brevetoxin and Nervous-System-Diseases

This review focuses on the neurobiological actions of ciguatoxins and brevetoxins which are phycotoxins produced respectively by the dinoflagellates Gambierdiscus toxicus and Ptychodiscus brevis. These actions are illustrated in particular by the effects of the toxins on myelinated nerve fibres and on skeletal neuromuscular junctions of vertebrates. Ciguatoxins and brevetoxins, through different vectors, are responsible for human intoxications characterized mainly by neurological disturbances. The molecular target of these families of lipid-soluble cyclic polyethers is the voltage-gated sodium channel, a fundamental transmembrane protein involved in cellular excitability. The different toxins share a common binding site (the receptor-site 5) located on the alpha sub-unit of this neuronal transmembrane protein. Electrophysiological studies of the mode of action of ciguatoxins and brevetoxins identify these toxins as specific sodium channel activators. Indeed, during the action of these phycotoxins, sodium channels remain permanently opened, at the resting membrane potential, which produces a continuous entry of sodium ions in most excitable cells. Such a sodium entry has various consequences on sodium-dependent physiological mechanisms, consisting in a membrane depolarization which, in turn, causes spontaneous and/or repetitive action potential discharges and thereby increases membrane excitability. These neuronal discharges may be transient or continuous according to the preparation and the toxin tested. The increase in membrane excitability during the action of ciguatoxins and brevetoxins is responsible for the different effects exerted by these toxins on various chemical synapses and secretory cells. Another consequence of the continuous entry of sodium ions into cells was revealed using confocal laser scanning microscopy and vital staining of plasma membranes with the fluorescent dye FM1-43. These techniques made feasible the dynamic study of morphological alterations produced by ciguatoxins and brevetoxins on various cellular preparations in situ. Thus, it has been possible to bring to the fore that these phycotoxins cause a marked increase in the volume of nodes of Ranvier of myelinated nerve fibres, motor nerve terminals innervating skeletal muscle and perisynaptic non-myelinating Schwann cell somata. This increase could be reversed by hyperosmotic external solutions and completely prevented by the blockade of voltage-gated sodium channels. The mech

Topics: Animals; Ciguatoxins; Humans; Marine Toxins; Nerve Fibers, Myelinated; Nervous System Diseases; Neuromuscular Junction; Neurotoxins; Oxocins

The application is in the field of neuronal growth and the activity of brevetoxins and their derivatives. It aims to characterize the activity of four generic formulae of brevetoxin derivatives--formulae I, II, III, and IV--and their compounds on the growth of neurites. The activity of the brevetoxin derivative compounds was tested on primary cultures of neocortical neurons. It was assayed in the presence and absence of antagonists of receptors and second-messenger signaling pathways, particulary NMDA receptors and the calmodulin-dependent protein-kinase kinase pathway. Brevetoxin derivatives stimulate neurite growth, particularly the growth of minor processes from which the axons form, on neurons in primary cultures. The activity is mediated by voltage-gated sodium channels and the N-methyl-d-aspartate-mediated intracellular Ca(2+) pathway. The application claims the use of the four generic formulae of brevetoxin derivatives (I, II, III, and IV) and their compounds for enhancing neuronal growth and for the treatment of neurodegenerative diseases and neurological disorders and injuries, such as Alzheimer's disease, amyotrophic lateral sclerosis, cerebral strokes, traumatic brain, and spinal cord injuries.

Topics: Animals; Humans; Marine Toxins; Nervous System Diseases; Neurites; Neurodegenerative Diseases; Neurons; Oxocins; Patents as Topic; Receptors, N-Methyl-D-Aspartate; Signal Transduction

Beginning in October 2000, subadult loggerhead sea turtles Caretta caretta showing clinical signs of a neurological disorder were found in waters off south Florida, USA. Histopathology indicated generalized and neurologic spirorchiidiasis. In loggerhead sea turtles (LST) with neurospirorchiidiasis, adult trematodes were found in the meninges of the brain and spinal cord of 7 and 3 affected turtles respectively, and multiple encephalic intravascular or perivascular eggs were associated with granulomatous or mixed leukocytic inflammation, vasculitis, edema, axonal degeneration and occasional necrosis. Adult spirorchiids were dissected from meningeal vessels of 2 of 11 LST brains and 1 of 10 spinal cords and were identified as Neospirorchis sp. Affected LST were evaluated for brevetoxins, ciguatoxins, saxitoxins, domoic acid and palytoxin. While tissues from 7 of 20 LST tested positive for brevetoxins, the levels were not considered to be in a range causing acute toxicosis. No known natural (algal blooms) or anthropogenic (pollutant spills) stressors co-occurred with the turtle mortality. While heavy metal toxicosis and organophosphate toxicosis were also investigated as possible causes, there was no evidence for their involvement. We speculate that the clinical signs and pathologic changes seen in the affected LST resulted from combined heavy spirorchiid parasitism and possible chronic exposure to a novel toxin present in the diet of LST.

Topics: Animals; Brain; Cholinesterases; Female; Florida; Kidney; Liver; Male; Marine Toxins; Metals, Heavy; Muscle, Skeletal; Nervous System Diseases; Oxocins; Sciatic Nerve; Trematoda; Trematode Infections; Turtles

Eutrophication phenomena in marine coastal waters can today be explained on the basis of natural or anthropogenic causes. Undesirable effects and also sanitary problems in both types of eutrophication are often produced, but they may differ greatly in frequency and significance. Some algal biotoxins can affect both marine animals and man, whilst others affect man alone. From data currently available it appears that the sanitary state of man can be affected through the digestive, respiratory and cutaneous apparatus. Four main dinoflagellate biointoxications are now recognized: paralytic shellfish poisoning (PSP), neurotoxic shellfish poisoning (NSP), diarrhoetic shellfish poisoning (DSP), and venerupin poisoning. Other biointoxications are due to a diatom bloom responsible for amnesic shellfish poisoning (ASP) and to blue algae blooms which have effects on the skin and the respiratory tract. All these marine toxins are considered and particular attention is paid to: producing organisms, chemistry of the components, compromised sea foods, methods of analysis, occurrence worldwide, human intoxications, toxicology and mechanism of action on a molecular level, therapeutical notes, tolerance levels and remarks on safety. Attention is also paid to the relationship between the anthropogenic eutrophication and PSP and DSP since these are the most widespread biointoxications from toxic marine dinoflagellates in the world today and for which the European Economic Community (EEC) is proposing health legislation such as tolerance limits and methods for official analysis. In view of the harmful potential of coastal anthropogenic eutrophication, the main current committment of various countries concerns control. Finally, it is important to develop a suitable monitor research system using all the specific standards of allowed toxic substances, and also research on effective antiodotes against all biotoxins.

Topics: Animals; Diarrhea; Dinoflagellida; Eutrophication; Food Contamination; Foodborne Diseases; Humans; Marine Toxins; Maximum Allowable Concentration; Nervous System Diseases; Oxocins; Saxitoxin; Shellfish