Transcript Principles and Practices of Toxicology in Public Health Ira S. Richards

Chapter 17:
The Nervous System
The Nervous System
• Neurotoxicity is the alteration of normal function of
the nervous system as the result of exposure to
natural or artificial neurotoxicants. The damage may
be specific to a particular cell type, a given region,
or a particular function. The nervous system is
structurally divided into two major anatomical
components:
– The central nervous system (CNS), consisting of the
brain, cranial nerves, and the spinal cord
– The peripheral nervous system (PNS), consisting of
sensory (afferent) neurons, which relay impulses from the
receptors to the CNS, and motor (efferent) neurons,
which relay impulses from the CNS to effectors such as
the glands and muscles of the body.
The Nervous System
The efferent division of the PNS can be
divided into:
– the voluntary or somatic nervous system,
which regulates skeletal muscle activity
– the autonomic or involuntary nervous system,
which regulates the glands and cardiac and
smooth muscles
The voluntary (somatic)
nervous system
• regulates skeletal muscle activity
• uses one group of motor neurons to stimulate
the effectors, whereas the autonomic nervous
system requires both a preganglionic and a
postganglionic neuron to stimulate the effector
• consists of the skeletal and cranial nerves that
send sensory information to the CNS and motor
nerve fibers that innervate the skeletal muscles.
The autonomic (involuntary)
nervous system
• regulates the glands and cardiac and
smooth muscles
• is composed of both sensory and motor
neurons that control the internal
environment of the body’s internal organs
• is further divided into the sympathetic and
parasympathetic systems.
The Nervous System
The sympathetic division of the autonomic
nervous system (the “fight or flight”
response system) is responsible for:
– Increasing cardiac output
– Elevating blood pressure
– Increasing heart rate
– Bronchodilatation
– Increasing pupil size
– Increasing blood flow from peripheral vessels
to skeletal muscle
– Mobilization of glycogen in fat
The Nervous System
The parasympathetic division of the
autonomic nervous system is generally
antagonistic to the sympathetic system
and is responsible for:
– Decreasing cardiac output
– Decreasing blood pressure
– Decreasing heart rate
– Decreasing pupil size
– Bronchoconstriction
– Increasing digestion and absorption of foods
– Eliminating wastes
The Nervous System – the Brain
• The brain can be divided into several
regions:
– Forebrain, consisting of the cerebrum and the
diencephalon (thalamus and the
hypothalamus)
– Midbrain (mesencephalon), consisting of the
tectum and tegmentum
– Hindbrain, consisting of the medulla
oblongata (myelencephalon) and the
metencephalon (pons and cerebellum)
The Nervous System – the Brain, cont.
• The cerebrum is the largest part of the brain and
can be subdivided as follows:
– Frontal lobe, which controls such things as creative
thought, intellect, problem solving, attention, behavior,
abstract thinking, smell, emotions, and coordination of
movement
– Temporal lobe, which controls such things as
language, auditory and visual memory, speech, and
hearing
– Parietal lobe, which controls such things as tactile
perception, responses to internal stimuli, sensory
interpretation, and some visual function
– Occipital lobe, which processes visual information
Cells of the Nervous System
• The neuron (single nerve cell) is the functional
unit of the nervous system. These are the
excitable cells that are capable of generating
and propagating an electrical signal, filing and
storing information to support basic
communication processes and higher functions
such as learning, memory, and behavior.
• The functional classes of neurons are:
– Sensory or afferent neurons that carry information to
the CNS
– Motor or efferent extrinsic neurons that carry
information from the CNS to the tissues and organs
Structure of a typical neuron
Cells of the Nervous System
• Neuroglial or glial cells are supportive to the
nervous system and are represented by several
types of cells in the CNS:
– Oligodendrocytes - responsible for the production of
myelin in the CNS and hence are responsible for normal
propagation of action potentials
– Astrocytes - the most abundant glia
•
•
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•
•
they comprise the largest portion of the blood–brain barrier (BBB)
located within the CNS
critical to the maintenance of the BBB
help to regulate concentrations of potassium (K+)
maintain extracellular pH, glutamate, and water
– Ependymal cells -line the ventricles in the CNS and
produce and circulate the cerebrospinal fluid through
ciliary activity
– Microglia - macrophages that differ from other glial cells
because they are monocyte derived.
The Blood-Brain Barrier (BBB)
• The BBB is an anatomical and physiological
“barrier” between the brain and circulation,
which regulates the entry and leaving of both
endogenous and exogenous substances into
and out of the brain.
• The key factors that determine this are:
–
–
–
–
–
Molecular size
Lipid solubility
Molecular charge
Concentration differences
Specialized transport mechanisms
The Blood-Brain Barrier (BBB)
• The BBB is composed of tight junctions (zonulae
occludens) between endothelial cells of brain
capillaries and astrocytic cell membrane
projections that surround these capillaries.
– The barrier is relatively ineffective for lipid-soluble
molecules, whereas water-soluble substances such
as glucose require special mechanisms for transport.
– Compounds that mimic essential chemicals such as
certain ions and nutrients can be actively transported
across the BBB as occurs when organic mercury
combines with the amino acid cysteine and is
transported by amino acid uptake systems.
– Certain ions such as Pb2+ can be transported by
normal ion exchange systems.
The Blood-Brain Barrier (BBB)
• The BBB is not a continuous barrier in that there
are places within the CNS where the barrier is
relatively ineffective, such as the median
eminence, pineal, neurohypophysis, and the
hypothalamus.
• The BBB is not fully developed in children, thus
making them much more susceptible to the
effects of certain chemicals when compared with
the adult brain.
– Small exposures to lead, for example, are of greater
concern in children than in adults due to the more
permeable nature of their cerebral capillaries.
Neuron Action Potential and
Synaptic Function
• The unequal distribution of ions across a neuron cell
membrane, like other excitable cells, is the basis for the
nervous action potential.
– This is brought about by electrical and chemical gradients that
are created across the cell membrane by active transport
mechanisms and selective membrane permeability.
– Electrical conduction involves the movement of sodium and
potassium ions across the nerve cell membrane through
sequential changes in its permeability to sodium (Na+) and
potassium (K+) ions.
– The membrane potential difference can be measured by
ascertaining the difference between the electrical charge inside
and outside the cell.
Neuron Action Potential and
Synaptic Function, cont.
• There are two basic kinds of electrical
signals in neurons:
– graded potentials –
• graded potentials travel short distances
– action potentials –
• action potentials travel over longer distances
• They do not lose amplitude as they travel, nor do
they vary
Neuron Action Potential and
Synaptic Function, cont.
• At the terminal end of an axon (i.e., the
presynaptic terminal) are synaptic vesicles
containing chemicals known as
neurotransmitters.
• Upon arrival of action potentials at the axon
terminals, a neurotransmitter is released that
diffuses across the synaptic or neuromuscular
junction and activates postsynaptic receptors,
thereby initiating another action potential or the
response of the effector cell.
Neuron Action Potential and
Synaptic Function, cont.
• Examples of neurotransmitters include:
– Acetylcholine
– Catecholamines (dopamine, norepinephrine,
epinephrine)
– Serotonin
– Glutamate
– Gamma-aminobutyric acid (GABA -an
inhibitory neurotransmitter)
– Peptides
Typical Synapse
Neurotoxicity
• Neuropathic damage can result from exposure
to neurotoxicants like carbon monoxide, carbon
tetrachloride, mercury, or lead.
– Lead is a ubiquitously occurring toxicant found
naturally in the environment and therefore can be
found in water, food, and air, as well as in many
manufactured products.
– Despite the efforts for lead reduction by the U.S.
Environmental Protection Agency (EPA) and the U.S.
Food and Drug Administration (FDA), lead exposures
still remain an important public health concern,
especially in children, who are both more likely to be
exposed to certain sources and more sensitive to the
effects of lead.
Neurotoxicity, cont.
– It is now clear that even relatively low lead
exposures during childhood development
have neurobehavioral and developmental
effects that may persist into adulthood.
– The problem is still of greatest concern in
urban environments where exposures to lead,
especially from lead-based paint and
plumbing fixtures in old housing, are
commonplace.
Neurotoxicity, cont.
• Neurotoxicity can be produced in the CNS
after exposure to a chemical agent. At the
cellular level, injury can occur at:
– Motor neurons, producing muscle dysfunction
and paralysis
– Interneurons, producing decrements in
memory and learning coordination
– Sensory neurons and sensory receptors,
producing dysfunction in vision, hearing, and
the senses of temperature, pressure, touch,
taste, smell, and pain
Neurotoxicity, cont.
• Injuries to the structure and physiological
perturbations in the nervous system include:
– Direct cytotoxicity and death of neurons and glia
– Conduction abnormalities and interference with
synaptic and neuroeffector transmission
• Damage occurs selectively in the tissues of the
nervous system, depending on the presence
and penetrability of barriers, differences in blood
flow, differences in metabolic rates, and
differences in metabolic function.
– Cells of the cerebellum and visual cortex, for
example, are preferentially killed by methylmercury.
Neurotoxicity, cont.
• Toxic responses to the nervous system
have been classified as falling into several
categories:
– Neuronopathy: damage to neuronal cell body
– Axonopathy: damage to axon or axonal
transport
– Myelinopathy: loss of or abnormal formation of
myelin
– Conduction/transmission: associated effects
where conduction or neurotransmitter functions
are altered
Examples of Neurotoxic Chemicals
Neurotransmission-associated
Toxicities
Represent a category of toxicities that refer
to any chemical that
– Affects the function of synaptic vesicles
– Blocks or activates synaptic or effector receptors
– Blocks the release of neurotransmitter
– Blocks the reuptake or degradation of
neurotransmitter
– Produces uncontrolled release of
neurotransmitter
– Interferes with action potential conduction
Neurotransmission-associated
Toxicities
Chemicals that can produce neurotransmissionassociated toxicities include those that:
– Block impulse conduction along axons (e.g., local
anesthetic and tetrodotoxin blockade of Na+ channel
function)
– Block synaptic function by interfering with the normal
calcium channel activity, which triggers the release of
synaptic vesicles (e.g., metals such as cadmium,
lead, nickel, and cobalt; toxins such as curare, alphabungarotoxin)
– Activate synaptic function (e.g., nicotine)
Neurotransmission-associated
Toxicities, cont.
– Block reuptake or breakdown of neurotransmitter
resulting in receptor overstimulation (e.g.,
organophosphates, carbamates, which competitively
bind acetylcholinesterase, thus blocking breakdown of
acetylcholinesterase; cocaine, which blocks
catecholamine reuptake)
– Produce massive release of neurotransmitter (e.g.,
black widow spider venom increases acetylcholine
and amphetamine increases norepinephrine releases)
– Block the release of neurotransmitter (e.g., botulinum
toxin blockage of acetylcholine release)