Neurotoxicology LECTURE NOTES PDF

Neurotox Jessica Legradi Learning goals Know what the nervous system is Understand how neurotransmitter signaling can be disrupted Know examples and the MoA of Pyrethroids Organophosphates Organochlorates Neonicotinoids Introduction to Toxicolo...

Neurotox Jessica Legradi Learning goals Know what the nervous system is Understand how neurotransmitter signaling can be disrupted Know examples and the MoA of Pyrethroids Organophosphates Organochlorates Neonicotinoids Introduction to Toxicology 2  Relevance A link between human exposure to some chemical substances and neurotoxicity has been firmly established (Anger, 1986; OTA, 1990). It has been estimated that alone in Europe, exposure to solely endocrine disrupters that lead to neurological disorders, costs society €150 billion per year (Bellanger 2015) The number of chemicals with neurotoxic potential has been estimated to range from 3% to 28% of all chemicals (OTA, 1990) Majority of the materials in commercial use have not been tested for neurotoxic potential (NRC, 1984)  What is neurotoxicity? Neurotoxicity is toxicity in the nervous system. It occurs when exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue wikipedia What is the nervous system? Where compounds could be active and how?  The nervous system nerve system = neural system = nervous system CNS: a) brain b) Spinal cord PNS: a) Somatic - voluntary movements b) Autonomic - sympathetic and parasympathetic c) Enteric - gastrointestinal system Structural elements Nerve cells Glial cells Molecular elements Neurotransmitter Enzymes Calcium, Sodium,.. ATP…. TNF-α, caspases,…  The Synapse 1. action potential arrives at presynaptic neurone 2. stimulates opening of voltage-gated channels for Ca2+ 3. Ca2+ diffuse into cytoplasm of presynaptic membrane 4+5. Ca2+ cause vesicles containing acetylcholine (ACh – a type of neurotransmitter) move towards the presynaptic membrane 6. Vesicle fuses with the membrane, Ach is released and diffuses across the synaptic cleft 7. Ach temporarily binds to receptor proteins on the postsynaptic membrane; causes chemically- gated ion channels for Na+ to open 8. Na+ diffuse through postsynaptic membrane àdepolarizes membrane à generates action potential Signaltransduction Blood-Brain-Barrier Neurogenesis  What is neurotoxicity? Neurotoxicity is toxicity in the nervous system. It occurs when exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue wikipedia  Neurotoxic Neurons can be damaged: Directly via substances (Neuronopathy) Indirectly by damaging the axon (Axonopathy) By damaging the myelin sheet or neuroglia (Myelopathy) By disturbing the synaptic signaling Pesticide classes Introduction to Toxicology 17 Acetylcholinesterase inhibition Mechanism of Action 18 Principle cholinesterase inhibition neurotransmission acetylcholine acetylcholinesterase (ACh) (AChE) neuron 1 neuron 2 + ACh + AChE + Inhibitor + AChE Mechanism of Action 19 Organophosphate esters and carbamatic esters AChE inbitors carbofuran methiocarb propoxur oxamyl Mechanism of Action 20 Sarin is a AChE inhibitor Mechanism of Action 21 Species differences in sensitivity to organophosphate esters Mechanism of Action 22 Ion channels Channels for …. ions Chloride Sodium Calcium Potassium Proton Non selective Blockage = Antagonist Activation = Agonist Introduction to Toxicology 23 Ion channel types Ligand-gated = Receptor gated  The Action Potential http://bcs.whfreeman.com/webpub/Ektron/Hillis%20Principles%20of%20Life2e/Animated%20Tutorials/pol2 e_at_3402_The_Action_Potential/pol2e_at_3402_The_Action_Potential.html  Organochlorine insecticides Accumulating in the environment and in biota Iterative evaporation and condensation: global distillation or grasshopper effect Low volatility Chemically stable Lipophilic Resistant All organochlorines are qualified as POPs (Stockhom convention) Mechanism of Action 26  DDT Responsible for decline in bird populations Eggshell thinning Endocrine disrupting Cl Cl Cl Cl Cl Mechanism of Action 27 p,p’-DDE causes eggshell thinning Interferes with Ca-ATPase Possible by inhibited synthesis of prostaglandin E2 (PGE2) Not true ENDOCRINE disruption, but MESSENGER disruption Mechanism of Action 28 Neurotoxic mechanism of action DDT Blocks voltage gated sodium channels in neurons Sodium channels do not close properly after depolarisation “After-potential” Faster new depolarisation “Repetitive firing” Mechanism of Action 29 Pyrethroids “Modern” insecticides (since 1980) Derived from pyrethrins Smell like chrysanths Type I (without CN group) and Type II (with CN group) Bind to Block voltag gated Na-channels pyrethrin I pyrethrin II permethrin cypermethrin deltamethrin Mechanism of Action 30  Pyrethroids Mode of action Prolonged Na-influx in the cell Negative after-potential as with DDT Type I Hyperexcitable state Repetitive firing Type II Loss of membrane potential Action potential impossible Advantage Very toxic (efficient) Degradable in sun light Degradable in water Disadvantage Very toxic (side effects) Fish are very sensitive Mechanism of Action 31  Neonicotinoids Derived from nicotine Most well-known example imidacloprid Activation of acetylcholine receptor nicotinic ACh-receptors are Na, Ca, K channels Neonicotinoids and bee decline Volkskrant 30 maart 201 Mechanism of Action 33 Curare = arrow poison 34 Mechanis m of Drugs Drugs cocaine Amphetamine Dopamin- Stimulant Medicine Potassium Channel Antagonist: used in the treatment of cardiac arrhythmia block the potassium channels, thereby prolonging repolarization Azimilide, Bretylium Potassium channel opener: smooth muscle relaxing activity, treat angina Diazoxide, Nicorandil Calcium Channel Antagonist: to reduce systemic vascular resistance and arterial pressure, treat angina Alcohol, Verapamil Introduction to Toxicology 37 Other mechanisms Introduction to Toxicology 38  Parkinsonism - MPTP Dopaminergic neurons get specifically damaged by 1-Methyl-4-phenyl- 1,2,3,6-tetrahaydropyridin (MPTP). Selectivity for dopaminergic neurons is based on a special transport mechanism: Astrocytes metabolise MPTP to Methylpyridin(MPP+) which is taken up specifically by dopaminergic neurons where it accumulates in the mitochondria  Botulinum toxin produced by the bacterium Clostridium botulinum In 1820, Justinus Kerner, a small-town German medical officer studied the sausage poisoning and discovered botox. He suggested the use for medical purposes. Used for cosmetic treatments and a variety of diseases (migraine, stigmatisms, chronic pain, sweating,…) Inhibits excretion of Acetylcholinesterase Mechanism of Action 40 Chronic solvent induced encephalopathy (CSE) a condition induced by long-term exposure to organic solvents often but not always in the workplace leads to a wide variety of persisting sensorimotor polyneuropathies and neurobehavioral deficits even after solvent exposure has been removed Figure 3. SPM maps of significant correlations (p < 0.001) between activation and lifetime solvent exposure in painters. Green indicates decreased activation with increased exposure levels (observed in anterior cingulate gyrus, prefrontal cortex, PC, and IC); blue indicates increased activation with increased exposure levels (no significant voxels present); and red indicates general group activation patterns with the N-Back task. Mechanism of Action 41