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TOXC707 (2007) Neurotoxicity of Natural Toxins Robert C. MacPhail, Ph.D. [email protected] September 19, 2007 Toxins Outline Toxins vs. toxicants Toxin producers and evolutionary significance Drugs derived from natural sources Pesticides derived from natural sources Cholinergics derived from natural sources Toxins derived from plants Toxins derived from aquatic organisms Herbal medicines and nutritional supplements Neurotoxicology of Natural Toxins Toxins vs. Toxicants ◄ Toxicants: A manufactured chemical. Drugs Pesticides Industrial chemicals By-products ◄ Toxins: Produced by an organism. Algae Fungi Invertebrates Vertebrates ◄ Distinctions are not always clear (e.g., methylmercury) Evolutionary Significance of Toxins ◄ Obvious functions: Predator avoidance Predation ◄ Not-so-obvious functions: Trophic functions? They weren’t designed to kill people! ◄ Some common features of toxins: Molecular complexity Mechanistic specificity ◄ Renewed interest in toxins: Pharmacognosy Ethnopharmacology Environmental deterioration Drugs Derived from Natural Sources ◄ Stimulants: Cocaine – coca leaves Khat (cathinone) – catha edulis Caffeine – coffee beans Ephedra – ma huang Nicotine – tobacco plants ◄ Euphorics: Morphine - poppies Codeine - opium Cannabinoids - marijuana Ethanol - yeast ◄ Convulsants: Picrotoxin – Cocculus indicus Strychnine – Strychnos nux-vomica ◄ Hallucinogens: LSD - fungus Peyote. mescaline – cactus Psilocybin – magic mushrooms Salvinorin A – Salvia divinorum Pesticides Derived from Natural Sources ◄ Pyrethrins ◄ Nicotine – insecticide, chrysanthemum – insecticide, tobacco plants ◄ Rotenone – piscisicide, cube resin, tropical plants ◄ Fluoroacetate ◄ Carbamates – rodenticide, gifblaar plants – insecticide, Physostigma venenosum ◄ Organophosphates …. (Neumann and Peter, 1987; Carmichael, 2001) Cholinergic Agents Derived from Natural Sources ◄ Muscarinic agonists: Muscarine Pilocarpine Arecoline Physostigmine ◄ Muscarinic anatgonists: “belladonna” Atropine Scopolamine ◄ Nicotinic agonists: Nicotine Epibatidine Anabaseine Anatoxin-a ◄ Nicotinic antagonists: Curare Alpha-bungarotoxin Toxins and Target Organs (Norton, 2001) ◄ Gastrointestinal system: Ricin – from castor beans – a “select agent” ◄ Lungs: Capsaicin – from cayenne, chili peppers – sensory irritation ◄ Cardiovascular: Digitalis – from foxglove – cardiac arythmias Veratrum alkaloids, aconitine – prolong sodium currents Grayanotoxins – mad honey poisoning Ergot – St. Anthony’s Fire – derivatives of lysergic acid ◄ Blood: Dicumarol – fungal-infected clover – hemorrhages Cyanogenics – amygdalin, from almonds casava and Konzo, from linamarin that produces thiocyanate, leading to spastic paralysis and motor neuron degeneration Toxins and Target Organs (Norton, 2001) ◄ The nervous system: Seizure-producing toxins – cicutoxin from hemlock, and monoterpenes from mint oils – block potassium channels Excitatory amino acids – Multiple glutamate receptors – AMPA, NMDA, kainate Overstimulation leads to neuronal destruction Kainic acid – from seaweed Domoic acid – diatom - mussel poisoning (PEI, 1987) Ibotenic acid – fly agaric (amanita muscaria) Lathyrism – chick peas, DABA and BOAA, motor neuron destruction Mannosidase inhibitors – swainsonine, from locoweed - cattle Toxins Derived from Aquatic Organisms ◄ Marine organisms: Dinoflagellates – brevitoxins, saxitoxins, ciguatoxins Diatoms – domoic acid ◄ Freshwater organisms: Cyanobacteria – anatoxins, saxitoxins, microcystins ◄ Harmful algal blooms (HABs): Impacts on human health, wildlife and the environment. Possible causes - anthropogenic influences? Van Dolah (2000) Marine Toxins: Many Named for Human Toxicity Marine toxins: Molecular Complexity Marine Toxins: Some Highly Selective Actions Poisons as probes of physiological functions World-wide Spread of Harmful Algal Blooms Neurotoxins Produced by Cyanobacteria ◄ Anatoxin-a: nicotinic agonist ◄ Homoanatoxin-a: ◄ Anatoxin-a(s): ◄ Saxitoxins nicotinic agonist cholinesterase inhibitor and neosaxitoxins: Na-channel blockers ◄ BMAA: a causative agent in cycad and other neurodegenerative diseases? Cox et al., PNAS (2005) Neurotoxins Produced by Cyanobacteria Toxins as Probes for Physiological Functions ◄ ◄ A long-standing tradition – Sherrington, Dale Advances in understanding the nicotinic cholinergic nervous system (Daly, 2005) Lots of receptors: alpha and beta subunits, gamma and delta Nicotinic agonists: Anatoxin-a Epibatidine Conotoxins Imidacloprid Nicotinic antagonists: Mecamylamine Hexamethonium Methyllycaconitine Dihydro-beta-erythroidine Herbal Medicines and Nutritional Supplements ◄ ◄ The heritage of folk remedies. Increasing use of dietary supplements and alternative medicines: Health-conscious Americans Increasing cost of medicines Increasing number of older adults Increasing number of scam artists ◄ Dietary Supplemental Health and Education Act (1994) “If nature made them they must be okay.” ◄ Principles of drug evaluation and regulation: Chemical identity Demonstrated efficacy Absence of toxicity Herbal Medicines and Nutriceuticals ◄ Chemical identity – standardization of ingredients Mixtures Variable dosages Impurities – do they really work? ◄ Toxicity – are they safe? ◄ Efficacy “Native” toxicity Interaction with drugs, other chemicals ◄ De Smet (2002) National Center for Complementary and Alternative Medicine (NIH) Recommended Readings Adams, M.E. and G. Swanson. Neurotoxins. Trends in Neurosciences supplement, 1994. Carmichael, W.W. Health effects of toxin-producing cyanobacteria: “The cyanoHABs.” Hum. Ecol Risk Assessment 7: 1393-1407, 2001. Cox, P.A., S.A. Banack, S.J. Murch et al. Diverse taxa of cyanobacteria produce B-N-methylamino-L-alanine, a neurotoxic amino acid. Proc. Natl. Acad. Sci. 102: 5074-5078, 2005. Daly, J.W. Nicotinic agonists, antagonists, and modulators from natural sources. Cell. Mol. Neurobiol. 25: 513-552, 2005. De Smet, P.A.G.M. Herbal remedies. The New England Journal of Medicine 347: 2046-2056, 2002. Dietary Supplemental Health and Education Act of 1994. Public Law 103-417. http://www.fda.gov/opacom/laws/dshea.html Fabricant, D.S. and N.R. Farnsworth. The value of plants used in traditional medicine for drug discovery. Environ. Hlth. Perspect. 109 (suppl. 1): 6975, 2001. Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.) Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 8 th edition, Plenum Press, 1990. Gribble, G.W. Amazing organohalogens. Amer. Scientist 92: 342-349, 2004. Kem, W.R. Properties and effects of natural toxins and venoms. In: Principles of Toxicology: Environmental and Industrial Applications. 2nd edition, P.L. Williams, R. C. James and S.M. Roberts (eds.), John Wiley & Sons, Inc. 2000. Chapter 17. Klaassen, C.D. (ed.) Cassarett and Doull’s Toxicoloy: The Basic Science of Poisons. 6 th edition, McGraw-Hill, 2001. Levin, E.D. A rat model of the cognitive impairment from Pfiesteria piscisida exposure. Environ. Hlth Perspect. 109: 757-763, 2001. National Center for Complementary and Alternative Medicine. http://nccam.nih.gov/. Neumann, R. and H.H. Peter. Insecticidal organophosphates: Nature made them first Experientia 43: 1235-1237, 1987. Norton, S. Toxic effects of plants. In: Klaassen, C.D. (ed.) Cassarett and Doull’s Toxicoloy: The Basic Science of Poisons. 6th edition, McGraw-Hill, 2001. Chapter 27. Olivera, B.M., L.J. Cruz and D. Yoshikami. Effects of conus peptides on the behavior of mice. Curr. Opinion Neurobiol. 9: 772-777, 1999. Paerl, H.W., R.S. Fulton III, P.H. Moisander and J. Dyble. Harmful freshwater algal blooms, with an emphasis on cyanobacteria. TheScientificWorld 1: 76-113, 2001. Russell, F.E. Toxic effects of terrestrial animal venoms and poisons. In: Klaassen, C.D. (ed.) Cassarett and Doull’s Toxicoloy: The Basic Science of Poisons. 6th edition, McGraw-Hill, 2001. Chapter 26. Schultes, R.E. Hallucinogens of plant origin. Science 163: 245-254, 1969. Spencer, P.S., H.H. Schaumburg and A.C. Ludolph. Experimental and Clinical Neurotoxicology. 2 nd edition, Oxford University Press, 2000. Van Dolah, F.M. Marine algal toxins: Origins, health effects, and their increased occurrence. Environ. Hlth. Perspect. 108 (suppl. 1): 133-141, 2000. Vortherms T.A. and B.L. Roth. Salvinorin A: From natural product to human therapeutics. Molecular Interventions 6: 257-265, 2006. Neurotoxicology of Natural Toxins ◄ Thank you