Neurotoxicology of Natural Toxins Robert C. MacPhail, Ph.D. macphail.robertepa.gov October 25, 2006

1. Neurotoxicology of Natural ToxinsRobert C. MacPhail, Ph.D.macphail.robert@epa.govOctober 25, 2006 TOXC707 (2006)

2. Toxins Outline Toxins vs. toxicantsToxin producers and evolutionary significance Drugs derived from natural sourcesPesticides derived from natural sourcesCholinergics derived from natural sourcesToxins derived from plantsToxins derived from aquatic organismsHerbal medicines and nutritional supplements

3. Neurotoxicology of Natural Toxins

4. Toxins vs. Toxicants Toxicants: Any manufactured chemical. Drugs Pesticides Industrial chemicals By-products Toxins: Produced by an organism. Algae Fungi Invertebrates Vertebrates Distinctions are not always clear (e.g., metals)

5. Evolutionary Significance of Toxins Obvious functions: Predator avoidance Predation Not-so-obvious functions: Trophic functions? Some common features of toxins: Molecular complexity Mechanistic specificity They weren�t designed to kill people Renewed interest in toxins: Pharmacognosy Ethnopharmacology

6. 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 � cactus Mescaline - cactus Psilocybin � magic mushrooms

7. Pesticides Derived from Natural Sources Pyrethrins � insecticide, chrysanthemum Nicotine � insecticide, tobacco plants Rotenone � piscisicide, cube resin, tropical plants Fluoroacetate � rodenticide, gifblaar plants Red Squill � rodenticide, Mediterranean squill plants Carbamates � insecticide, Physostigma venenosum Organophosphates �.

8. 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

9. Toxins and Target Organs (Norton) 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

10. Toxins and Target Organs (Norton) 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

11. Toxins Derived from Aquatic Organisms Marine organisms: Dinoflagellates � brevitoxins, ciguatoxins Diatoms � domoic acid Freshwater organisms: Cyanobacteria � anatoxins, saxitoxins, microcystins Harmful algal blooms (HABs): Impacts on human health and the environment. Possible causes - anthropogenic influences?

12. Marine Toxins: Many Named for Human Toxicity

13. Marine toxins: Molecular Complexity

14. Marine Toxins: Some Highly Selective Actions

15. World-wide Spread of Harmful Algal Blooms

16. Neurotoxins Produced by Cyanobacteria Anatoxin-a: nicotinic agonist Homoanatoxin-a: nicotinic agonist Anatoxin-a(s): cholinesterase inhibitor Saxitoxins and neosaxitoxins: Na-channel blockers BMAA: causative agent in cycad disease?

17. Neurotoxins Produced by Cyanobacteria

18. 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 Imidacloprid Conotoxins Nicotinic antagonists: Mecamylamine Hexamethonium Methyllycaconitine Dihydro-beta-erythroidine

19. 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 can�t be bad.� Principles of drug evaluation and regulation: Chemical identity Demonstrated efficacy Absence of toxicity

20. Concerns over Herbal Medicines and Nutriceuticals Quality control � standardization of ingredients Toxicity � are they safe? �Native� toxicity Interaction with drugs, other chemicals Efficacy � do they really work?

21. National Center for Complementary and Alternative Medicine (NIH)

22. 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. 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): 69-75, 2001. Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.) Goodman and Gilman�s The Pharmacological Basis of Therapeutics. 8th 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. 6th 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. 2nd 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.

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