1 / 44

Neurotoxicity:

Toxicology of the Nervous System. Neurotoxicity:. John J Woodward, PhD Department of Neurosciences IOP471N woodward@musc.edu www.people.musc.edu/~woodward. Historical Events. 1930’s – Ginger-Jake Syndrome

reilly
Download Presentation

Neurotoxicity:

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Toxicology of the Nervous System Neurotoxicity: John J Woodward, PhD Department of Neurosciences IOP471N woodward@musc.edu www.people.musc.edu/~woodward

  2. Historical Events • 1930’s – Ginger-Jake Syndrome • During prohibition, an alcohol beverage was contaminated with TOCP (triortho cresyl phosphate) causing paralysis in 5,000 with 20,000 to 100,000 affected. • 1950’s – Mercury poisoning • Methylmercury in fish cause death and severe nervous system damage in infants and adults.

  3. 'Drink this, honey' Radio talk-show host James Keown was arrested during a commercial break for the slow poisoning murder of his wife. Massachusetts authorities believe there was a lot James Keown’s wife didn’t know about him. They say that before Julie Keown slipped into a coma in September 2004, James Keown had woven a tale of deception so convincing that his 31-year-old wife would never have suspected her gregarious, redheaded husband was slowly poisoning her with a chemical (Ethylene glycol) found in antifreeze.

  4. Central Nervous System (CNS) • Brain & Spinal Cord • Peripheral Nervous System (PNS) • Afferent (sensory) Nerves – Carry sensory information to the CNS • Efferent (motor) Nerves – Transmit information to muscles or glands

  5. Cells of the Nervous System • Neurons • Signal integrators/Information conductors • Supporting Cells (Glia cells) • Astrocytes (CNS – blood brain barrier) • Oligodendrocytes (CNS – myelination) • Schwann cells (PNS – myelination)

  6. NEURONS

  7. Neuronal Synapses Specialized structure between neurons Specific for each type of neurotransmitter Fundamental unit of the nervous system

  8. CELL MEMBRANE AND MEMBRANE PROTEINS • Ion Channels • Important for nerve conduction • Voltage-sensitive • Ligand-gated • Selective for different ions

  9. Normal Receptor-Ligand Interaction 1 Ligand Outside Cell Receptor Cell Membrane 2 Inside Cell Ligand binds to receptor 3 Signal Protein Positive Response

  10. Inactivation of Receptor Mechanism of Receptor Blockade by Toxicant Competition For Receptor 1 1 Toxicant Ligand Toxicant Toxicant inactivates receptor Toxicant out competes normal ligand 2 2 3 Ligand cannot bind receptor 3 No Response No Response

  11. Brain Physiological Sensitivity/Vulnerability • Dependence on oxygen • Little anaerobic capacity • Cyanide – inability to use oxygen • Dependence on glucose • Sole energy source (no glycolysis) • High metabolic rate

  12. Blood Supply to the Brain

  13. ROUTES OF ADMINISTRATION

  14. Blood-brain Barrier • Anatomical Characteristics • Capillary endothelial cells are tightly joined – no pores between cells • Capillaries in CNS surrounded by astrocytes • Active ATP-dependent transporter – moves chemicals into the blood • Not an absolute barrier • Caffeine (small) • Methylmercury cysteine complex • Lipids (barbiturate drugs and alcohol) • Susceptible to various damages

  15. BBB can be broken down by: • Hypertension: high blood pressure opens the BBB • Hyperosmolarity: high concentration of solutes can open the BBB. • Infection: exposure to infectious agents can open the BBB. • Trauma, Ischemia, Inflammation, Pressure: injury to the brain can open the BBB. • Development: the BBB is not fully formed at birth.

  16. Underlying Cellular Biology Cellular Events in Neurodevelopment • Events: • Division • Migration • Differentiation • Neurogenesis • Formation of synapses • Myelination • Apoptosis Active throughout childhood & adolescence

  17. Neural Proliferation (rodent) P Rodier EHP 102(Suppl 2) 1994

  18. General principles for toxic response: • Blood-brain barrier (not completely developed in infants) • Sensitivity to oxygen and mitochondria function: • Maintenance of ion gradients by ATP and ATP-dependent membrane pumps (Na+,K+-ATPase, Ca2+-ATPase etc.) e.g., Cyanide deprives the brain of oxygen by binding to cytochrome oxidase; prevents mitochondria from utilizing oxygen and generating ATP. • C. Distance: Nervous system extends over space with complex • geometry (axonal transport over long distances). • D. Lipid condition and composition: Environment rich in lipids; maintenance of myelin is dependent upon many membrane proteins and lipid metabolism; affect receptors, channel and transport function. • E. Synaptic transmission: Target of many drugs

  19. What causes neurotoxicity? Wide range of agents – chemical and physical

  20. Toxicants and Exposure • Inhalation (e.g. solvents, nicotine, nerve gases) • Ingestions (e.g. lead, alcohol, drugs such as MPTP) • Skin (e.g. pesticides, nicotine) • Physical (e.g. load noise, trauma)

  21. Types Of Neurotoxicity • Neuronopathy • Cell Death. Irreversible – cells not replaced. • MPTP, Trimethyltin • Axonopathy • Degeneration of axon. May be reversible. • Hexane, Acrylamide • Myelinopathy • Damage to myelin (e.g. Schwann cells) • Lead, Hexachlorophene • Transmission Toxicity • Disruption of neurotransmission • Organophosphate pesticides, DDT, Cocaine

  22. Types of Neurotoxic Injury Normal Axonopathy Transmission Neuronopathy Myelinopathy Neuron Myelin Axon Synapse

  23. Mechanism of Action Neuronal Membrane and proteins Toxic substances may act on membrane proteins (receptors, channels, transporters, enzymes etc.). Naturally occurring toxic substances such as tetrodotoxin (from the puffer fish) and saxitoxin (from the marine alga responsible for paralytic shellfish poisoning) block ion channels, initially is followed by difficulty in speaking and swallowing and by an inability to coordinate muscular movements. In severe cases, respiratory paralysis may result. Scorpion toxin and the pesticide DDT act by increasing the flow of sodium ions.

  24. Mechanism of Action Neuronal Structures Organic mercury can cause degeneration of neurons in the cerebellum. Lead affects the cortex of the immature brain, causing irreversible mental retardation in young children. The peripheral nervous system is not protected by the blood-brain barrier. Degeneration of the axon is one of the most frequently encountered neurotoxic effects, leading to loss of sensation in the hands and feet or muscular weakness. Numerous toxic substances cause central-peripheral distal axonopathy (CPDA), including carbon disulfide and hexane.

  25. Mechanism of Action Glial Cells and Myelin Diphtheria toxin interferes with the glial cell body. Hexachlorophene interferes with mitochondria within glial cells. Perhexilline maleate, a drug used to treat the chest pain of angina pectoris, sometimes causes degeneration of myelin and leads to numbness in the hands and feet and muscle weakness.

  26. Mechanism of Action Neurotransmitter System Nicotine mimics the effects of acetylcholine. Organophosphorous compounds, such as insecticides and nerve gases, act by inhibiting acetylcholinesterase. A build-up of acetylcholine can lead to loss of appetite, anxiety, muscle twitching, and paralysis. Amphetamines stimulate the nervous system by causing the release of norepinephrine and dopamine from nerve cells. Cocaine affects both the release and reuptake of norepinephrine and dopamine. Both amphetamines and cocaine can cause paranoia, hyperactivity, and aggression, as well as high blood pressure and abnormal heart rhythms. Opium-related drugs such as morphine and heroin act at specific opioid receptors in the brain. Drugs acting at opioid receptors cause sedation and euphoria and reduce pain. They are highly addictive. Withdrawal from these drugs leads to impaired vision, restlessness, and tremors. Addicted infants born to women who use drugs suffer from symptoms of withdrawal seen in adults.

  27. Case Studies of Neurotoxicology • Lead – damages developing brain • Alcohol – Fetal alcohol syndrome • Mercury – environmental threat

  28. Ancient Awareness “LEAD MAKES THE MIND GIVE WAY” Dioscorides - GREEK 2ND BC

  29. Ancient/Premodern History Lead oxide as a sweetening agent Lead pipes (“plumbing”) Ceramics Smelting and foundries Modern History Gasoline Ceramics Crystal glass Soldering pipes “tin” cans car radiators House paint Historical Sources of Lead Exposure

  30. Nervous Systems Effects Lead Neurotoxicity • Developmental Neurotoxicity • Reduced IQ • Impaired learning and memory • Life-long effects • Related to effects on ion channels (NMDA, Ca++ channels)

  31. Mechanisms of Damage to the Nervous System by Lead Central • Cerebral edema • Apoptosis of neuronal cells • Necrosis of brain tissue • Glial proliferation around blood vessels Peripheral • Demyelination • Reversible changes in nerve conduction velocity (NCV) • Irreversible axonal degeneration

  32. TOXICOLOGY OF ALCOHOL • FREELY SOLUBLE, DISTRIBUTED TO ALL TISSUES • IMPAIRMENT EVALUATED BY BLOOD-ALCOHOL LEVELS (0.08% = 17 mM) • PEAK CONCENTRATIONS USUALLY REACHED IN 30-90 MINUTES • SLOW METABOLISM (zero order kinetics)

  33. Alcohol - Ethanol Vulnerability of Developing Nervous System FAS – Fetal Alcohol Syndrome (or Fetal Alcohol Spectrum Disorders: FASD affects 1 in 100 live births or as many as 40,000 infants each year)

  34. FAS Child

  35. EFFECTS OF PRENATAL ALCOHOL EXPOSURE • Structural-observable physical damage • Neurological-signs of impairment in motor skills, sensory integration or evidence of seizure activity • Functional-deficits or delays in normal developmental processes, impulse control, memory, etc.

  36. Toxicity of Mercury • Different chemical forms – inorganic, metallic, organic ( • Organic mercury (methylmercury) is the form in fish; bioaccumulates to high levels • Organic mercury from fish is the most significant source of human exposure • Brain and nervous system toxicity • Cardiovascular toxicity Hg0 Hg2+ CH3Hg+)

  37. Organic mercury • Readily crosses the placenta and enters the brain of the fetus (and adult) • Converted to inorganic Hg in brain with long half-life (months, years) • High fetal exposures: mental retardation, seizures, blindness • Low fetal exposures: memory, attention, language disturbances

  38. Effects On The Brain • Decrease in brain size • Cell loss (apoptosis) • Disorganization of cells (affect enzymes, membrane function, neurotransmitter levels, mitochondria function) • Cell migration failures

  39. Environmental Sources of Mercury • Natural Degassing of the earth • Combustion of fossil fuel • Industrial Discharges and Wastes • Incineration & Crematories • Dental amalgams

  40. Atmospheric Hg

  41. MeHg Consumption Limits US EPA – 0.1 ug/kg-day US FDA – 1 ppm (mg/kg) in tuna Consuming large species such as tuna and swordfish even once a week may be linked to fatigue, headaches, inability to concentrate and hair loss, all symptoms of low-level mercury poisoning. In a study of 123 fish-loving subjects, the researchers found that 89% had blood levels of methylmercury that exceeded the EPA standard by as much as 10 times. How Much Tuna Can You Eat Each Week? A safe level would be approximately 1oz for every 20lb of body weight. So for a 125lb (57kg) person, 1 can of tuna a week maximum.

  42. END

More Related