Transcript Biochemical Toxicology of the CNS

TOXC707 (2006)
Neurotoxicology of Natural Toxins
Robert C. MacPhail, Ph.D.
[email protected]
October 25, 2006
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: Any manufactured
Drugs
Pesticides
Industrial chemicals
By-products
◄
chemical.
Toxins: Produced by an organism.
Algae
Fungi
Invertebrates
Vertebrates
◄
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 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
Pesticides Derived from Natural Sources
◄ Pyrethrins
◄ Nicotine
– insecticide, chrysanthemum
– insecticide, tobacco plants
◄ Rotenone
– piscisicide, cube resin, tropical plants
◄ Fluoroacetate
◄ Red
– rodenticide, gifblaar plants
Squill – rodenticide, Mediterranean squill plants
◄ Carbamates
– insecticide, Physostigma venenosum
◄ Organophosphates
….
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)
◄
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)
◄ 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:
◄ Anatoxin-a(s):
◄ Saxitoxins
◄ BMAA:
nicotinic agonist
cholinesterase inhibitor
and neosaxitoxins: Na-channel blockers
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 delta
Nicotinic agonists:
Anatoxin-a
Epibatidine
Imidacloprid
Conotoxins
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 can’t be bad.”
◄
Principles of drug evaluation and regulation:
Chemical identity
Demonstrated efficacy
Absence 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.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.
Neurotoxicology of Natural Toxins
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