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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

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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
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 in Japan cause death and severe nervous system damage in infants and adults (Minimata disease).
slide3

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
cells of the nervous system
Cells of the Nervous System
  • Neurons
    • Signal integration/generation; direct control of skeletal muscle (motor axons)
  • Supporting Cells (Glia cells)
    • Astrocytes (CNS – blood brain barrier)
    • Oligodendrocytes (CNS – myelination)
    • Schwann cells (PNS – myelination)
    • Microglia (activated astrocytes)
cellular events in neurodevelopment

Underlying Cellular Biology

Cellular Events in Neurodevelopment
  • Events:
  • Division
  • Migration
  • Differentiation
  • Neurogenesis
  • Formation of synapses
  • Myelination
  • Apoptosis

Active throughout

childhood &

adolescence

slide6

Development of GABA and Glutamate Synapses in Primate Hippocampus

  • GABA synapses develop on contact
  • Glutamate synapses develop but require a developed spine to become active
  • GDPs dominate early developmental neuronal activity and disappear prior to birth (primates) or during early neonatal life (rodents)
why is the brain particularly vulnerable to injury
Why is the Brain Particularly Vulnerable to Injury?
  • Neurons are post-mitotic cells
  • High dependence on oxygen
    • Little anaerobic capacity
    • Brief hypoxia/anoxia-neuron cell death
  • Dependence on glucose
    • Sole energy source (no glycolysis)
    • Brief disruption of blood flow-cell death
  • High metabolic rate
  • Many substances go directly to the brain via inhalation
blood brain barrier
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), nicotine
    • Methylmercury cysteine complex
    • Lipids (barbiturate drugs and alcohol)
    • Susceptible to various damages
bbb can be broken down by
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.
what causes neurotoxicity
What causes neurotoxicity?

Wide range of causes

Chemical

Physical

toxicants and exposure
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)
slide14

CELL MEMBRANE AND MEMBRANE PROTEINS

  • Ion Channels
  • Important for establishing resting membrane potetial
  • Synaptic transmission/nerve conduction
  • Voltage-sensitive
  • Ligand-gated

Sodium channel

types of neurotoxic injury
Types of Neurotoxic Injury

Normal

Axonopathy

Transmission

Neuronopathy

Myelinopathy

Neuron

Myelin

Axon

Synapse

types of neurotoxicity
Types Of Neurotoxicity
  • Neuronopathy
    • Cell Death. Irreversible – cells not replaced.
    • MPTP, Trimethyltin
  • Axonopathy
    • Degeneration of axon. May be reversible.
    • Hexane, Acrylamide, physical trauma
  • Myelinopathy
    • Damage to myelin (e.g. Schwann cells)
    • Lead, Hexachlorophene
  • Transmission Toxicity
    • Disruption of neurotransmission, toxins, heavy metals, organophosphate pesticides, DDT, drugs (eg., cocaine, amphetamine, alcohol)
slide17

Ion Channels are Targets for a Variety of Toxins, Chemicals and Therapeutic Compounds

Natural Toxins

Snake, insect,plant toxins

(cobra venom, scorpion, curare)

Environmental Chemicals

Heavy metals, industrial solvents

(lead, benzene, aromatic hydrocarbons)

Therapeutic Drugs

Anesthetics, Benzodiazepines

(lidocaine, halothane, valium)

Drugs of abuse

(Ketamine, alcohol, inhalants)

neurotoxicology
Neurotoxicology
  • Heavy Metals
  • Lead – environmental exposure (paint, fuels)
  • Mercury – exposure via diet (bioaccumulation in fish)
historical sources of lead exposure
Ancient/Premodern History

Lead oxide as a sweetening agent

Lead pipes (“plumbing”)

Ceramics

Smelting and foundries

Modern History

Gasoline (leaded)

Ceramics

Crystal glass

Soldering

pipes

“tin” cans

car radiators

House paint

Historical Sources of Lead Exposure
nervous systems effects
Nervous Systems Effects

Lead

Neurotoxicity

  • Developmental Neurotoxicity
  • Reduced IQ
  • Impaired learning and memory
  • Life-long effects
  • Related to effects on calcium permeable channels (NMDA, Ca++ channels)
mechanisms of damage to the nervous system by lead
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
environmental sources of mercury
Environmental Sources of Mercury
  • Natural Degassing of the earth
  • Combustion of fossil fuel
  • Industrial Discharges and Wastes
  • Incineration & Crematories
  • Dental amalgams
  • CF bulbs
toxicity of mercury
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
    • High fetal exposures: mental retardation, seizures, blindness
    • Low fetal exposures: memory, attention, language disturbances

Hg0

Hg2+

CH3Hg+)

mehg consumption limits
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.

excitotoxicity glutamate mediated cell death
Excitotoxicity-Glutamate Mediated Cell Death

Experimental Observations

  • Glutamate induces a delayed cell death in neurons
  • This cell death requires extracellular calcium and is blocked by antagonists of NMDA receptors
  • Hypothesis: Prolonged or inappropriate activation of NMDA receptors underlies glutamate excitotoxicity of neurons
slide26

Glutamate Synapses

Excitatory synapse of brain

Required to generate action potentials

Both AMPA and NMDA receptors are critical for normal brain function

NMDA-hi Ca++ permeability

Glutamate synapse

overview of glutamate and excitotoxicity
Overview of Glutamate and Excitotoxicity

Glutamate activates two types of ion channels (AMPA and NMDA)

Cell Death is associated with excessive calcium entry through NMDA receptors

both native and recombinant nmda receptors can cause excitotoxicity
Both Native and Recombinant NMDA Receptors Can Cause Excitotoxicity

Neurons

Transfected CHO cells

nmda induced excitotoxicity is nr2 subunit dependent in recombinant expression systems
NMDA-induced Excitotoxicity is NR2 Subunit Dependent in Recombinant Expression Systems

NMDARS require two NR1 subunits and two NR2 subunits

-NR2 family-NR2A, 2B, 2C, 2D

-NR2A, NR2B high excitotoxicity potential

-NR2C, NR2D lower excitotoxicity potential

calcium and excitotoxicity
Calcium and Excitotoxicity

Glutamate-mediated apotosis in spinal motor neurons is blocked by calpain inhibitors

Expose cells to 10 µM Glu in absence or presence of calpeptin

Monitor apoptosis (left panel) or membrane potential (right panel)

the calcium that triggers excitotoxicity is source dependent
The Calcium That Triggers Excitotoxicity is Source-Dependent
  • Calcium entry via NMDA receptors can trigger neuronal cell death
  • Calcium entry through other channels (eg. VSCC) does not
  • Location of NMDA receptors is also important, synaptic versus extrasynaptic
slide32

Mitochondrial Dysfunction Resulting from Calcium Overload is Source-Specific

CalciumMito Vm

  • Synaptic and non-synaptic NMDA Receptors Increase Calcium
  • L-type calcium channel increase calcium
  • Synaptic NMDA receptors and L-type channels do no affect mitochondrial function
  • Extrasynaptic NMDA receptors disrupt mitochondrial function and are linked to excitotoxicity
glutamate excitoxicity in oligodendrocytes
Glutamate Excitoxicity in Oligodendrocytes
  • Historically, oligos were thought to lack NMDA receptors
  • More recent studies demonstrate NMDA and non-NMDA currents in oligos
  • These receptors may be activated by injury or ischemic conditions that result in the release of glutamate
  • Loss of oligo processes may underlie myelin degeneration associated with many diseases such as cerebral palsy, spinal cord injury and multiple sclerosis
glutamate excitoxicity in oligodendrocytes34
Glutamate Excitoxicity in Oligodendrocytes
  • Oxygen-glucose deprivation (OGD)-model of ischemic damage
  • Leads to loss of oligo processes
  • This is prevented by blockers of NMDA receptors (MK801)
glutamate in human brain following stroke
Glutamate in Human Brain Following Stroke

Glutamate

Threonine

Glutamate levels remain high after stroke

Threonine, a structural amino acid, is measured as a control