioremediation potential of different P. palmata strains. Recent developments in uses of P. palmata as food supplement, source of bioactive compounds, animal feed and compound for biofuels are presented. Finally, the possibilities of cultivation of P. palmata enhance the prospects for the expansion of the cultivation of this seaweed. However, future research is needed regarding balance of culture conditions, costs and biomass in land-based tank culture and in terms of site selection, system design, maintenance and harvest techniques in sea cultivation to establish a commercialization of the aquaculture of this species in Europe.
... Thus, the mechanism of action of domoic acid occurs on excitatory amino acid receptors and on synaptic transmission. The domoic acid is therefore, considered an excitatory amino acid, a neurotransmitter and a neurotoxin to the central nervous system and it operates similarly to the structurally similar compounds to the kainic acid (Hampson & Wenthold 1988;Laycock et al. 1989). The CA1 and CA3 areas of the hippocampus, liable for learning and memory processing, are particularly susceptible (Ramsdell & Gulland 2014). ...
Several marine microalgae produce dangerous toxins very damaging to human health, aquatic ecosystems and coastal resources. These Harmful Algal Blooms (HABs) in recent decades seem greatly increased regarding frequency, severity and biogeographical level, causing serious health risks as a consequence of the consumption of contaminated seafood. Toxins can cause various clinically described syndromes, characterised by a wide range of symptoms: amnesic (ASP), diarrhoetic (DSP), azaspirazid (AZP), neurotoxic (NSP) and paralytic (PSP) shellfish poisonings and ciguatera fish poisoning. The spread of HABs is probably a result of anthropogenic activities and climate change, that influence marine planktonic systems, including global warming, habitat modification, eutrophication and growth of exogenous species in response to human pressures. HABs are a worldwide matter that requests local solutions and international cooperation. This review supplies an overview of HAB phenomena, and, in particular, we describe the major consequences of HABs on human health.
... DOM has been isolated from the rhodophyte Alsidium corallinum on the coast of Sicily [13], and Chondria baileyana in Nova Scotia and Prince Edward Island (PEI), Canada [64]. It is further identified in Amansia glomerata, Digenea simplex, and Vidalia obtusiloba that belong to the family Rhodomelaecae [65]. ...
Domoic acid is a potent neurotoxin, glutamate agonist and natural marine biotoxin. It is produced by several diatom algal species of genetically diverse genus Pseudo-nitzschia, red alga Chondria armata and other related species. Historically, widespread domoic acid intoxication incidents have occurred globally. Particularly, in 1987, domoic acid caused an outbreak of human poisoning in Canada by the consumption of contaminated blue mussels (Mytilus edulis) that gave rise to countless clinical illnesses and human deaths. The toxin targets glutamate receptors present in various vital organs and a cascade of ailments characterized the poisoning. The specifically listed neural disorders include memory impairment, coma, recurrent seizures, and epilepsy that led to the name amnesic shellfish poisoning. The occurrence of domoic acid in test samples has been determined by various novel techniques such as liquid chromatography-mass spectrometry, biosensors, enzyme-linked immunosorbent assay and other related hi-tech detection methods. Since the Canada incident, the toxin has intoxicated several marine mammals, sea birds, and contaminated colonized coastal waters around the globe. Subsequently, domoic acid producing algal blooms are accelerating frequently worldwide. Therefore, it poses a global health, safety threat and exposure risks to a significant number of marine and human lives. Genetics of domoic acid producing algal species, molecular markers and therapeutics are currently least known. Therefore, the present review addresses intriguing attributes of domoic acid, such as physicochemical, pharmacological and biological features, sources, and genetic diversity of the producers. In addition, exposure risks including toxicologic pathology of domoic acid poisoning, neurotoxic pathways, detection methods and therapeutics have been inclusively discussed.
... by epilepsy and abnormal behaviour lJsting long after the initial exposure (Goldstein et al. 2008) and is a result of lasting da1nage in the CNS and the progressive and cumulative effect~ from seizure propagation (Goldstein et al. 2008). Damage to the CNS occurs because DA acts as a glutamate Jgonist, the normal neuroexcitatory ligand for glutamate receptors in the vertebrate CNS (Laycock et al. 1989). DA has J higher binding affinity than glutmnate, and overstimulation of glutamate receptors by DA causes neuronal injury primarily via N-methyl-d-aspartate (NMDA) receptors, which are activated secondarily as a consequence of alpha-amino-3-hydroxyl-5-methyl-4-isox-azole propionate (AMPA) receptor over excitation by DA resulting in stereotypic lesions in specific brain regions (Berman and Murray 1997). ...
... DA is an excitatory amino acid derivative, a neurotoxin and a neurotransmitter in the central nervous system (CNS), in a manner analogous to the structurally related compound, kainic acid (Hampson and Wenthold, 1988;Laycock et al., 1989). DA is 2-3 times more potent neuroexcitator than kainic acid, and up to 100 times more potent than glutamic acid (Biscoe et al., 1975(Biscoe et al., , 1976Coyle, 1983;Debonnel et al., 1989;Olney, 1990). ...
... The neurotoxic effect of kainic acid is caused by a binding of kainic acid to certain non-NMDA ionotropic kainic receptors that are involved in excitatory neurotransmission and synaptic plasticity (Swanson and Sakai 2009). Due to its structural similarity to the neurotransmitter glutamate, kainic acid is a potent glutamate agonist (Nadler 1979;Laycock et al. 1989). Kainic acid in large doses is known to exhibit neurotoxic effects possibly leading to brain damage (Lothman and Collins 1981;Nadler et al. 1981;Coyle 1983;Strain and Tasker 1991). ...
The red seaweed dulse (Palmaria palmata) is one of the more popular seaweed species for human consumption in the Western world. With a documented historical use up to present days in Ireland, Brittany (France), Iceland, Maine (USA), and Nova Scotia (Canada), it has remained a snack, a food supplement, and an ingredient in various dishes. The trend towards more healthy and basic foodstuffs, together with an increasing interest among chefs for the seaweed cuisine, has posed the need for more quantitative knowledge about the chemical composition of dulse of relevance for human consumption. Here, we report on data for amino acid composition, fatty acid profile, vitamin K, iodine, kainic acid, inorganic arsenic, as well as for various heavy metals in samples from Denmark, Iceland, and Maine.
... The other precursor, drawn from a different pool, is thought to be an isoprenoid unit, geranyl pyrophosphate. Assembly of the proline ring portion of the DA molecule is then believed to occur by condensation of the activated glutamate derivative with the isoprenoid chain, consistent with the pathway proposed by Laycock et al. (1989). The differences in the level of acetate incorporation into the two key biosynthetic intermediates indicate they are drawn from different acetate pools, though it is also possible that the isoprenoid portion is principally derived from an alternate pathway involving a different primar precursor (J.L.C. ...
... t the enhanced production of DA in our experiments only occurs at initially high, potentially toxic levels of ammonium. This was observed for ammonium concentrations at or exceeding 220 jJ.M. It is possible that ammonium toxicity may redirect some intracellular glutamate from the pathway of "normal" amino acid synthesis to that of DA synthesis (cf. Laycock et al. 1989;), perhaps as a response to detoxify intracellular ammonium. The increased production of DA at high concentrations of ammonium may thus be a useful tool for studying the biosynthesis of this toxin. It is not possible to extrapolate results of this laboratory study to a field situation because of differences in the concentrations of both ...
Four clones of Nitzschia pungens f. multiseries (toxin-producing form) and two of N. pungens f. pungens (nontoxic) were grown in batch culture at initial nitrogen concentrations of 55, 110, 220, 440, and 880 μM in the form of either nitrate or ammonium. As expected, only N. pungens f. multiseries clones produced the neurotoxin, domoic acid (DA). Ammonium at 880 μM prevented the growth of all N. pungens clones but not of Skeletonema costatum, although division rate was reduced. At 440 μM, ammonium lowered the cell yield obtained during the stationary phase, inhibited photosynthesis, and caused a lag phase during which DA was produced (by f. multiseries). At 220 and 440 μM ammonium, in contrast with the same concentrations of nitrate, stationary phase cellular DA production was enhanced by two- to fourfold. At 110 and 55 μM nitrogen, cell yield and DA production were equivalent for nitrate and ammonium but less DA was produced relative to the higher nitrogen concentrations, possibly due to nitrogen depletion. Enhanced production of DA at elevated ammonium concentrations may be a response to ammonia toxicity. This could be a useful tool for studying mechanisms of DA production and for maximizing the yield of this valuable toxin in large-scale cultures.
... This nitro-gen is involved in the synthesis of amino acids (e.g. glutamate), which may then be used for domoic acid production (Laycock et al. 1989). Extracellular nitrogen, rather than previously stored nitrogenous organic compounds, thus appears to be the primary nitrogen source for domoic acid production. ...
Nitzschia pungens f. multiseries (clone NPARL) was grown in nonaxenic batch culture under a range of growth conditions. Domoic acid (DA) was not detected during exponential growth, but production promptly started at a rate of approximately 1 pg DA∙cell−1∙d−1 at the onset of the stationary phase, in this case induced by silicate limitation. Cellular DA reached a maximum of 7 pg∙cell−1; thereafter, DA production continued at the same rate, with cellular levels remaining relatively constant due to concurrent release of DA into the culture medium. DA production ceased in the absence of nitrogen during the stationary phase, but resumed when nitrate was added back to the medium. Low irradiance slowed the division rate and consequently delayed the attainment of the stationary phase, but DA production rates were comparable with the control once stationary phase was reached. Cells during the dark period of a light–dark cycle, or placed into darkness, or in the presence of the photosynthetic inhibitor DCMU promptly ceased DA production. We conclude that at least three conditions are required for DA production by clone NPARL: cessation of cell division, availability of nitrogen during the stationary phase, and the presence of light. Growth in medium f/2 fulfils these requirements.
... Genetic isolation probably also occurs in the freeliving forma aegagropila of F. lumbricalis, which reproduces only vegetatively (Bird, Saunders & McLachlan, 1991), and may occur in free-living populations of A.plicata as well (Norton & Mathieson 1981). In P. palmata, dwarf mutants have been observed to differ chemically as well as morphologically from normal populations (Laycock et al., 1989; Laycock & Bird, unpubl. ), signifying probable genetic divergence that may be maintained by the apparent sterility of such forms (Bird, unpubl.) . ...
18S rRNA gene sequences are presented for Ahnfeltia plicata, Chondrus crispus, Furcellaria lumbricalis and Palmaria palmata, commercially important marine algae of the North Atlantic. The sequences range from 1765 to 1777 nucleotides in length, with guanine + cytosine content of 50.1% to 52.4%. Sequence divergence between species in different orders was 11.3–12.3%, whereas the variation between C. crispus and F. lumbricalis, both from the Gigartinales, was only 3.6%. Based on limited experience with other groups of Rhodophyta, these sequences obtained from single populations are likely to be representative of the species as a whole, with little variation expected among conspecifics regardless of morphological aberration or apparent genetic isolation.
... Caulerpenyne is a sesquiterpene isolated form marine alga Caulerpa taxifolia and has shown antiproliferative activity in human neuroblastoma cell lines, as well as cytotoxic effect in several cell lines (Helms et al., 1988). Red alga Amphiroa zonata has shown the presence of palmitic acid, which has shown antitumor activity in both in vivo and ex vivo (Laycock et al., 1989). Nostoc a cyanobacterium is known to produce cryptophycine which is a depsipeptide, which can bind to microtubule end at vinca binding site to exhibit antimitotic activity (Morton and Bomber 1994). ...
Production of the neurotoxin domoic acid (DA) by benthic diatom Nitzschia navis-varingica poses considerable health and economic concerns. In this study, we employed whole genome sequencing and transcriptomic analyses of regionally distinct N. navis-varingica strains to unravel the genomic underpinnings of DA biosynthesis. Our analyses revealed sizable genomes—characterized by an abundance of repetitive elements and noncoding DNA—that exceed the size of any other pennate diatoms. Central to our findings is the discovery of an expanded domoic acid biosynthesis ( dab ) gene cluster, spanning over 60 kb and marked by a unique organization that includes core genes interspersed with additional genetic elements. Phylogenetic and syntenic comparisons indicate that transposition events may have driven the expansion and reorganization of this cluster. Biochemical assays validated that the kainoid synthase encoded by dabC catalyzes the formation of isodomoic acid B, thereby establishing a distinct chemotype in contrast to the DA profiles of planktonic diatoms. These results highlight the evolutionary trajectory of DA biosynthesis in diatoms and potential advantages conferred by genome expansion and enzyme diversification in dynamic marine environments.
IMPORTANCE
Domoic acid (DA) is a potent neurotoxin produced by marine micro- and macroalgae problematic to fisheries and toxic to humans and animals. Our study elucidates the molecular mechanisms underlying DA production in the widespread Western Pacific benthic diatom, Nitzschia navis-varingica . Genomic and biochemical insights add information to our understanding of the evolution of toxin production across diverse phyla and also fill a gap in the knowledge of secondary metabolism in marine diatoms. These findings provide a genetic framework for identifying toxin production and its impacts in the benthos of vulnerable, coastal ecosystems.
This work purpose a contribution to the study of toxic diatoms from the genus Pseudo-nitzschia sp. , responsibles for shellfish contaminations by ASP (Amnesic Shellfish Poisoning). Influence of silicium and nitrogen nutriments on growth and toxinic production by tree species – P. Multiseries, P. Australis et P. Pungens – has been studied. Chemical synthesis of ASP toxinic analogues has been investigated too, in order to develop new biocaptors. Experiments on silicium showed that this element influenced the intracellular toxins content, but was not directly implicated in this toxinic production. New organic nitrogen species assimilated by P. Multiseries and P. Australis has been identified, showing a negative correlation between growth rate and toxins production. Diversity of physiological responses showed an high intra- and interspecific variation by Pseudo-nitzschia sp. Toxins production dynamics showed a possible production of domoic acid during growth phase. Studies on continuous cultures on P. Multiseries and P. Pungens indicated an higher toxinic production at steady state in presence of urea and nitrates. Theses results gaves clues to a significative influence of organic nitrogen in situ (anthropic or natural) on Pseudo-nitzschia bloomings
The chapter deals with paralytic shellfish poisoning (PSP), neurotoxic shellfish poisoning (NSP), ciguatera, diarrhetic shellfish poisoning (DSP) and other miscellaneous toxins. The origin, chemistry, properties and mode of action of saxitoxin, neosaxitoxin, gonyautoxins I–VIII, tetrodotoxins and its congeners; brevetoxin-A and brevetoxin-B, ciguatoxin and its congeners; maitotoxin, palytoxin and its congeners, okadaic acid and its congeners; pectenotoxins, yessotoxin, amphidinolides, amphidinol, proprocentrolide, neosurugatoxin, surugatoxin and prosurugatoxin; goniodomin-A, polycavenoside-A, toxic substances of Chondria armata, aplysiatoxin, debromoaplysiatoxin, toxic peptides, nodularin and microcystin, lyngbyatoxin-A, and isodysiden have been discussed. Transfer of toxins between organisms and methods of detection of paralytic shellfish toxins have also been discussed.
Domoic acid (DA) is classified as a potent neurotoxin, an excitatory amino acid naturally produced by several diatom species belonging to the genus Pseudo-nitzschia. The molecule is excitotoxic in the vertebrate central nervous system, myocardium and other organs that contain glutamate receptors. The biggest risk of DA exposure for humans comes from the consumption of DA-contaminated shellfish. Algal blooms, including diatom blooms, are an excellent source of biomass for filter-feeding marine organisms, which makes the knowledge of DA occurrence quite relevant. In recent years, DA exposure has become more widespread due to the higher prevalence of toxigenic Pseudo-nitzschia blooms and increased human consumption of seafood. There is therefore an urgent need to update frequently the latest information on DA. Symptoms of having consumed high doses of DA are known but there are still significant gaps in knowledge of the health effects of chronic exposure to low levels of DA as well as of effective methods for removing DA from shellfish tissues. Here we summarize current knowledge about DA: its structure and biological activity, degradation in seawater, ecological and physiological roles, new producers, and risks of human exposure to high and low concentrations of this toxin.
In most maritime countries, the seafood industry is an important source of revenue and accounts for a significant portion of the country's food supply. However, certain seafood, in particular shellfish, may become contaminated with naturally occurring toxins. The existence of shellfish toxins has been known for centuries and early attempts to deal with this threat led to the creation of folklore rituals and religious customs among tribal and ethnic groups. Eventually it was found that these toxins are produced by microbial organisms, usually phytoplankton, that occur naturally in the ocean. In Canada, as well as other countries with cold or temperate coastal waters, three groups of toxins are of particular importance and these are the paralytic shellfish poisoning (PSP) toxins, the diarrhetic shellfish poisoning (DSP) toxins and amnesic shellfish poisoning (ASP) toxin. Since it is virtually impossible to prevent the occurrence of these toxins, the approach in modern times has been to monitor seafood for the presence or absence of toxins using a standardized mouse bioassay. However, not all toxins can be detected effectively by this method and there is a trend in several countries to dispense with the mouse bioassay. Furthermore, there are differences between countries as to the preferred method of sampling and analysis and there is not agreement between all countries concerning tolerance levels of the various toxins in seafood. These difficulties, the occurrence of new toxins, and the rapid expansion of the shellfish aquaculture industry have put considerable pressure upon the scientific community to develop new methods of coping with these toxins, including more sensitive chemical or biochemical assays that are rapid and inexpensive. The possibilities and options for coping with these ubiquitous toxins are presented and discussed.
Labelling experiments with [1-13C]acetate and [1,2-13C]acetate provide evidence that the neurotoxin domoic acid, produced by the diatom Nitzschia pungens, is derived by the novel condensation of a geranyl unit with an activated citric acid cycle derivative and subsequent cyclisation to form a proline ring system.
Marine Toxins: An Overview.- Conotoxins: Molecular and Therapeutic Targets.- Sodium Channel Inhibiting Marine Toxins.- Sea Anemone Toxins Affecting Potassium Channels.- Ligands for Ionotropic Glutamate Receptors.- Marine Toxins Potently Affecting Neurotransmitter Release.- Toxins Affecting Actin Filaments and Microtubules.- Carcinogenic Aspects of Protein Phosphatase 1 and 2A Inhibitors.
This chapter describes recent advances in the field of marine biosynthesis. The literature from 1991 - 1997 has been reviewed and organized phylogenetically. In addition to presenting the results of studies directed at elucidating the biosynthetic origin of marine natural products, recent experiments directed at identifying the organism responsible for an observed biosynthetic transformation in host-symbiont associations are also discussed. Further, the utility of cultured marine bacteria and enzyme preparations of macroorganisms as a tool to conduct precursor-directed biosynthesis is emerging and is discussed herein. The techniques used for the administration of labeled precursors varies widely between phyla and individual methods employed for each group of organisms is presented.
A single strain of Pseudo-nitzschia multiseries was grown axenically and in parallel cultures to which selected bacterial species isolated previously from P. multiseries cultures were added (non-axenic culture), an Alteromonas sp. (a producer of gluconic acid/gluconolactone when grown with glucose) and a Moraxella sp. (a non-producer of gluconic acid/gluconolactone). When gluconic acid/gluconolactone was added to the axenic culture the production of domoic acid was increased to double that produced by the non-axenic culture. The effect of the gluconic acid/gluconolactone on domoic acid production was concentration dependent and could be offset completely by the addition of glutamic acid or proline to cultures containing gluconic acid/gluconolactone. Domoic acid, depending upon culture conditions, was partitioned in varying percentages between the diatom cells and the culture filtrates. It is suggested that the enhancement of the algal production of domoic acid in the presence of specific bacteria could be influenced by production of gluconic acid/gluconolactone by bacteria; this effect may be a direct result of the antagonistic effect of the powerful sequestering properties of gluconic acid which, through tying up nutrients, induces the diatom to produce a counter chelating agent, domoic acid.
Production of domoic acid (DA) by the pennate diatom Pseudo-nitzschia multiseries is
associated with physiological stress caused by silicate (Si) and/or phosphate (P) limitation. Such limitation
may promote DA synthesis by (1) reducing primary metabolic activity, thus making available necessary
precursors, high energy compounds, and cofactors, and (2) favoring the expression of genes involved in
the biosynthesis of this toxin. In the case of Si and P-limitation, DNA synthesis and the progression through
the cell division cycle are slowed, perhaps prolonging or arresting the cells in the stage of the division cycle
which is most conducive to DA production. However, N-limitation results in an insuf®cient pool of cellular
free N, which restricts synthesis of this nitrogenous toxin. A continuous supply of photophosphorylated
high-energy intermediates (e.g., ATP and NADPH) is necessary for DA synthesis. In order to better
understand the mechanism(s) of DA production, more studies are needed to elucidate: (1) the details of
the biosynthetic pathway, (2) the regulation of enzymes involved in the pathway, (3) the relation between
DA synthesis and the cell division cycle, (4) the cellular compartmentalization of DA biosynthesis, and (5)
other environmental factors that may trigger DA production. Finally, these studies should be extended to
include toxigenic Pseudo-nitzschia species other than P. multiseries, to con®rm the commonality of these
mechanisms.
The diatom species Pseudonitzschia australis Frenguelli has been implicated as the source of the domoic acid that contaminated anchovy species in Monterey Bay, California, during 1991. In other geographic areas, as well as in laboratory cultures of isolates obtained from various geographic areas, other Pseudonitzschia species have been shown to produce domoic acid. The stomach contents of anchovies caught in Monterey Bay during the following summer were analyzed to identify and determine the abundance of each of the Pseudonitzschia species present. Pseudonitzschia species present in net-tow samples taken at the same time from Monterey Bay were also recorded. In the stomach samples, nine different Pseudonitzschia species were found, including four that have produced domoic acid either under natural or laboratory conditions. These findings illustrate the risk of possible neurotoxin accumulation inherent in the diets of the anchovies studied. The planktophagous diet of the anchovies reflected the plankton composition of the surrounding water and also demonstrates the anchovies' ability to filter pennate diatoms from the near-surface seawater.
The solubility of domoic acid (DA) in H2O and D2O, in aqueous NaCl solution and in several non-aqueous solvents was measured by NMR and UV spectroscopies. The solubility in water is comparable with that of aminoacids such as glutamic acid and aspartic acid. It is markedly pH-dependent, passing through a minimum at the isoelectric point, the increase towards both higher and lower pH values indicating that the anionic and cationic forms are more soluble than the neutral form. The effect of NaCl on the solubility of DA in water is negligible. The solubility of DA in alcohols is lower than in water but it is much higher than the solubility of glutamic acid or aspartic acid. The octanol–water partition coefficient for DA at pH 5.32, Kow = 0.0037, was obtained by a direct UV measurement. The low value of Kow indicates that aquatic organisms cannot take up DA directly from the water and bioaccumulation may proceed only through dietary intake. Key words: solubility of domoic acid, NMR of domoic acid, UV spectra of domoic acid, octanol–water partition coefficient of domoic acid.
Marine algae of economic importance encompass species of positive value, such as seaweeds harvested for food or hydrocolloid extractives, and species with negative effect, such as toxic phytoplankton or nuisance macrophytes. Only a small part of the global algal resource is obtained in Canada, and the overall benefit to the nation's economy is relatively minor, but there exists the potential for further development of useful species. On the other hand, the negative effects of toxic microalgae are increasing, in the form of losses to the shellfish fishery and aquaculture industry and the cost of providing toxicity-testing and phytoplankton-monitoring services. It is obvious that effective utilization of valuable algae, or defense against undesirable ones, must be attended by sound taxonomy to ensure that algae of interest are correctly identified and recognizable. However, the algae present particular problems to systematists, a major one being the variety of life histories, which may involve independent and conspicuous dissimilar phases. In addition, many algae are phenotypically highly variable in response to environment, which is often insufficiently appreciated. The converse situation also exists, in that morphologically similar species are sometimes regarded as a single entity. Algal taxonomists should strive to determine which variations are genetic and therefore taxonomically significant. To illustrate these points, we review recent taxonomic studies on some algal genera of present or potential economic importance in Canada. Key words: marine algae, systematics, economic potential, variability, genetics.
Marine organisms have long been recognized as rich source of bioactive material with numerous health benefit effects. Among bioactive material, proteins and peptides derived from marine organisms have been shown to inhibit the development of neuro-degenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The neuro-protective action of protein and peptide seem to be mediated through direct interaction of absorb protein and peptide with a numerous of cellular and molecular targets with enzyme/ion channels. This contribution presents an overview of marine proteins and peptides neuro-protective effect and their potential application in neuro-protection.
Chemistry of marine toxins implicated in seafood poisoning is reviewed. Chemical structure and mode of action are described. Abundant bibliographical information is also provided.
Upon enrichment with lithium 385.6 μM Li, culture of Pseudo-nitzschia multiseries Hasle produces substantially higher level of the neurotoxin domoic acid DA 230 fg · cell-1 than the control 135 fg · cell-1. We hypothesize that in Cardigan Bay, where the first domoic acid episode was reported, high levels of Li could have originated via a massive freshwater run-off involving an adjacent dump. Lithium enrichment may have played a part in enhancing DA production leading to the intoxication episodes of 1987. Thus, anthropogenic activities may play a role as a sustainer of algal blooms and should be included in habitat management considerations involving coastal and inshore algal blooms, both toxigenic and non-toxigenic.
Phytoestrogens are naturally occurring plant compounds which have oestrogenic and/or anti-oestrogenic activity. They are present in many human foodstuffs including beans, sprouts, cabbage, spinach, soyabean, grains and hops. The main classes are the isoflavones, coumestans and lignans. This review assesses the evidence that these substances may have adverse and/or beneficial impacts on the risk of several hormone-dependent diseases in humans. Evidence from studies of various animal species has demonstrated that ingestion of high levels of phytoestrogens can produce adverse effects on reproductive endpoints including fertility. Studies in laboratory animals have also shown that exposure to high doses of phytoestrogens during development can adversely affect brain differentiation and reproductive development in rodents, but may also have possible beneficial effects. In humans, there is a lack of information concerning the possible effects of high doses of phytoestrogens in infants and this should be addressed as a matter of priority so that any risks (or benefits) can be established. In adults, no current data exist to suggest that consumption of phytoestrogens at the levels normally encountered in the diet is likely to be harmful. Epidemiological studies suggest that foodstuffs containing phytoestrogens may have a beneficial role in protecting against a number of chronic diseases and conditions. For cancer of the prostate, colon, rectum, stomach and lung, the evidence is most consistent for a protective effect resulting from a high intake of grains, legumes, fruits and vegetables; it is not possible to identify particular food types or components that may be responsible. Dietary intervention studies indicate that in women soya and linseed may have beneficial effects on the risk of breast cancer and may help to alleviate postmenopausal symptoms. For osteoporosis, tentative evidence suggests phytoestrogens may have similar effects in maintaining bone density to those of the related pharmaceutical compound ipriflavone. Soya also appears to have beneficial effects on blood lipids which may help to reduce the risk of cardiovascular disease and atherosclerosis. Generally, however, little evidence exists to link these effects directly to phytoestrogens; many other components of soya and linseed are biologically active in various experimental systems and may be responsible for the observed effects in humans. It is concluded that dietary phytoestrogens may have a role in the prevention of several types of chronic disease including certain cancers. However, at present the evidence is not sufficient to recommend particular dietary practices or changes. Encouraging findings from laboratory and clinical studies indicate the need for further research to clarify the biological activities of phytoestrogens in humans. Copyright © 1998 John Wiley & Sons, Ltd.
In the last decade the screening of microalgae, especially the cyanobacteria (blue-green algae), for antibiotics and pharmacologically
active compounds has received ever increasing interest. A large number of antibiotic compounds, many with novel structures,
have been isolated and characterised. Similarly many cyanobacteria have been shown to produce antiviral and antineoplastic
compounds. A range of pharmacological activities have also been observed with extracts of microalgae, however the active principles
are as yet unknown in most cases. Several of the bioactive compounds may find application in human or veterinary medicine
or in agriculture. Others should find application as research tools or as structural models for the development of new drugs.
The microalgae are particularly attractive as natural sources of bioactive molecules since these algae have the potential
to produce these compounds in culture which enables the production of structurally complex molecules which are difficult or
impossible to produce by chemical synthesis.
In the past five years, awareness of domoic acid has increased from localized problems in Canada to outbreaks along both North American coasts. The phycotoxin domoic acid causes Amnesic Shellfish Poisoning (ASP) in humans and can be fatal. The known species of phytoplankton responsible for production of domoic acid include some pennate diatom species of the genus Nitzschia, sensu latu, which form stepped chains typical of the Pseudonitzschia. These diatoms are widely distributed, but their life histories and population dynamics are poorly understood. This review addresses histories of occurrences, morphology, geographical distributions, seasonal patterns, growth requirements, domoic acid production, and trophic interactions, with emphasis on a comparison of Pseudonitzschia pungens f. multiseries (Hasle) Hasle and Pseudonitzschia australis Frenguelli. Through continued research it will become possible to provide guidelines for regulatory agencies that protect both the consumer and the seafood industry.
Domoic acid is a potent neurotoxin that is naturally produced by several diatom species of the genus Pseudo-nitzschia. The toxin acts as a glutamate agonist and is excitotoxic in the vertebrate central nervous system and other glutamate receptor-rich organs. Human exposure to domoic acid occurs via the consumption of contaminated shellfish that have accumulated the toxin while filter feeding on toxigenic phytoplankton during blooms. The first reported human domoic acid poisoning event occurred in Canada in 1987 during which clinical signs of acute toxicity such as gastrointestinal distress, confusion, disorientation, memory loss, coma and death were observed. The illness was named amnesic shellfish poisoning (ASP) and due to effective seafood monitoring programs there have been no documented ASP cases since 1987. However, domoic acid poisoning has a significant effect on marine wildlife and multiple poisoning events have occurred in marine birds and mammals over the last few decades. Currently, domoic acid producing diatom blooms are thought to be increasing in frequency world wide, posing an increasing threat to wildlife and human health. Of particular concern are the potential impacts of long-term low-level exposure in “at risk” human populations. The impacts of repetitive low-level domoic acid exposure are currently unknown. This review provides a basic description of the mechanism of action of domoic acid as well as a synthesis of information pertaining to domoic acid exposure routes, toxin susceptibility, and the importance of effective monitoring programs. The importance of investigating the potential human health impacts of long-term low-level domoic acid exposure in “at risk” human populations is also discussed.
Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is one of the more common forms of chronic epilepsy. Its aetiology is unknown, though an early developmental insult is thought by some to be an important trigger. There is not a strong genetic predisposition; gene–environment interactions are more significant considerations. Environmental risk factors for TLE-HS are under-researched. Domoic acid (DA) is an environmental neurotoxin of algal origin that can contaminate marine food webs. DA can cross the placenta, is significantly more toxic to the developing brain compared to the adult brain, and has affected humans and marine wildlife through mass poisonings. DA coincidentally has a decades-long history of use as a chemical model of temporal lobe epilepsy, along with its close structural analogue kainic acid (also of algal origin). The principal hypothesis presented here is that dietary exposure to doses of DA that are sub-clinical in pregnant women may be sufficient to damage the foetal hippocampus and initiate epileptogenesis. The hypothesis could be tested both experimentally by in vivo proof-of-concept animal studies that expand on current knowledge of prenatal susceptibility to DA neurotoxicity, and by epidemiological investigations directed towards dietary exposure to marine food products. If only a small proportion of the attributable risk for TLE-HS is found to be due to gestational exposure to DA, the public health implications would still be of great significance, as this would represent a potentially preventable exposure.
We have determined the inhibitory potencies of domoic acid and a series of derivatives of domoic acid at kainic acid and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) binding sites in rat forebrain membranes. These derivatives of domoic acid differed in the configuration, stereochemistry, and degree of saturation of the side chain attached to C-4 of the prolyl ring. The binding data were analyzed in terms of one or two classes of sites as appropriate. Domoic acid and kainic acid displayed similar inhibition constants at [3H]kainic acid sites (IC50 = 5 and 7 nM, respectively). At both kainic acid and AMPA binding sites, all of the compounds tested were less potent than domoic acid itself. At high affinity [3H]kainic acid sites, the derivatives could be categorized into two groups; those with nanomolar affinity and those with micromolar affinity. All members of the former group possessed a side chain with the first double bond intact and in the Z (cis) configuration. The more distal atoms present in the extended side chain of domoic acid did not appear to contribute to the high affinity interaction with the kainic acid receptor. Although all the compounds tested were weaker inhibitors of [3H]AMPA binding compared to [3H]kainic acid binding, there was a high correlation between the rank order of potency of the seven domoic acid derivatives at [3H]kainic acid and at [3H]AMPA binding sites. The inhibition data for kainic acid at [3H]AMPA binding sites were described adequately in terms of a 1-site model, whereas the data for domoic acid required two classes of sites.(ABSTRACT TRUNCATED AT 250 WORDS)
Marine organisms represent an enormous, essentially unexploited, resource of natural products. Globally, the race to develop marine-derived drugs is well under way with many pharmaceutical companies positioning themselves to reap large profits by the exploitation of the ocean's rich chemical diversity. Targeted strategies, often in combination with high-throughput screening, are being employed in this hunt for novel pharmacotherapeutic agents. David de Vries and Phil Beart examine the potential, problems and technologies of an international pharmaceutical search that has important ethical considerations.
The distribution of kainic acid among various red algae was investigated. Analysis of free amino acids from different populations of Palmaria palmata showed that some were unable to accumulate kainic acid to detectable concentrations, whereas in two dwarf mutants it was a major component of the free amino acid composition. The amino acid profiles were also examined for unknown amino acids in the search for possible intermediates in kainic acid biosynthesis. The only unknown amino acid present in P. palmata extracts was isolated and identified by NMR spectroscopy as 1'-hydroxykainic acid. This compound was found in all samples that contained kainic acid. To investigate the effect of growth conditions on kainic acid production different strains of P. palmata were grown at 5, 10, and 15 degrees C with or without added nitrate. No effect on production was observed, suggesting that the growth conditions in these experiments do not affect the level of gene expression in the pathway of kainic acid biosynthesis. Furthermore, changing the growth conditions did not induce synthesis of kainic acid in the non-producing strains of Palmariales.
Occurrence of secondary metabolites in microalgae (protoctista) is discussed with respect to the phylogenic or taxonomic relationships of organisms. Biosynthetic mechanisms of certain metabolites such as paralytic shellfish poisoning toxins and polyether toxins are also discussed, and genetic aspects of the secondary metabolite production as well.
The causative agent of toxicity in cultured mussels from a localized area of eastern Prince Edward Island has been identified as domoic acid, a neuroexcitatory amino acid. The toxin was isolated by a number of different bioassay-directed separation techniques including high-performance liquid chromatography, high-voltage paper electrophoresis, and ion-exchange chromatography, and characterized by a number of spectroscopic techniques including ultraviolet, infrared, mass spectrometry, and nuclear magnetic resonance. The isolation and purification methods are described in detail and some new analytical data for domoic acid are reported. Keywords: shellfish toxin, domoic acid, neurotoxin, bioassay-directed analysis.
An outbreak of shellfish poisoning in Canada during November, 1987, was traced to cultured blue mussels (Mytilus edulis L.) from the Cardigan River region of eastern Prince Edward Island (P.E.I.). The shellfish toxin, identified as domoic acid, has not previously been found in any shellfish and this outbreak represents the first known occurrence of human poisoning from this neurotoxin. In this report we document the occurrence and distribution of toxic mussels in inshore waters of P.E.I. We relate this to the spatial and temporal abundance of macrophytes and phytoplankton and to their level of contamination by domoic acid. Our analysis of the relationship between these data sets has led us to conclude that the pennate diatom, Nitzschia pungens f. multiseries, was the major source of the domoic acid contained in the digestive glands of toxic mussels from the Cardigan River region of eastern P.E.I.
During late 1987, an outbreak of poisoning resulting from the ingestion of cultivated blue mussels (Mytilus edulis) from a localized area in eastern Canada (Cardigan Bay, Prince Edward Island) was associated with massive blooms of Nitzschia pungens, a widely distributed diatom not previously known to produce toxins; human fatalities resulted. Here we provide proof that the causative agent, domoic acid, is indeed produced by this diatom. Although no domoic acid could be detected (<2 ng∙mL−1) in culture medium (FE) prepared from Cardigan River water, it was found in cultures of Nitzschia pungens grown in this medium at concentrations ranging from 0.03 to 0.8 pg∙cell−1 in various separate cultures harvested for chemical analysis 7–68 d after inoculation.
There is convincing evidence that acidic amino acids, in particular L-glutamate, or substances containing them serve as the major excitatory neurotransmitters in the brain. At least three distinct receptors mediate the excitatory effects of this class of neurotransmitters. Pharmacological studies with agonists and antagonists of these receptors suggest that they may mediate the neurodegenerative consequences of Huntington's disease, status epilepticus, and hypoxemia, and that glutamate receptor antagonists have clinical potential as anticonvulsants, analgesics, and neuroprotective agents.
Clinical tests revealed that the decoction of Chondria armata (KÜTZING) OKAMURA (Rhodomelaceae) had a marked anthelmintic action and further examinations were made on the anthelmintic components of this seaweed. It was found that this anthelmintic principle transited from aqueous extract to hydrous methanol from which it is adsorbed on alumina and eluted from it by water. The principle is adsorbed on activated carbon from aqueous extract and eluted from it by methanol, or adsorbed on Amberlite IR-120 and eluted from it by alkali solution. Anthelmintic effective fraction was prepared by the use of these properties.
This effective fraction was submitted to paper partition chromatography and paper electrophoresis, and spots coloring yellow to ninhydrin were detected at Rf 0.31-0.32 and 0.54-0.56 in the former, and at migration distance of +52-+57 and +99-+102.
The behavior of the anthelmintic principles of Chondria armata was very similar to those (Rf 0.50 and migration distance +70) of kainic acid, the anthelmintic principle of Digenea. From these facts it was assumed that the anthelmintic principle of this seaweed is a substance related to kainic acid.
Domoic acid isolated from a seaweed, Chondria armata, showed extremely strong insecticidal activity against cockroaches and houseflies. The minimum effective dose against the American cockroach by subcutaneous injection was 0.8μg/g. This compound also induced significant contraction of the hindgut excised from the American cockroach. The site of action may be the neuromuscular junction, similar to that of α-kainic acid. The structureactivity relationships of domoic and α-kainic acids and their analogs were also investigated. The synthetic analogs were useful tools for delineating the structurally essential requirement for the insecticidal activity.
Three novel amino acids with insecticidal activity, isodomoic acids A, B and C, were isolated from water extracts of the red alga Chondria armata. Their structures were elucidated by spectroscopic analysis.
Amino acids and low-MW carbohydrates of 18 red algae have been analyzed. Several non-protein amino acids have been identified, including pyrrolidine-2,5-dicarboxylic acid (3c) and N-methylmethionine sulfoxide (5), new natural products, and 13 known compounds, citrulline, β-alanine, γ-aminobutyric acid, baikiain (1), pipecolic acid (2), domoic acid (3a), kainic acid (3b), azetidine-2-carboxylic acid (4), methionine sulfoxide taurine, N-methyltaurine, N,N-dimethyltaurine and N,N,N-trimethyltaurine. Sugars present were mainly floridoside, isofloridoside and mannoglyceric acid. Details of the structural elucidation of new compounds are also given.
Behind the recent explosion of interest in the field, there lies a long period of relatively slow progress in the characterization of excitatory amino acid receptors. In this article, Jeff Watkins and Harry Olverman summarize the emergence of current ideas relating to receptor differentiation and describe some of the molecular features of agonists and antagonists that activate and block them.
D~aring late 1987, an outbreak of poisoning resulting from the ingestion sf cultivated blue mussels (Mytilus edeblis) from a localized area in eastern Canada (Cardigan Bay, Prince Edward Island) was associated with massive blooms of Nitzschia pungens, a widely distributed diatom not previously known to produce toxins; human fatalities resulted. Here we provide proof that the causative agent, dornoic acid, is indeed produced by this diatom. Although no dornoic acid could be detected (
The minute amount of toxic principles, acromelic acids A (ca. 110 μg) and B (ca. 40 μg), was isolated from a poisonous mushroom Clitocybe acromelalga. Spectral analyses and biogenetic consideration led to the structures 1 and 2 for acromelic acids A and B, respectively. The syntheses of 1 and 2 starting from L-α-kainic acid 3 established the proposed structures. Both amino acids show extremely potent neuroexcitatory action.
Observations have been made on seasonal fluctuations in dissolved inorganic nutrients, internal reserves of nitrogen and growth rates in Laminaria longicruris. The onset of winter growth in shallow-water stations (6 and 9 m) correlated well with improved dissolved nitrate conditions in the sea. During the winter, reserves of NO
3
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were accumulated by the plants and reached maximum values of 150 moles per g fresh weight in March. This represents a concentration factor of approximately 28,000 over the ambient levels, or an internal nitrogen reserve of 2.1% of the dry weight of the tissue. Depletion of this nitrogen pool followed the disappearance of the external NO
3
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with a lag period of up to 2 months. Rapid kelp growth was measured during this period. Reserves of organic nitrogen also reached maximum values in March and declined slowly throughout the summer into autumn. It is suggested that the combined inorganic and organic nitrogen reserves sustain the rapid growth rates into July and at reduced rate through the late summer. Fertilization of an experimental perimental kelp bed with NaNO3 increased the internal plant reserves of NO
3
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and produced a much improved summer growth rate. The enriched plants developed very small reserves of carbohydrate during the rapid summer growth phase.
A novel long chain fatty ester, pentyl hentriacontanoate 1 and an orange red pigment, caulerpin 2 have been isolated and characterised from a red alga Chondria armata. The pigment caulerpin hitherto known to be a constituent of green algae of genus Caulerpa is being reported here for the first time from a red alga
THE finding that kainic acid (Fig. 1a) is a potent glutamate-like excitant of rat cerebral1 and cat spinal2 neurones has led us to test domoic acid (Fig. 1b), which is structurally related to kainic acid and wnich also occurs in certain marine algae and has similar anthelmintic properties3,4. We have also compared the actions of these two compounds with those of alpha-allo-kainic acid (Fig. 1c), a stereo-isomer of kainic acid and a weaker excitant of rat cerebral neurones1, and with quisqualic acid (Fig. 1d), an ascaricidal compound isolated from seeds of the plant genus Quisqualis5. Quisqualic acid is highly potent as a glutamate agonist at the crayfish neuromuscular junction6. Compounds were tested on rat spinal interneurones by micro-electrophoresis7 and on frog spinal motoneurones by superfusion of the procaine-blocked8 hemisected spinal cord in vitro9. On both these preparations (see Table 1), the anions of domoic and quisqualic acids were found to be at least two orders of magnitude more potent than L-glutamate, and equal to or stronger than kainate, whereas alpha-allo-kainate was a considerably weaker excitant.
NUMEROUS investigations have shown that certain amino-acids, including several which are present in the mammalian central nervous system, strongly influence the behaviour of neurones when applied extracellularly1-4. These amino-acids fall into two groups; neutral amino-acids related to γ-amino-n-butyric acid (GABA), which depress the activity of neurones, and acidic amino-acids related to glutamic acid, which excite neurones3. An analysis of the effects of these substances on mammalian spinal neurones indicates that whereas the mechanism of action of GABA differs from that of mammalian inhibitory transmitters5, the action of L-glutamie acid has certain features in common with that of excitatory transmitter substances3,6. Recently, several substances were found to have a much greater potency than GABA and glutamic acid as depressants and excitants respectively of neurones within the isolated and sagitally hemisected spinal cord of the toad7. In particular, N-methylaspartic acid and homocysteic acid were found to be potent excitants, and 3-amino-1-propanesulphonic acid was a powerful depressant. The potencies of these and related amino-acids on mammalian spinal and cortical neurones have now been determined.
Bacteria-free clones of the small centric diatom Cyclotella nana Hustedt were isolated, three from estuarine localities, one from Continental Shelf waters, and one from the Sargasso Sea. Detonula confervacea was isolated from Narragansett Bay. Morphology of all clones was studied with the light and electron microscopes. Morphological differences between clones of C. nana do not at present warrant separating any as distinct species.Clones of C. nana require only vitamin B12; D. confervacea has no vitamin requirement.Growth of the estuarine clones of C. nana was unaffected by salinity down to 0.5‰ and increased with temperature to 25 °C. The Shelf clone grew more rapidly at salinities above 8‰ and at temperatures between 10° and 20 °C. The Sargasso Sea clone did not survive below 15 °C or 17.5‰, while D. confervacea did not survive at temperatures above 15° or at salinities below 8‰. The physiological differences between clones correspond roughly to the conditions obtaining in nature where each was collected.
Amino acids from marine algae Marine natural products
- E Fattorusso
- Piattelli
Fattorusso E, Piattelli M, (1980) Amino acids from marine algae. In P.J. Scheuer, Marine natural products, Academic Press, NY. vol. 3; 95-139.
Amino acids and peptides in seven species of marine green algae
- K Miyazawa
- K Ito
- Matsumoto
Miyazawa K, Ito K, Matsumoto F, (1976) Amino acids and peptides in seven species of marine green algae. J. Fac. Fish Anim. Husb., Hiroshima Univ. 15: 161-169.
Gastrointestinal and neurological illness related to mussels from Prince Edward Island: A new clinical syn-drome associated with domoic acid
- Perl T M Bedard L
- T Kosatsly
- J Hockin
Perl T.M., Bedard L, Kosatsly T, Hockin J, Remis R S, (1988) Gastrointestinal and neurological illness related to mussels from Prince Edward Island: A new clinical syn-drome associated with domoic acid. Epidemic Intelligence Service Conference, Center for Disease Control, Atlanta, Georgia, 19 April, (unpublished).
Investigations on the source of domoic acid responsible for the outbreak of amnesic shell-fish poisoning (ASP) in eastern Prince Edward Island Domoic acid and quisqualic acids as potent amino acid excitants of frog and rat spinal neurones
- S S Bates
- C J Bird
- R K Boyd
- A W M Falk
- R A Foxall
- L A Hanic
- W D Jamieson
- A W Mcculloch
- P Odense
- M A Quilliam
- P G Sim
- P Thibault
- J A Walter
- C J J Wright
- R H Evans
- P M Headly
- Martin M Watkins
Bates S S, Bird C J, Boyd R K, deFreitas A S W, Falk M, Foxall R A, Hanic L A, Jamieson W D, McCulloch A W, Odense P, Quilliam M A, Sim P G, Thibault P, Walter J A, Wright J L C, (1988). Investigations on the source of domoic acid responsible for the outbreak of amnesic shell-fish poisoning (ASP) in eastern Prince Edward Island. Atlantic Research laboratory, Halifax, N.S., Technical Re-port 57. 59 pp. Biscoe T J, Evans R H, Headly P M, Martin M, Watkins J C, (1975) Domoic acid and quisqualic acids as potent amino acid excitants of frog and rat spinal neurones. Na-ture (London) 255: 166-167.
Determination of domoic acid in shellfish tissue by HPLC
- M A Quilliam
- P G Sim
- A W Mcculloch
- A Mcinnes
Quilliam M A, Sim P G, McCulloch A W, McInnes A G, (1988) Determination of domoic acid in shellfish tissue by HPLC. Atlantic Research Laboratory, Halifax, N.S., Technical Report 55: pp.
Glutamate and related acidic excitatory neurotransmitters: from basic science to clinical application Domoic acid-a neurotoxic amino acid produced by the marine diatom Nitzschia pungens in culture
- Robinson M B Coyle
- J Subba
- D V Quilliam
- M A Pocklington
Robinson M B, Coyle J T, (1987) Glutamate and related acidic excitatory neurotransmitters: from basic science to clinical application. FASABJ 1: 446-455. Subba Rao D V, Quilliam M A, Pocklington R, (1989) Domoic acid-a neurotoxic amino acid produced by the marine diatom Nitzschia pungens in culture. Can. J. Fish Aquat. Sci. 2076-2079.
Gastrointestinal and neurological illness related to mussels from Prince Edward Island: A new clinical syndrome associated with domoic acid. Epidemic Intelligence Service Conference
- T M Perl
- L Bedard
- T Kosatsly
- J Hockin
- R Remis