Neurotoxicity:

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Neurotoxicity
Toxicology of the Nervous System
John J Woodward, PhD Department of
Neurosciences IOP471N woodward_at_musc.edu www.peopl
e.musc.edu/woodward
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Historical Events

• 1930s 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.
• 1950s Mercury poisoning
• Methylmercury in fish cause death and severe
  nervous system damage in infants and adults.

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'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 Keowns wife didnt
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.
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• 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

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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)

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NEURONS
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Neuronal Synapses
Specialized structure between neurons Specific
for each type of neurotransmitter Fundamental
unit of the nervous system
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CELL MEMBRANE AND MEMBRANE PROTEINS

• Ion Channels
• Important for nerve conduction
• Voltage-sensitive
• Ligand-gated
• Selective for different ions

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Normal Receptor-Ligand Interaction
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Ligand
Outside Cell
Receptor
Cell Membrane
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Inside Cell
Ligand binds to receptor
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Signal Protein
Positive Response
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Inactivation of Receptor
Mechanism of Receptor Blockade by Toxicant
Competition For Receptor
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1
Toxicant
Ligand
Toxicant
Toxicant inactivates receptor
Toxicant out competes normal ligand
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2
3
Ligand cannot bind receptor
3
No Response
No Response
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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

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Blood Supply to the Brain
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ROUTES OF ADMINISTRATION
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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

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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.

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Cellular Events in Neurodevelopment
Underlying Cellular Biology

• Events
• Division
• Migration
• Differentiation
• Neurogenesis
• Formation of synapses
• Myelination
• Apoptosis

Active throughout childhood adolescence
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Neural Proliferation (rodent)
P Rodier EHP 102(Suppl 2) 1994
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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

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What causes neurotoxicity?

• Wide range of agents chemical and physical

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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)

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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

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Types of Neurotoxic Injury
Normal
Axonopathy
Transmission
Neuronopathy
Myelinopathy
Neuron
Myelin
Axon
Synapse
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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.
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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.
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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.
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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. Ampheta
mines 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.
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Case Studies of Neurotoxicology

• Lead damages developing brain
• Alcohol Fetal alcohol syndrome
• Mercury environmental threat

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Ancient Awareness

• LEAD MAKES THE MIND GIVE WAY
• Dioscorides - GREEK 2ND BC

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Historical Sources of Lead Exposure

• 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

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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)

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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

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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)

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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)
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FAS Child
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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.

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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)
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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

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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

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Environmental Sources of Mercury

• Natural Degassing of the earth
• Combustion of fossil fuel
• Industrial Discharges and Wastes
• Incineration Crematories
• Dental amalgams

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Atmospheric Hg
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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.
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