Transcript Toxicology of the Nervous System

Neurotoxicity:
Toxicology of the Nervous System
John J Woodward, PhD
Department of Neurosciences
IOP471N
[email protected]
www.people.musc.edu/~woodward
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.
'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.
 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
 Neurons
• Signal integrators/Information
conductors
 Supporting Cells (Glia cells)
• Astrocytes (CNS – blood brain barrier)
• Oligodendrocytes (CNS – myelination)
• Schwann cells (PNS – myelination)
NEURONS
Neuronal Synapses
Specialized
structure between
neurons
Specific for each
type of
neurotransmitter
Fundamental unit of
the nervous system
CELL MEMBRANE AND MEMBRANE PROTEINS
Ion Channels
•Important for
nerve conduction
•Voltage-sensitive
•Ligand-gated
•Selective for
different ions
Normal Receptor-Ligand Interaction
1
Ligand
Receptor
2
Cell
Membrane
Outside Cell
Inside Cell
Ligand binds to receptor
Signal Protein
3
Positive Response
Mechanism of Receptor Blockade by Toxicant
Inactivation of Receptor
Competition For Receptor
1
1
Toxicant
Ligand
Toxicant
2
Toxicant
inactivates
receptor
Toxicant
out competes
2 normal ligand
3
3 Ligand cannot bind
receptor
No
Response
No Response
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
Blood Supply to the Brain
ROUTES OF
ADMINISTRATION
Blood-brain Barrier
 Anatomical Characteristics
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•
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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
•
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Caffeine (small)
Methylmercury cysteine complex
Lipids (barbiturate drugs and alcohol)
Susceptible to various damages
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.
Underlying Cellular Biology
Cellular Events in Neurodevelopment
Events:
 Division
 Migration
 Differentiation
 Neurogenesis
 Formation of synapses
 Myelination
 Apoptosis
Active
throughout
childhood &
adolescence
Neural Proliferation (rodent)
P Rodier EHP 102(Suppl 2) 1994
General principles for toxic response:
A. Blood-brain barrier (not completely developed in infants)
B. 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
What causes neurotoxicity?
Wide range of agents –
chemical and physical
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)
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
Types of Neurotoxic Injury
Normal
Neuron
Myelin
Axon
Synapse
Axonopathy
Transmission
Neuronopathy
Myelinopathy
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.
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.
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.
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.
Case Studies of Neurotoxicology
Lead – damages developing brain
Alcohol – Fetal alcohol syndrome
Mercury – environmental threat
Ancient Awareness
“LEAD MAKES THE
MIND GIVE WAY”
Dioscorides - GREEK 2ND BC
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
Lead
Neurotoxicity
Nervous Systems Effects
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Developmental Neurotoxicity
Reduced IQ
Impaired learning and memory
Life-long effects
Related to effects on ion channels
(NMDA, Ca++ channels)
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
TOXICOLOGY OF
ALCOHOL
• FREELY SOLUBLE, DISTRIBUTED TO ALL
TISSUES
• IMPAIRMENT EVALUATED BY BLOODALCOHOL LEVELS (0.08% = 17 mM)
• PEAK CONCENTRATIONS USUALLY
REACHED IN 30-90 MINUTES
• SLOW METABOLISM (zero order kinetics)
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)
FAS Child
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.
Toxicity of Mercury
• Different chemical forms – inorganic,
Hg2+
CH3Hg+)
metallic, organic ( Hg0
• 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
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
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
Environmental Sources of Mercury
• Natural Degassing of the earth
• Combustion of fossil fuel
• Industrial Discharges and Wastes
• Incineration & Crematories
• Dental amalgams
Atmospheric Hg
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.
END