Neurotoxicology of Natural Toxins

Robert C. MacPhail, Ph.D.

macphail.robert@epa.gov

October 25, 2006

TOXC707 (2006)

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

Neurotoxicology of Natural Toxins

Toxins vs. Toxicants

◄ Toxicants: Any manufactured chemical.DrugsPesticidesIndustrial chemicalsBy-products

◄ Toxins: Produced by an organism.AlgaeFungiInvertebratesVertebrates

◄ Distinctions are not always clear (e.g., metals)

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

Drugs Derived from Natural Sources

◄ Stimulants:Cocaine – coca leavesKhat (cathinone) – catha edulisCaffeine – coffee beansEphedra – ma huangNicotine – tobacco plants

◄ Euphorics:Morphine - poppiesCodeine - opiumCannabinoids - marijuanaEthanol - yeast

◄ Convulsants:Picrotoxin – Cocculus indicusStrychnine – Strychnos nux-vomica

◄ Hallucinogens:LSD - fungusPeyote – cactusMescaline - cactusPsilocybin – magic mushrooms

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 ….

Cholinergic Agents Derived from Natural Sources

◄ Muscarinic agonists:MuscarinePilocarpineArecolinePhysostigmine

◄ Muscarinic anatgonists: “belladonna”AtropineScopolamine

◄ Nicotinic agonists:NicotineEpibatidineAnabaseineAnatoxin-a

◄ Nicotinic antagonists:CurareAlpha-bungarotoxin

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 arythmiasVeratrum alkaloids, aconitine – prolong sodium currentsGrayanotoxins – mad honey poisoningErgot – St. Anthony’s Fire – derivatives of lysergic acid

◄ Blood:Dicumarol – fungal-infected clover – hemorrhagesCyanogenics – amygdalin, from almonds

casava and Konzo, from linamarin that produces thiocyanate, leading to spastic paralysis and motor neuron degeneration

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

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?

Marine Toxins: Many Named for Human Toxicity

Marine toxins: Molecular Complexity

Marine Toxins: Some Highly Selective Actions

World-wide Spread of Harmful Algal Blooms

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?

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 deltaNicotinic agonists:

Anatoxin-a EpibatidineImidaclopridConotoxins

Nicotinic antagonists:MecamylamineHexamethoniumMethyllycaconitineDihydro-beta-erythroidine

Herbal Medicines and Nutritional Supplements

◄ The heritage of folk remedies.◄ Increasing use of dietary supplements and alternative

medicines:Health-conscious AmericansIncreasing cost of medicinesIncreasing number of older adultsIncreasing 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 identityDemonstrated efficacyAbsence of toxicity

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?

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.Dietary Supplemental Health and Education Act of 1994. Public Law 103-417. http://www.fda.gov/opacom/laws/dshea.htmlFabricant, 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. 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. 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. 6 th 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.

Neurotoxicology of Natural Toxins

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