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Introduction to Neurotoxicology

Introduction to Neurotoxicology. Functions of the Nervous System. Detect sensory inputs Communication Integration and processing of responses Neuroendocrine. Organization of the Nervous System. Macroscopic organization: CNS and PNS Cellular organization Neurons Glial cells Astrocytes

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Introduction to Neurotoxicology

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  1. Introduction to Neurotoxicology

  2. Functions of the Nervous System • Detect sensory inputs • Communication • Integration and processing of responses • Neuroendocrine

  3. Organization of the Nervous System • Macroscopic organization: CNS and PNS • Cellular organization • Neurons • Glial cells • Astrocytes • Oligodendrocytes • Schwann cells • Microglia

  4. Structure of a Neuron

  5. Neurotransmission

  6. Myelin Formation

  7. Unique Features of the Nervous System • Several features of the nervous system predispose it to chemically-induced injury • High metabolic rate • Neurons dependent on aerobic glycolysis • Brain is 2% of body weight, but 15% of cardiac output • Great distance from cell body to axon • Limited capacity for repair • Blood-Brain-Barrier (incomplete)

  8. Evidence of Neurotoxicity Humans • Epidemiological • Clinical case reports • Neurotoxicity first noted in humans • Metals (lead, mercury, manganese) • Drugs (MPTP) Animals • Experimental studies • Clinical case reports

  9. Evaluation of Neurotoxicity in Animals • Structure - Neuropathology (Light and electron microscopy, and special studies) • Functional – Neurochemistry (Neurotransmitter binding and receptor studies, and metabolism) • Behavioral – Sensory, motor, autonomic and cognitive function • Electrophysiology – EEG, evoked potential

  10. Cognitive deficits in lead exposed children

  11. Toxicants Affecting Neurotransmission • Functional nervous system requires a balance of stimulatory and inhibitory signals • Often see clinical effects without pathology • Toxic agents include organophosphates, strychnine, DDT, MPTP, glutamine, domoic acid, and agents with anesthetic properties.

  12. Organophosphates and Carbamates • Common insecticides and war gases that block acetylcholinesterase • Acute toxicity-SLUD and tremors • Treat with atropine and 2-PAM • Chronic toxicity affects memory and OPIDN- delayed neuropathy. Humans, cat, chicken are sensitive (Ginger Jake)

  13. Interference with Dopamine • MPTP (1-Methyl-4-Phenyl-1,2,3,6-Tetra-hydropyridine) and manganese • Causes a Parkinson’s like disease • Toxicity of MPTP appears to be due to the generation of free radicals that lead to the death of dopaminergic neurons

  14. Excitotoxicity • Glutamate is the major excitatory amino acid in the CNS • NMDA receptor opens and permits influx of Ca++ that leads to cell death • Neurotoxic agents include domoic acid from shellfish, monosodium glutamate, long-term mercury, kanic and quisqualic acid

  15. Neuronopathies • Toxicity primarily affects neurons • Hypoxia and ischemia due to decreased blood flow, methemoglobin and carboxy-hemoglobin, and cyanide • Hypoglycemia - neurons have little or no anaerobic glycolysis • Blockage of protein synthesis - Cisplatin, methyl mercury, organomercurials

  16. Axonopathies • Toxicity damages the axon • The longest axons usually exhibit the greatest toxicity • Chemicals include acrylamide, carbon disulfide, hexacarbons, and organophosphates

  17. Myelinopathies • Can affect central and peripheral nervous system • Triethyltin and hexachlorophene cause CNS myelinopathies

  18. Examples of Neurotoxicants

  19. Reading Material • Casserett and Doull’s Toxicology • US EPA Neurotoxicity Risk Assessment Guidelines http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=4555

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