NBB 4910 Principles of Neurobiology INSECTICIDE NEUROTOXICOLOGY Jeff Scott Guest Lecture Spring 2015
References Soderlund, D., 2012 Molecular mechanisms of pyrethroid insecticide neurotoxicity: recent advances. Archives of Toxicology 86: 165–181. Raymond-Delpuch, V., K. Matsuda, B. M. Sattelle, J. J. Rauh & D. B. Sattelle. 2005. Ion channels: molecular targets of neuroactive insecticides. Invert Neurosci 5: 119- 133. Zlotkin, E. 2001. Insecticides Affecting Voltage-Gated Ion Channels In: Biochemical Sites of Insecticide Action and Resistance (I. Ishaaya ed) pp. 43-76. Springer-Verlag Berlin, Heidelberg.E. J. R. Bloomquist, 1996. Ion channels as targets for insecticides, Ann. Rev. Entomol. 41: 163-90.
Pesticides The USA uses 1.0-1.5 billion pounds of pesticides (herbicides, insecticides, etc.) per year
Historical Perspective Long, long ago Inorganics Long ago botanicals 1880 Commercial production (inorganics) 1941 DDT Effective insect control 1946 Cyclodienes 1947 Organophosphates 1950 Carbamates 1970 Insect Growth regulators 1980 Pyrethroids #2 1995 Genetic engineering 2000 Neonicotinoids #1
Historical Perspective Long, long ago Inorganics Long ago botanicals 1880 Commercial production (inorganics) 1941 DDT Effective insect control 1946 Cyclodienes 1947 Organophosphates 1950 Carbamates 1970 Insect Growth regulators 1980 Pyrethroids #2 1995 Genetic engineering 2000 Neonicotinoids #1
Perspective and Predictions In addition to pest control, neurotoxic insecticides have played key roles in characterization of the nervous system (e.g. DFP characterized serine in active site of AChE) Synthetic insecticides w ill continue to be a major factor for pest control into the foreseeable future .
Neurophysiology of insecticides acting on sodium channels DDT & pyrethroids To investigate the mechanism of action of neurotoxins there are two main types of data one can gather: behavior and neurophysiology Usually both provide very useful information
HISTORY OF DDT H Cl C Cl CCl 3 (DichloroDiphenylTrichloroethane) • Synthesized in 1874 by Ziedler • Insecticidal activity discovered by Paul Muller of Geigy in 1939. • Won the Nobel prize in 1948. • DDT opened the era of synthetic organic insecticides and "efficient" insect control. Called "miracle insecticide" or "the insecticide that won the w ar" in the mid 1940s. • Extremely effective against a broad range of insects (LD 50 1 - 1000 ug/g to insects).
HISTORY OF DDT • Relatively safe to humans (oral LD 50 to humans 250 mg/kg, 115 mg/kg to rats, practically non-toxic by dermal exposure). • Cheap !!!!!!! ~$0.50 per pound. • DDT has saved millions of lives. Controls vectors of diseases such as typhus, yellow fever or malaria. Use of DDT nearly eradicated malaria from the planet. Some areas still are malaria free w hile other have resurgence in the number of cases. • >2,000,000 tons of DDT have been manufactured (Mellanby 1992) • 1962 Silent Spring labels DDT the “Elixir of Death”
Military use of DDT
Civilian use of DDT
In vivo poisoning symptoms
American Cockroach CNS Cockroach cercal nerve-giant axon preparation
In situ poisoning symptoms
Voltage Clamp
Voltage Clamp Normal
Voltage Clamp TTX
Normal vs. TTX Voltage Clamp
Voltage Clamp TEA
Normal vs. TEA Voltage Clamp
Voltage Clamp DDT
Normal vs. DDT Voltage Clamp
Voltage Clamp DDT + TEA
DDT alone vs.. Voltage Clamp DDT + TEA
Voltage Clamp DDT + TTX
Voltage Clamp TTX alone vs.. DDT + TTX
Do the voltage clamp experiments explain the repetitive discharges? Do repetitive discharges explain the symptoms?
Pyrethroids • Based upon a natural product - pyrethrins • First pyrethroids w ere synthesized in the 1940s, but they w ere not stable under field conditions. • Field stable pyrethroids discovered in the 1960s. • The 2nd largest class of insecticides in use today
Pyrethrins and the first pyrethroids These insecticides appear to be “super DDT” Symptoms are similar Both cause repetitive discharges Both prolong the opening of the sodium channel Both are more toxic at low er temperatures VIDEO ? H H O = Cl C Cl H C O CCl 3 H O DDT Pyrethrin I But then something unusual happened
α -CN pyrethroids (Type II) Symptoms of poisoning are radically different from DDT or Type I pyrethroids VIDEO There are no repetitive discharges VIDEO
Structures Type I Type II O O O C O C N C O O CN Cl O fenvalerate tetramethrin CN O O O O C O C O phenothrin cyphenothrin CN O O O O Cl Cl C O C O Cl Cl permethrin cypermethrin
Identify the site of action type II pyrethroids What w ould you do?
clamp data Patch Type I Yamamoto et al (1983 )
Control 10 μ M deltamethrin Patch clamp data Type II Chinn and Narahashi 1986
Patch clamp summary Insecticide Open Time none 1-2 msec DDT 10-20 msec Type I pyrethroid 20-80 msec Type II pyrethroid >80 msec How does this explain the lack of repetitive discharges?
Both DDT and pyrethroids (both Type I and Type II) hold the voltage gated sodium channel in the open state Differences in symptoms (and potencies) can be explained by differences in kinetics
Any questions?
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