Download PDF
Semin Neurol 2005; 25(3): 278-289
DOI: 10.1055/s-2005-917664
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Tropical Marine Neurotoxins: Venoms to Drugs

Michael R. Watters1
  • 1Professor of Medicine, Division of Neurology, University of Hawaii, Honolulu, Hawaii
Further Information

Publication History

Publication Date:
19 September 2005 (online)

    Permissions and Reprints

ABSTRACT

Neurotoxic venoms are common among tropical marine creatures, which have specialized apparatuses for delivery of the venoms. These include jellyfish and anemones, venomous cone snails, venomous fish, stingrays, sea snakes, and venomous octopuses. Numerous toxic neuropeptides are found within these venoms, and some can discriminate between closely related intracellular targets, a characteristic that makes them useful to define cation channels and attractive for drug development. A synthetic derivative of an omega-conotoxin is now available, representing a new class of analgesics. In general, toxic marine venoms contain proteins that are heat labile, providing opportunity for therapeutic intervention following envenomation, while ingestible seafood toxins are thermostable toxins. Ingestible toxins found in the tropics include those associated with reef fish, pufferfish, and some shellfish, which serve as food-chain vectors for toxins produced by marine microorganisms.

KEYWORDS

Marine venoms - coelenterate toxins - nematocysts - conotoxins - neuron-specific voltage-gated calcium channels - venomous fish - sea snakes - ingestible seafood - toxins - tetrodotoxin - ciguatera

REFERENCES

  • 1 Watters M R, Cannard K R. Marine neurotoxins. In: Chopra JS, Sawhney IMS Neurology in Tropics. New Delhi; Churchill Livingstone 1999: 45-68
    Google Scholar
  • 2 Tomchik R S, Russell M R, Szmant A M, Black N. Clinical perspectives on sunbather's eruption, also known as “sea lice.”  JAMA. 1993;  269 1669-1672
    CrossrefPubMedGoogle Scholar
  • 3 Watters M R, Yanagihara A A. Marine neurotoxins: envenomations and contact toxins. In: Watters MR (dir) Marine Toxins, AAN Syllabus 5BS.003. St. Paul, MN; American Academy of Neurology 2003: 1-27
    Google Scholar
  • 4 Hodgson W C. Pharmacological action of Australian venoms.  Clin Exp Pharmacol Physiol. 1997;  24 10-17
    CrossrefPubMedGoogle Scholar
  • 5 Watters M R, Stommel E W. Marine toxins: envenomations and contact toxins.  Curr Treat Options Neurol. 2004;  6 115-123
    PubMedGoogle Scholar
  • 6 Chung J J, Ratnapala L A, Cooke I M, Yanagihara A A. Partial purification and characterization of the hemolysin (CAH1) from Hawaiian box jellyfish (Carybdea alata) venom.  Toxicon. 2001;  39 981-990
    CrossrefPubMedGoogle Scholar
  • 7 Fenner P J, Williamson J A. Worldwide deaths and severe envenomation from jellyfish stings.  Med J Aust. 1996;  165 658-661
    PubMedGoogle Scholar
  • 8 Edwards L, Hessinger D A. Portuguese man-of-war (Physalia physalis) venom induces calcium influx into cells by permeabilizing plasma membranes.  Toxicon. 2000;  38 1015-1028
    CrossrefPubMedGoogle Scholar
  • 9 Fenner P, Seymour J. Irukandji jellyfish. Available at: http://www.reef.crc.org.au/aboutreef/coastal/irukandji.html
    Google Scholar
  • 10 Walker M JA. Coelenterate and echinoderm toxins: mechanisms and actions. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 280-325
    Google Scholar
  • 11 Auerbach P S. Marine envenomation. In: Auerbach PS Wilderness Medicine: Management of Wilderness and Environmental Emergencies. 3rd ed. St Louis; Mosby 1995: 1327-1374
    Google Scholar
  • 12 Ludolph A C. Sea anemone toxins. In: Spencer PS, Schaumburg HH Experimental and Clinical Neurotoxicology. 2nd ed. Oxford; Oxford University Press 2000: 1099-1100
    Google Scholar
  • 13 Norton R S. Structure and structure-function relationships of sea anemone proteins that interact with the sodium channels.  Toxicon. 1991;  29 1051-1084
    CrossrefPubMedGoogle Scholar
  • 14 Thomas C S, Scott S A, Galanis D J et al.. Box jellyfish (Carybdea alata) in Waikiki: their influx cycle plus the analgesic effect of hot and cold packs on their stings to swimmers at the beach: a randomized, placebo-controlled, clinical trial.  Hawaii Med J. 2001;  60 100-107
    PubMedGoogle Scholar
  • 15 Yoshimoto C M, Yanagihara A A. Cnidarian (coelenterate) envenomations in Hawaii improve following heat application.  Trans R Soc Trop Med Hyg. 2002;  96 300-303
    CrossrefPubMedGoogle Scholar
  • 16 Nomura J T, Sato R L, Ahern R M et al.. A randomized paired comparison trial of cutaneous treatments of acute jellyfish (Carybdea alata) stings.  Am J Emerg Med. 2002;  20 624-626
    CrossrefPubMedGoogle Scholar
  • 17 Fenner P. Chironex fleckeri (multi-tentacled box jellyfish). Available at: http://www.marine-medic.com
    Google Scholar
  • 18 Farr-Jones S, Miljanich G P, Nadasdi L, Ramachandran J, Basus V J. Solution structure of omega-conotoxin MVIIc, a high affinity ligand of P-type calcium channels, using 1H NMR spectroscopy and complete relaxation matrix analysis.  J Mol Biol. 1995;  248 106-124
    CrossrefPubMedGoogle Scholar
  • 19 Fainzilber M, Hasson A, Oren R et al.. New mollusk-specific alpha-conotoxins block Aplysia neuronal acetylcholine receptors.  Biochemistry. 1994;  33 9523-9529
    CrossrefPubMedGoogle Scholar
  • 20 Hill J M, Alewood P F, Craik D J. Three-dimensional solution structure of muconotoxin GIIIb, a specific blocker of skeletal muscle sodium channels.  Biochemistry. 1996;  35 8824-8835
    CrossrefPubMedGoogle Scholar
  • 21 Cruz L J. Conotoxins. In: Spencer PS, Schaumburg HH Experimental and Clinical Neurotoxicology. 2nd ed. Oxford; Oxford University Press 2000: 417-419
    Google Scholar
  • 22 Auerbach P S. Clinical therapy of marine envenomation and poisoning. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 493-565
    Google Scholar
  • 23 Olivera B M, Cruz L J, de Santos V et al.. Neuronal calcium channel antagonists: discrimination between calcium channel subtypes using omega-conotoxin from Conus magnus venom.  Biochemistry. 1987;  26 2086-2090
    CrossrefPubMedGoogle Scholar
  • 24 Zamponi G W. Interactions of voltage gated calcium channels with peptide toxins from spiders and snails. Presented at the Venom to Drugs International Symposium, July 2002 Heron Island, Australia;
    Google Scholar
  • 25 Olivera B M, Bandyopadhyay P K, Wilcox K S, Grzegorz B, White H S, McIntosh J M. Conus peptides, a conceptual overview of the pharmacological resource: specific issues relevant to drug development. Presented at the Venom to Drugs International Symposium, July 2002 Heron Island, Australia;
    Google Scholar
  • 26 Azimi-Zonooz A, Kawa C B, Dowell C D, Olivera B M. Autoradiographic localization of N-type VGCCs in gerbil hippocampus and failure of w-conotoxin MVIIa to attenuate neuronal injury after transient cerebral ischemia.  Brain Res. 2001;  907 61-70
    CrossrefPubMedGoogle Scholar
  • 27 Berman R F, Verweij B H, Muizelaar J P. Neurobehavioral protection by the neuronal calcium channel blocker Ziconotide in a model of traumatic diffuse brain injury in rats.  J Neurosurg. 2000;  93 821-828
    PubMedGoogle Scholar
  • 28 Watters M R. Update in pain, conotoxins as analgesics: ziconotide. In: Watters MR (dir) Update in Neurology Western Winter Meeting, AAN Syllabus. St. Paul, MN; American Academy of Neurology 2004: 1-13
    Google Scholar
  • 29 Newcomb R, Abbruscato T J, Singh T et al.. Bioavailability of ziconotide in brain: influx from blood, stability, and diffusion.  Peptides. 2000;  21 491-501
    CrossrefPubMedGoogle Scholar
  • 30 Brammar W J. Voltage-gated calcium channels. In: Conley EC, Brammer WJ Ion Channel Facts Book. Vol. 4: Voltage-Gated Channels. London; Academic Press 1999: 22-153
    Google Scholar
  • 31 Catterall W A. Structure and function of neuronal calcium channels and their role in neurotransmitter release.  Cell Calcium. 1998;  24 307-323
    CrossrefPubMedGoogle Scholar
  • 32 Cox B. Calcium channel blockers and pain therapy.  Curr Rev Pain. 2000;  4 488-498
    PubMedGoogle Scholar
  • 33 Santicioli P, Del Bianco E, Tramontana M et al.. Release of calcitonin gene-related peptide-like immunoreactivity induced by electrical field stimulation from rat spinal afferents is mediated by conotoxin-sensitive calcium channels in rat sensory neurons.  Neurosci Lett. 1992;  136 161-164
    CrossrefPubMedGoogle Scholar
  • 34 Holz G G, Dunlap K, Kream R M. Characterization of the electrically evoked release of substance P from dorsal root ganglion neurons: methods and dihydropyridine sensitivity.  J Neurosci. 1988;  8 463-471
    PubMedGoogle Scholar
  • 35 Malmberg A B, Yaksh T L. Voltage-sensitive calcium channels in spinal nociceptive processing: blockage of N- and P-type channels inhibits formalin-induced nociception.  J Neurosci. 1994;  14 4882-4890
    PubMedGoogle Scholar
  • 36 Jain K K. An evaluation of intrathecal ziconotide for the treatment of chronic pain.  Expert Opin Investig Drugs. 2000;  9 2403-2410
    CrossrefPubMedGoogle Scholar
  • 37 Wermeling D, Drass M, Ellis D et al.. Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients.  J Clin Pharmacol. 2003;  43 624-636
    PubMedGoogle Scholar
  • 38 Smith M T, Cabot P J, Ross F B, Robertson A D, Lewis R J. The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices.  Pain. 2002;  96 119-127
    CrossrefPubMedGoogle Scholar
  • 39 Wang Y X, Pettus M, Gao D, Phillips C, Bowersox S S. Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain.  Pain. 2000;  84 151-158
    CrossrefPubMedGoogle Scholar
  • 40 Wang Y X, Bowersox S S. Analgesic properties of ziconotide, a selective blocker of N-type neuronal calcium channels.  CNS Drug Rev. 2000;  6 1-20
    PubMedGoogle Scholar
  • 41 Mathur V S. Ziconotide: a new pharmacological class of drug for the management of pain.  Semin Anesth Periop Med Pain. 2000;  19 67-75
    PubMedGoogle Scholar
  • 42 Staats P S, Yearwood T, Charapata S G et al.. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial.  JAMA. 2004;  291 63-70
    CrossrefPubMedGoogle Scholar
  • 43 Bowersox S, Tich N, Mayo M et al.. SNX-111 antinociceptive agent N-type voltage-sensitive calcium channel blocker.  Drugs Future. 1998;  23 152-160
    PubMedGoogle Scholar
  • 44 Penn R D, Paice J A. Adverse effects associated with the intrathecal administration of ziconotide.  Pain. 2000;  85 291-296
    CrossrefPubMedGoogle Scholar
  • 45 Wang Y X, Gao D, Pettus M, Phillips C, Bowersox S S. Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive calcium channels, with morphine on nociception in rats.  Pain. 2000;  84 271-281
    CrossrefPubMedGoogle Scholar
  • 46 Mathur V, McGuire D, Bowersox S et al.. Neuronal N-type calcium channels: new prospect in pain therapy.  Pharm News. 1998;  5 25-29
    PubMedGoogle Scholar
  • 47 Brown C K, Shepherd S M. Marine trauma, envenomations, and intoxications.  Emerg Med Clin North Am. 1992;  10 385-408
    PubMedGoogle Scholar
  • 48 Maretic Z. Fish venoms. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 445-476
    Google Scholar
  • 49 Auerbach P S. Marine envenomations.  N Engl J Med. 1991;  325 486-493
    CrossrefPubMedGoogle Scholar
  • 50 Kizer K W, McKinney H E, Auerbach P S. Scorpaenidae envenomation: a five-year poison control experience.  JAMA. 1985;  253 807-810
    CrossrefPubMedGoogle Scholar
  • 51 Wasserman G S, Johnston R M. Poisoning from lionfish sting.  Vet Hum Toxicol. 1979;  21 344-345
    PubMedGoogle Scholar
  • 52 Tu A T. Sea snakes and their venoms. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 379-344
    Google Scholar
  • 53 Ludolph A C. Erabutoxins. In Spencer PS, Schaumburg HH Experimental and Clinical Neurotoxicology. 2nd ed. Oxford; Oxford University Press 2000: 534-535
    Google Scholar
  • 54 Burne J A, Webster M E. The action of erabutoxins “b” on spontaneous and glutamate-induced cortical activity.  Life Sci. 1977;  20 2023-2028
    CrossrefPubMedGoogle Scholar
  • 55 Taub A M, Elliott W B. Some effects of snake venoms on mitochondria.  Toxicon. 1964;  104 87-92
    PubMedGoogle Scholar
  • 56 Baxter E H, Gallichio H A. Cross-neutralization by tiger snakes (Notechis scutatus) antivenin and sea snake (Enhydrina schistosa) antivenin against several sea snake venoms.  Toxicon. 1974;  12 273-278
    CrossrefPubMedGoogle Scholar
  • 57 Tu A T, Gulde G. Sea snake bite.  Clin Dermatol. 1987;  5 118-126
    PubMedGoogle Scholar
  • 58 Narahashi T. Tetrodotoxin. In: Spencer PS, Schaumburg HH Experimental and Clinical Neurotoxicology. 2nd ed. Oxford; Oxford University Press 2000: 1162-1164
    Google Scholar
  • 59 Narahashi T. Mechanism of tetrodotoxin and saxitoxin action. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 185-210
    Google Scholar
  • 60 Watters M R. Organic neurotoxins in seafoods.  Clin Neurol Neurosurg. 1995;  97 119-124
    CrossrefPubMedGoogle Scholar
  • 61 Fuhrman F A. Tetrodotoxin, tarichtoxin, and chiriquitoxin: historical perspectives.  Ann N Y Acad Sci. 1986;  479 1-14
    PubMedGoogle Scholar
  • 62 Kaempfer E. History of Japan. Vol. 1. Scheuchzer JG, trans. London; Johann Gaspar Scheuchzer; 1727
    Google Scholar
  • 63 Mills A R, Passmore R. Pelagic paralysis.  Lancet. 1988;  1 161-164
    PubMedGoogle Scholar
  • 64 Halstead B W. Poisonous and Venomous Marine Animals of the World. Princeton; Darwin Press 1988
    Google Scholar
  • 65 Stommel E W, Watters M R. Marine neurotoxins: ingestible toxins.  Curr Treat Options Neurol. 2004;  6 105-114
    PubMedGoogle Scholar
  • 66 Watters M R. Geographic medicine: the hazards of eating seafood. In: Marra C (dir) Infections of the Nervous System, AAN Syllabus 7FC.006. St. Paul, MN; American Academy of Neurology 1998: 159-171
    Google Scholar
  • 67 DiNubile M J, Hokama Y. The ciguatera poisoning syndrome from farm-raised salmon.  Ann Intern Med. 1995;  122 113-114
    PubMedGoogle Scholar
  • 68 Hokama Y. Simplified solid-phase immonobead assay for detection of ciguatoxin and related polyethers.  J Clin Lab Anal. 1990;  4 213-217
    PubMedGoogle Scholar
  • 69 Kodama A M, Hokama Y, Yasumoto T et al.. Clinical and laboratory findings implicating palytoxin as cause of cituatera poisoning due to Decapterus macrosoma (mackerel).  Toxicon. 1989;  27 1051-1053
    CrossrefPubMedGoogle Scholar
  • 70 Hirata Y. Chemistry and pharmacology of palytoxin. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 242-258
    Google Scholar
  • 71 Withers N W. Ciguatera fish toxins and poisonings. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 31-61
    Google Scholar
  • 72 Pearn J. Neurology of ciguatera.  J Neurol Neurosurg Psychiatry. 2001;  70 4-8
    CrossrefPubMedGoogle Scholar
  • 73 Bagnis R, Kuberski T, Lamgier S. Clinical observations on 3,009 cases of ciguatera (fish poisoning) in the South Pacific.  Am J Trop Med Hyg. 1979;  28 1067-1073
    PubMedGoogle Scholar
  • 74 Schnorf H, Taurarii M, Cundy T. Ciguatera fish poisoning: a double-blind randomized trial of mannitol therapy.  Neurology. 2002;  58 873-880
    CrossrefPubMedGoogle Scholar
  • 75 Underman A E, Leedom J M. Fish and shellfish poisoning.  Curr Clin Top Infect Dis. 1993;  13 203-225
    PubMedGoogle Scholar
  • 76 Watters M R. Organic neurotoxins in seafoods. In: Rose FC Recent Advances in Tropical Neurology. Amsterdam; Elsevier Science 1995: 299-312
    Google Scholar
  • 77 Taylor T J, Smith N C, Langford M J et al.. Effect of palytoxin on endothelium-dependent and -independent relaxation in rat aortic rings.  J Appl Toxicol. 1995;  15 5-12
    PubMedGoogle Scholar
  • 78 Stommel E W, Parsonnet J, Jenkyn L R. Polymyositis after ciguatera toxin exposure.  Arch Neurol. 1991;  48 874-877
    PubMedGoogle Scholar
  • 79 Stommel E W, Jenkyn L R, Parsonnet J. Another case of polymyositis after ciguatera toxin exposure.  Arch Neurol. 1993;  50 571
    PubMedGoogle Scholar
  • 80 Cameron J, Flowers A E, Capra M F. Effects of ciguatoxin on nerve excitability in rats (part I).  J Neurol Sci. 1991;  101 87-92
    CrossrefPubMedGoogle Scholar
  • 81 Benoit E, Juzans P, Legrand A M, Molgo J. Nodal swelling produced by ciguatoxin-induces selective activation of sodium channels in myelinated nerve fibers.  Neuroscience. 1996;  71 1121-1131
    CrossrefPubMedGoogle Scholar
  • 82 Mattei C, Dechraoui M Y, Molgo J et al.. Neurotoxins targeting receptor site 5 of voltage-dependent sodium channels increase the nodal volume of myelinated axons.  J Neurosci Res. 1999;  55 666-673
    CrossrefPubMedGoogle Scholar
  • 83 Allsop J L, Martini L, Lebris H et al.. Neurologic manifestations of ciguatera: 3 cases with a neurophysiologic study and examination of one nerve biopsy.  Rev Neurol (Paris). 1986;  142 590-597
    PubMedGoogle Scholar
  • 84 Cameron J, Flowers A E, Capra M R. Electrophysiological studies on ciguatera poisoning in man (part II).  J Neurol Sci. 1991;  101 93-97
    CrossrefPubMedGoogle Scholar
  • 85 Palafox N A, Jain L G, Pinano A Z et al.. Successful treatment of ciguatera fish poisoning with intravenous mannitol.  JAMA. 1988;  259 2740-2742
    CrossrefPubMedGoogle Scholar
  • 86 Pearn J, Lewis R. Ciguatera and mannitol: experience with a new treatment regimen.  Med J Aust. 1989;  151 77-80
    PubMedGoogle Scholar
  • 87 Legrand A M, Galonnier M, Bagis R. Studies on the mode of action of ciguateric toxins.  Toxicon. 1982;  20 311-315
    CrossrefPubMedGoogle Scholar

Michael R WattersM.D. 

Department of Medicine, John A. Burns School of Medicine

1356 Lusitana Street, 7th Floor

Honolulu, HI 96813

      >