CNS Flashcards
three basic functions of the NS
- Relays information
- Motor functions
- Integrates thought processes, learning, and memory
two fundamental divisions
CNS and PNS
- Composed of 2 organs: brain and spinal cord
CNS
- Control center
- processes and analyzes information received from the sensory receptors
- issues motor commands to control body functions
CNS
Six Primary Areas of the Brain
- cerebrum
- diencephalon
- midbrain
- pons
- cerebellum
- medulla oblongata
Contains 2 forms of nerves: afferent and efferent
PNS
relay sensory information to the CNS
Afferent nerves
relay motor commands to the various muscles and glands
Efferent nerves
Efferent nerves are organized into two systems:
Somatic and autonomic NS
- also known as the voluntary nervous system
- carries motor information to the skeletal muscles
somatic ns
- Carries motor information to the smooth muscles (e.g. cardiac muscles) and other various glands (e.g. gastric system)
- These are the things that happen without effort coming from the brain. The major difference between these 2 systems pertains to conscious control
- Can be classified as sympathetic or parasympathetic
autonomic ns
2 categories of cells found in the nervous system
neurons and glial cells (neuroglia)
are the functional nerve cells directly responsible for transmission of information to and from the CNS to other areas of the body and vice versa
neurons
provide support to the neural tissue, regulate the environment around the neurons, and protect against foreign invaders
Glial cells (also known as neuroglia)
- communicate with all areas of the body and are present within both the CNS and PNS
- They serve to transmit rapid impulses to and from the brain and spinal cord to virtually all tissues and organs of the body
- They are an essential cell and their damage or death can have critical effects on body function and survival
neurons
When neurons die, they are not replaced (t or f)
T
As neurons are lost, so are certain neural functions such as:
memory, ability to think, quick reactions, coordination,
muscular strength, sight,
hearing, and taste
If the neuron loss or impairment is substantial, severe and permanent disorders can occur, such as
blindness, paralysis, and death
Neurons consist of a _______
cell body
2 types of extensions of the neuron
axons and dendrites
- may extend to long distances (over a meter
in some cases); usually transmit information from
one part of the body to another
axons
specialized in receiving incoming information and sending to the neuronal cell body with transmission or electrical charge down the
axon to one or more junctions with other neurons or muscle cells, also known as synapse
dendrites
intracellular space between 2 neurons
synapse
- covers axon
- insulating fatty layer that can speed up transmission
of electrical signals or even the neurotransmitters - Multilayer coating that wraps the axon and help
insulate the axons from surrounding tissue or fluids - Prevent the electrical charge or stimulus from
escaping the axon. - Guides the electrical impulses
myelin sheath
common parts that toxicants would attack:
nucleus, cell body, axons, myelin sheath, the transmission of neurotransmitters
____________ status of the nervous system with the maintenance of a biochemical barrier between the ____ and the _____
(7 generalities)
privileged; brain and the blood
importance of ____________ requirements of the brain
(7 generalities)
high energy
_________ of the nervous system as long cellular process and the requirements of cells with such a complex geometry
(7 generalities)
spatial extensions
maintenance of an environment rich in ______
(7 generalities)
lipids
transmission of information across ________ at the _________
(7 generalities)
extracellular space; synapse
distance over which ____________ must be transmitted, coordinated, and integrated
(7 generalities)
electrical impulses
development of ___________ pattern of the nervous system
(7 generalities)
regenerative
The nervous system is protected from the adverse effects of many potential toxicants by an anatomical barrier between the blood and the brain called
blood-brain barrier (BBB)
Most of the brain, spinal cord, retina, and PNS maintain this barrier with blood, this is not similar to the interface between cells and the extracellular space (t or f)
(BLOOD-BRAIN BARRIER)
F
To gain entry to the nervous system, molecules must pass into the _________________ of endothelial cells of the brain rather than between endothelial cells, as they do in other tissue
(BLOOD-BRAIN BARRIER)
cell membranes
The principal basis of the BBB ___________ cells in the brain’s ___________ aided by
interactions with ____
(BLOOD-BRAIN BARRIER)
specialized endothelial; microvasculature; glia
brain, spinal cord, and peripheral nerves are not completely covered with continuous lining of specialized cells
that limits the entry of molecules from adjacent tissues (t or f)
(BLOOD-BRAIN BARRIER)
F
In the brain and spinal cord (surface of specialized cells)
(BLOOD-BRAIN BARRIER)
meningeal surface
in the peripheral nerves, each _______ of nerve is surrounded by
_________
(BLOOD-BRAIN BARRIER)
fascicle; perineural cells
Among the unique properties of the endothelial cells in the nervous system is the presence of ______________ between cells
(BLOOD-BRAIN BARRIER)
tight junctions
The BBB also contains ______________ that transport some xenobiotics that have diffused through the endothelial cells back into the blood
(BLOOD-BRAIN BARRIER)
xenobiotic transporters
If not actively transported into the brain, the penetration of toxicants or their metabolites is largely related to their _____________ and to their ability to pass through the plasma
membrane of a cell, forming now the barrier
(BLOOD-BRAIN BARRIER)
lipid solubility
If the drug is _______, it can usually pass through
the BBB if it does not avail the active transport
(BLOOD-BRAIN BARRIER)
lipophilic
Sites within the brain that are not protected by the blood-tissue barrier
This discontinuity of the barrier is the basis for
______________ of some compounds
(BLOOD-BRAIN BARRIER)
Spinal ganglia, autonomic ganglia, and a small number of other sites
selective neurotoxicity
The BBB is completely developed at birth and even more so in premature infants. (t or f)
(BLOOD-BRAIN BARRIER)
F
Neurons are highly dependent on _____________ - maintain proper ion gradients
(ENERGY REQUIREMENTS)
aerobic metabolism
The brain is extremely sensitive to even brief interruptions in the supply of _______ or _______
(ENERGY REQUIREMENTS)
oxygen or glucose
exposure to chemicals or toxicants that exhibit
aerobic respiration such as _________or _______ can lead to early signs of neuronal dysfunction
(ENERGY REQUIREMENTS)
Cyanide or CO poisoning
Damage to the nervous system is a combination of ___________ on neurons and secondary damage from systemic ________ or _________
(ENERGY REQUIREMENTS)
direct toxic effects; hypoxia or ischemia
Impulses are conducted over great distance at a rapid speed, providing information about the environment to the organism in a coordinated manner that allows an organized response to be
carried out at a specific site (t or f)
(AXONAL TRANSPORT)
T
2 immediate demands placed on the neurons
(AXONAL TRANSPORT)
- maintenance of a much larger cellular volume, requiring more protein synthesis
- transport of intracellular materials over great distances using various mechanisms
neuronal demands require ATP (t or f)
(AXONAL TRANSPORT)
T
moves protein products from the cell body to
the appropriate site in the axon
(AXONAL TRANSPORT)
Axonal transport
Many proteins associated with vesicles migrate through the axon at a rate of ________
(AXONAL TRANSPORT)
400 mm/day
This process is dependent on microtubule-associated ___________ and the microtubule-associated motor proteins (____________) that provide both the mechanochemical
force in the form of a microtubule-associated ATPase and the
interface between microtubules as the track and vesicles as the cargo
(AXONAL TRANSPORT)
ATPase activity; kinesin and dynein
Vesicles are transported rapidly in an ___________ by kinesin, and they are transported in a ___________ by dynein
(AXONAL TRANSPORT)
anterograde direction; retrograde direction
The transport of some organelles, including , ___________ constitutes an intermediate component of axonal transport, moving at __________
(AXONAL TRANSPORT)
mitochondria; 50 mm/day
The slowest component of axonal transport represents the movement of the ______________
(AXONAL TRANSPORT)
cytoskeleton itself
is composed of microtubules formed by the association of tubulin subunits and neurofilaments formed by
the association of three neurofilament protein subunits
(AXONAL TRANSPORT)
cytoskeleton
_________and _________ move at a rate of approximately _________ and make up the majority of ____, which is the slowest moving component of axonal transport
(AXONAL TRANSPORT)
Neurofilaments and microtubules; 1 mm/day; SCa
The slowest moving component of axonal transport
(AXONAL TRANSPORT)
SCa
Moving at only a slightly more rapid rate of 2 to 4 mm/day in an anterograde direction is ______, which is composed of many
proteins
(AXONAL TRANSPORT)
SCb
Included in SCb are several structural proteins, such as the component of microfilaments (______) and several microfilament-associated proteins (____________), as
well as ______ and many soluble proteins
(AXONAL TRANSPORT)
actin; M2 protein and fodrin; clathrin
This continual transport of proteins from the cell body through the various components of ____________ transport is the
mechanism through which the neuron provides the distal axon with its complement of functional and structural proteins
(AXONAL TRANSPORT)
anterograde axonal
Some vesicles are also moving in a ___________ and undoubtedly provide the cell body with information concerning the status of the distal axon
(AXONAL TRANSPORT)
retrograde direction
toxicant-induced irreversible loss of neurons, including its cytoplasmic extensions, dendrites, axons, and the myelin ensheathing the axon
(AXONAL DEGENERATION)
neuronopathy
when the neuronal cell body has been lethally injured and it degenerates
(AXONAL DEGENERATION)
neuronopathy
This is characterized by the loss of the cell body and
all of its processes, with no potential for regeneration
(AXONAL DEGENERATION)
neuronopathy
when the injury is at the level of the axon, the axon
may degenerate while the neuronal cell body
continues to survive
(AXONAL DEGENERATION)
Axonopathy
there is a potential for regeneration and recovery
from the toxic injury as the axonal stump sprouts
and regenerates
(AXONAL DEGENERATION)
Axonopathy
The result of axotomy (transection of an axon) is that the distal axon is destined to degenerate, a process known as axonal degeneration, which is unique to the NS (t or f)
(AXONAL DEGENERATION)
T
The cell body of the neuron responds to the axotomy as well and undergoes a process of _________
(AXONAL DEGENERATION)
chromatolysis
The sequence of events that occurs in the distal stump of an axon following transection is referred to as __________
(AXONAL DEGENERATION)
Wallerian degeneration
Because the axonal degeneration associated
with chemicals and some disease states is thought to occur through a similar sequence of events, it is often referred to as
________________
(AXONAL DEGENERATION)
Wallerian-like axonal degeneration
Following axotomy, there is degeneration of the distal nerve stump, followed by generation of a microenvironment
supportive of ____________ and involving the distal axon, ensheathing glial cells and the blood nerve barrier
(AXONAL DEGENERATION)
regeneration
Initially there is a period during which the distal stump survives and maintains relatively normal structural, transport, and conduction properties (t or f)
(AXONAL DEGENERATION)
T
The duration of survival is inverse to the length of the axonal stump, and this relationship appears to be maintained across species
(AXONAL DEGENERATION)
F (proportional)
Terminating the period of survival is an __________ that digests the axolemma and axoplasm, leaving only a myelin sheath surrounding a swollen degenerate axon
(AXONAL DEGENERATION)
active proteolysis
Digestion of the axon appears to be an allornone event effected through ___________ proteases that are activated through increased levels of intracellular free ______
(AXONAL DEGENERATION)
endogenous; Ca2+
In the PNS, __________ respond to loss of axons by
decreasing synthesis of ________, down-regulating genes encoding _____________, and dedifferentiating to a
_________ mitotic Schwann cell phenotype
(AXONAL DEGENERATION)
Schwann cells; myelin lipids; myelin proteins; premyelinating
The proliferating Schwann cells create a tubular structure around the axon (referred to as a band of ______), providing
physical guidance for regenerating axons
(AXONAL DEGENERATION)
Bungner
These tubes also provide trophic support from __________, _________, __________, and corresponding receptors produced by the
associated Schwann cells
(AXONAL DEGENERATION)
- nerve growth factor (NGF)
- brain-derived neurotrophic factor
- insulin-like growth factor
Resident ___________ distributed along the endothelium within the endoneurium and the denervated Schwann cells assist in clearing ___________, but the recruitment of hematogenous macrophages accounts for the removal of the
_________ of myelin
(AXONAL DEGENERATION)
macrophages; myelin debris; majority
Another essential role of recruited, circulating macrophages is the production of _____________, which is responsible for
stimulating production of __________ by Schwann cells
(AXONAL DEGENERATION)
interleukin1 (IL1); NGF
A critical difference exists between axonal degeneration in the CNS compared with that in the PNS:
(AXONAL DEGENERATION)
peripheral axons can regenerate, whereas central axons cannot
Main factors contributing to the inability of the CNS to
regenerate include inhibitory factors secreted by ________
(AXONAL DEGENERATION)
oligodendrocytes, astrocyte scarring, and glial interference
Interestingly, experiments involving cellular transplants of Schwann cells to the CNS or CNS neurons to the PNS show that the regenerative capability of CNS neurons depends on both
_____________ and the _____________
(AXONAL DEGENERATION)
the microenvironment; properties of mature neurons
________________ was long thought to be a________
process that proceeded inexorably after separating the axon from the trophic support provided by the cell body
(AXONAL DEGENERATION)
Wallerian degeneration; passive
However, we now know from several lines of evidence that Wallerian degeneration is an ___________ mediated by the axon itself, and that it is possible to ____________ its progression
(AXONAL DEGENERATION)
active process; slow or even halt
Myelin is formed in the CNS by _____________ and in the PNS by ______________
(MYELIN FORMATION AND MAINTENANCE)
oligodendrocytes; Schwann cells
Both of these cell types form concentric layers of __________ by the progressive wrapping of their cytoplasmic processes around the axon in successive loops
(MYELIN FORMATION AND MAINTENANCE)
lipid-rich myelin
These cells exclude _________ from the inner surface of their membranes to form the major dense line of myelin
(MYELIN FORMATION AND MAINTENANCE)
cytoplasm
Some toxic compounds interfere with this complex process of the maintenance of myelin and result in the toxic _____________
(MYELIN FORMATION AND MAINTENANCE)
“myelinopathies”
In general, the loss of myelin with the preservation of axons is referred to as ____________
(MYELIN FORMATION AND MAINTENANCE)
demyelination
Intercellular communication is achieved in the NS through the synapse
(NEUROTRANSMISSION)
neurotransmission
Neurotransmitters released from one neuron act as the __________
(NEUROTRANSMISSION)
first messenger
Binding of the transmitter to the postsynaptic receptor is
followed by _________ of an ion channel or __________ of a second-messenger system, leading to changes in the responding cell
(NEUROTRANSMISSION)
modulation; activation
Various therapeutic drugs and toxic compounds impact the process of neurotransmission. (t or f)
(NEUROTRANSMISSION)
T
expresses itself in terms of altered conduction
and propagation of nerve impulses and changes in functions such as behavior, performance, and conditioning
(NEUROTRANSMISSION)
Neurotoxicity
In terms of toxicity, many side effects of neurological drugs may be viewed as short-term interactions that are reversible with time or that may be counteracted by the use of appropriate antagonists (t or f)
(NEUROTRANSMISSION)
T
Excessive stimulation of neurotransmitter systems may also have long-term consequences; e.g., ____________ (e.g.,
glutamate) produces ________ that is manifest as CNS diseases and nerve cell death.
(NEUROTRANSMISSION)
excitatory system; excitotoxicity
The NS begins development during ________ and continues through _________
(DEVELOPMENT OF THE NS)
gestation; adolescence
are the basic processes that
underlie development of the NS, and these occur in a tightly choreographed sequence that depends on the region, cell type, and neurotrophic signals
(DEVELOPMENT OF THE NS)
- proliferation
- migration
- differentiation
- synaptogenesis
- apoptosis
- myelination
______________ occur in waves that are specific for brain regions, but in general, the brain develops in a caudal to rostral direction (with ___________ development being a notable exception)
(DEVELOPMENT OF THE NS)
proliferation and migration; cerebellar
During differentiation (___________) and
synaptogenesis (___________________), the circuitry of the NS is established.
(DEVELOPMENT OF THE NS)
phenotype expression; formation of functional synaptic connections
Chemicals such as _____________, ____________, and ____________ serve as ____________ signals;
neurotransmitter developmental signals are separate from their synaptic transmission function
(DEVELOPMENT OF THE NS)
- nerve growth factors
- adhesive molecules
- neurotransmitters
- morphogenic
Selected cells are also removed during __________ via __________ (programmed cell death), which results in the appropriate cell types in the correct regions.
(DEVELOPMENT OF THE NS)
ontogeny; apoptosis
The ___________ develop last, and myelination is
protracted.
(DEVELOPMENT OF THE NS)
glial supportive cells
Chemicals that alter the timing and formation of neural connections could result in temporary malformations, the
consequences of which may be quite unlike the chemical’s effects in the adult NS (t or f)
(DEVELOPMENT OF THE NS)
F (permanent)
Furthermore, while synaptogenesis can ______________, proliferation cannot; therefore, the CNS is unique in that damaged neural cells are not readily replaced
(DEVELOPMENT OF THE NS)
continue throughout life
A classic example of toxicant-induced neurodegeneration is
exposure to __________________, which is a by-product of the opioid analgesic,
(FACTORS RELEVANT TO THE NEURODEGENERATIVE DISEASES)
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP); MPPP
Exposure to a sufficient amount of MPTP can lead to
immediate ______________, a disease in which dopaminergic neurons of the substantia nigra are lost.
(FACTORS RELEVANT TO THE NEURODEGENERATIVE DISEASES)
parkinsonism
Exposure to an amount of MPTP insufficient to cause
immediate parkinsonism leads to early signs of the disease years later (t or f)
(FACTORS RELEVANT TO THE NEURODEGENERATIVE DISEASES)
T
It does not seem likely that an early sublethal injury to
dopaminergic neurons later becomes lethal, rather, smaller exposures to MPTP may cause a decrement in
the population of dopaminergic neurons and leave the individual vulnerable to further loss of dopaminergic neurons (t or f)
(FACTORS RELEVANT TO THE NEURODEGENERATIVE DISEASES)
T
Epidemiological studies also implicate exposure to herbicides, pesticides, and metals as risk factors for _________. Several studies suggest that _________ also play an important role
(FACTORS RELEVANT TO THE NEURODEGENERATIVE DISEASES)
Parkinson’s disease
(PD); dithiocarbamates
Some studies suggest that may have a ____________ protective effect against both Alzheimer’s disease and PD
(FACTORS RELEVANT TO THE NEURODEGENERATIVE DISEASES)
cigarette smoking
The study of epigenetics has established two categories of mechanisms affecting gene expression:
(FACTORS RELEVANT TO THE NEURODEGENERATIVE DISEASES)
- DNA methylation
- histone posttranslational modifications
In most instances, methylation of the ___________ results in
transcriptional repression of the gene
(FACTORS RELEVANT TO THE NEURODEGENERATIVE DISEASES)
promotor region
Histone posttranslational modifications are characterized by ___________
(FACTORS RELEVANT TO THE NEURODEGENERATIVE DISEASES)
- lysine acetylation
- arginine and lysine methylation
- serine phosphorylation
- lysine ubiquitylation
Finally, it is necessary to recognize that _________ provide regulatory control over gene expression
(FACTORS RELEVANT TO THE NEURODEGENERATIVE DISEASES)
microRNAs (miRNAs)
mRNAs can control developmental timing, cell proliferation, cell death, and patterning of the NS, thus providing extensive
regulatory networks with a complexity comparable to that of transcription factors (t or f)
(FACTORS RELEVANT TO THE NEURODEGENERATIVE DISEASES)
T
More than _______ miRNAs have been already identified, but their mRNA targets and functions have yet to be fully appreciated
(FACTORS RELEVANT TO THE NEURODEGENERATIVE DISEASES)
250
a battery of tests — screening potentially neurotoxic compounds
(FUNCTIONAL ASSESSMENT)
FUNCTIONAL ASSESSMENT
Specific behavioral methods:
(FUNCTIONAL ASSESSMENT)
- Functional observational
batteries (FOBs) - Irwin screens
- tests of motor activity
- expanded clinical observations
sensory-specific
information on nerve conduction velocity and
integrity
(FUNCTIONAL ASSESSMENT)
Electrophysiological tests
Autonomic function includes evaluations of
(FUNCTIONAL ASSESSMENT)
cardiovascular status and cholinergic/adrenergic
balance
toxicant-induces _____________ loss of neurons, including its cytoplasmic extensions, dendrites, axons, and the myelin ensheathing the axon
(NEURONOPATHIES)
irreversible
Unique features of the neuron that place it at risk for the action of cellular toxicants include
(NEURONOPATHIES)
- high metabolic rate
- a long cellular process that is supported by the cell body
- excitable membrane that is rapidly depolarized and
repolarized
The initial injury to neurons is followed by ________________, leading to permanent loss of the neuron
(NEURONOPATHIES)
apoptosis or necrosis
- quinone-containing anthracycline antibiotic
- antimitotics in cancer chemotherapy
- clinical application of doxorubicin is greatly limited by its acute and chronic cardiotoxicity
Doxorubicin
- Would usually injure neurons in the PNS, specifically those of the dorsal root ganglia and the autonomic ganglia by
intercalating with DNA and interfering with the transcription process - its interaction with topoisomerase II, which forms a DNAcleavable complex and generation of ROS by enzymatic electron reduction of _________ by variety of oxidases,
reductases, and dehydrogenases - The vulnerability of sensory and autonomic neurons appears to
reflect the lack of protection of these neurons by a blood–tissue barrier within ganglia
Doxorubicin
- is a common pollutant in hazardous waste sites in the
United States - _______ poisoning varies with both the severity of exposure and
the age of the individual at the time of exposure. - Would usually affect neurons of the visual cortex. It can cause massive degeneration that could lead to blindness and ataxia
in adults. - For children, it can cause developmental disabilities, retardation, and cognitive deficits
Methyl mercury (MeHg)
- these differences are caused by an immature blood–brain barrier causing a more generalized distribution of mercury in
the developing brain - neurons that are most sensitive to the toxic effects of MeHg are those that reside in the dorsal root ganglia, perhaps again reflecting the vulnerability of neurons not shielded by
blood–tissue barriers - The mechanism of _________ toxicity remains unknown whether the ultimate toxicant is _____ itself or the liberated mercuric ion.
Methyl mercury (MeHg)
- In addition, there is evidence for enhanced oxidative injury and
altered calcium homeostasis. Exposure to _______ leads to widespread neuronal injury and subsequently to a diffuse encephalopathy
Methyl mercury (MeHg)
- plasticizers, antifungal agents, or pesticide
- Causes irreversible limbic-cerebellar syndrome in humans and similar behavioral changes in primates
- gains access to the NS where, by an undefined
mechanism, it leads to diffuse neuronal injury - Several hypotheses are suggested for the mechanism, including energy deprivation and excitotoxic damage
Trimethyltin
Primary site of toxicity - axon
AXONOPATHIES
The axon degenerates, and with it the myelin surrounding the
axon; however, the neuron cell body remains intact.
AXONOPATHIES
The toxicant results in a “chemical transection” of the axon at some point along its length, and the axon distal to the
transection degenerates
Axonopathies
In the ____ the axons can regenerate
PNS
support axonal regeneration
glial cells and macrophages
In the _____, axons cannot regenerate
CNS
interferes with regeneration
(Factors of inability to regenerate)
- inhibitory factors from
oligodendrocytes - astrocyte scarring
- glial interference
The neuronal body can exist even if the axon is damaged (t or f)
T
Axonopathies can be considered to result from a chemical transection of the axon (t or f)
T
are first impaired in the most distal extent of the axonal processes as the axons degenerate
sensations and motor
strength (e.g., the hands and feet)
As the axons degenerate, sensations and motor strength are first impaired in the most distal extent of the axonal processes (e.g., the hands and feet), resulting in a ________
“glove-and-stocking” neuropathy
With time and continued injury, the deficit progresses to involve more ________ areas of the body and the long axons of the spinal cord
proximal
Humans develop a progressive sensorimotor distal axonopathy
when exposed to high concentrations of a simple alkane, n-hexane, day after day in work settings or after repeated intentional inhalation of hexane-containing glues. An identical
axonopathy can be produced by methyl-n butyl ketone
(2-hexanone)
Gamma-diketones - n-hexane, 2-hexanone
The ω1 oxidation of n-hexane results in the γ-diketone, 2,5-hexanedione (HD), which reacts with amino groups in all tissues to form pyrroles that derivatize and crosslink neurofilaments, leading to development of neurofilament aggregates of the distal, subterminal axon
Gamma-diketones - n-hexane, 2-hexanone
The pathologic processes of neurofilament accumulation and degeneration of the axon are followed by the emergence of a _______________________
clinical peripheral neuropathy
- occurred in the vulcan rubber and viscose rayon industries
- High Level exposures of humans cause a distal axonopathy that is identical pathologically to that caused by hexane
- Covalent cross-linking of neurofilaments also occurs and it is known that _____ is itself the ultimate toxicant
Carbon disulfide (CS2)
The clinical effects of exposure to _____ in the chronic setting are very similar to those of hexane exposure, with the development of sensory and motor symptoms occurring
initially in a “glove-and-stocking” distribution
CS2
Can also lead to aberrations in mood and signs of diffuse
encephalopathic disease
CS2
bizarre “waltzing syndrome”
Iminodipropionitrile (IDPN)
- Particularly in rats and animals
- Causes excitement, circling, head twitching, over alertness, which appears to result from degeneration of the vestibular sensory hair cells
Iminodipropionitrile (IDPN)
- leads to accumulation of
neurofilaments in the proximal axon, leading to swelling without degeneration in most animals. These neurofilament swellings are similar to those observed in carbon disulfide or γ-diketone toxicity
Iminodipropionitrile (IDPN)
Repeated exposure leads to demyelination and _____________ , and eventually can produce distal axonal atrophy due to a reduction in anterograde neurofilament transport to the distal axon
(Iminodipropionitrile (IDPN)
onion bulb formation
- This impairment of axonal transport results from the disruption of the association between microtubules and neurofilaments by _________, causing neurofilament accumulation. This leads to
complete disturbance of the cytoskeleton of the axon
Iminodipropionitrile (IDPN)
distal axonopathy characterized by multiple axonal swellings
Acrylamide
- man made vinyl monomer used widely in water purification, paper manufacturing, mining, and waterproofing, in biochemical laboratories, and in many foods prepared at high temperatures.
- Although it can be dangerous if not handled carefully, most toxic events in humans have been observed as peripheral neuropathies in factory workers exposed to high doses.
Acrylamide
- A single large dose is sufficient to produce these
swellings - repeated dosing results in a more proximal axonopathy, in a “dying back” process. These changes are caused by accumulations of neurofilaments at the nerve terminal
- Recently it has been observed that nerve terminal
degeneration occurs prior to development of axonopathy, suggesting that this degeneration is the primary lesion.
Acrylamide
- used as insecticides, chemical warfare agents, chemical intermediates, flame retardants, fuel additives, hydraulic
fluids, lubricants, pharmaceuticals, and plasticizers. - insecticides and nerve agents are designed to inhibit AChE, causing accumulation of acetylcholine in cholinergic
synapses resulting in cholinergic toxicity and death
(Organophosphorus (OP) compounds)
Organophosphorus (OP) compounds
Some OP compounds, such as, ___________ can cause a severe sensorimotor central peripheral distal axonopathy called ___________ without inducing cholinergic poisoning
(Organophosphorus (OP) compounds)
- triocresyl phosphate (TOCP)
- OP compound–induced delayed neurotoxicity (OPIDN)
Many OP compounds are _________ and readily enter the NS, where they can phosphorylate neural target proteins.
(Organophosphorus (OP) compounds)
lipophilic
When the principal target is ________, cholinergic toxicity can ensue, either because of ____________ of inhibition or inhibition plus aging
(Organophosphorus (OP) compounds)
AChE; suprathreshold levels
When aging of inhibited AChE also occurs (i.e., net loss of a
ligand from the phosphorus of the OPenzyme conjugate,
leaving a _________ phosphoryl moiety attached to the active site), the qualitative nature of the toxicity does not change. Instead, the inhibited AChE becomes intractable to
reactivation.
(Organophosphorus (OP) compounds)
negatively charged
When the principal target is neuropathy target esterase
(neurotoxic esterase, NTE), OPIDN can result only if both
suprathreshold (>70%) inhibition occurs and the inhibited enzyme undergoes aging. Thus, in the case of NTE and OPIDN, inhibition alone is insufficient to precipitate toxicity (t or f)
(Organophosphorus (OP) compounds)
T
Neuropathic (aging) inhibitors of NTE include compounds from
the _______________ classes of OP compounds
(Organophosphorus (OP) compounds)
phosphate, phosphonate, and phosphoramidate
Axonal degeneration does not commence immediately after acute exposure to a neuropathic OP compound but is delayed for at least _________ days between the acute high dose exposure
and clinical signs of axonopathy
(Organophosphorus (OP) compounds)
eight
Some effective regeneration of axons occurs in the PNS while axonal degeneration is progressive and persistent in the long tracts of the ________
(Organophosphorus (OP) compounds)
spinal cord
Human cases of OPIDN are now _________ and usually arise from intentional ingestion of massive doses of OP insecticides in _________
(Organophosphorus (OP) compounds)
rare; suicide attempts
____________ is a debilitating and incurable condition. While the preceding discussion was limited to organic compounds of
pentacovalent phosphorus, organic compounds of _________ phosphorous also produce axonal degeneration in the CNS and PNS albeit in a different form than classical OPIDN
(Organophosphorus (OP) compounds)
OPIDN; trivalent
is a chelating agent that is usually encountered as the zinc complex, called ____________, which has antibacterial and antifungal properties and is a component of shampoos that are effective in the treatment of seborrhea and
dandruff
Pyridinethione; zinc pyridinethione (ZPT)
Although the compound is applied to the human scalp in
antidandruff shampoos, dermal absorption of ZPT is ___________ and exposure primarily occurs ________
(Pyridinethione)
minimal; orally
Only the _____________ is absorbed following ingestion, with the majority of zinc eliminated in the _____
(Pyridinethione)
pyridinethione moiety; feces
Pyridinethione appears to interfere with the ___________, impairs the turn around of rapidly transported vesicles, and slows the retrograde transport of vesicles
(Pyridinethione)
fast axonal transport systems
As these materials accumulate in one region of the axon, the axon degenerates in its more __________ regions beyond the accumulated structures
(Pyridinethione)
distal
The earliest signs are diminished __________ and changes of the axon terminal, leading to a peripheral neuropathy
(Pyridinethione)
grip strength
A number of plant alkaloids alter the assembly and
depolymerization of microtubules in nerve axons, causing neurotoxicity
(Microtubule-associated Neurotoxicity)
Microtubule-associated Neurotoxicity
The oldest known of these are ________ and the __________, which bind to tubulin and cause depolymerization of
microtubules.
(Microtubule-associated Neurotoxicity)
colchicine; vinca
alkaloids
is an alkaloid pharmaceutical used in the
treatment of gout, familial Mediterranean fever, and
other disorders
(Microtubule-associated Neurotoxicity)
Colchicine
are two vinca alkaloids
used as chemotherapeutic agents
(Microtubule-associated Neurotoxicity)
Vincristine and vinblastine
Both colchicine and the vinca alkaloids produce a
similar peripheral axonal neuropathy (t or f)
(Microtubule-associated Neurotoxicity)
T
Hallmarks of this neuropathy include
(Microtubule-associated Neurotoxicity)
- paresthesia (tingling) of the fingers
- generalized weakness
- clumsiness
another plant alkaloid, has become a popular chemotherapeutic drug used to treat a variety of neoplasms
(Microtubule-associated Neurotoxicity)
Paclitaxel (Taxol)
side effects include a predominantly sensory
neuropathy, beginning in the hands and feet.
(Microtubule-associated Neurotoxicity)
Paclitaxel (Taxol)
Like colchicine and the vinca alkaloids, _________ binds to tubulin; however, instead of leading to depolymerization, it promotes the formation of microtubules. Once formed, these microtubules
remain stabilized by ________ even in conditions
that normally lead to dissociation of tubulin
subunits, including cold temperatures or the
presence of calcium
(Microtubule-associated Neurotoxicity)
Paclitaxel (Taxol)
Although colchicine leads to atrophy of the axon and a
decrease in the number of microtubules, paclitaxel causes the aggregation to form a matrix that may inhibit fast axonal transport, which has been demonstrated with both colchicine and paclitaxel (t or f)
(Microtubule-associated Neurotoxicity)
T
Microtubule-associated Neurotoxicity examples
colchicine, vinca, and paclitaxel
- Attacks myelin sheath
MYELINOPATHIES
provides electrical insulation of neuronal processes; its absence leads to slowing of conduction and aberrant conduction of impulses between adjacent processes
myelin
caused by alterations in
transcript levels of myelin basic protein mRNA
Intramyelinic edema
(Separation of myelin lamella)
may result from progressive
intramyelinic edema or from direct toxicity to
myelinating cell.
Demyelination
(selective loss of the myelin)
________________ in the CNS occurs to only a limited extent after demyelination.
Remyelination
____________ in the PNS are capable of remyelinating the axon
Schwann cells
cause neurotoxicity when newborn infants were bathed with the compound to avoid staphylococcal skin infections. Exposure happens when skin absorption occurs. It may enter the nervous system and cause intramyelinic edema, leading to formation of vacuoles creating a spongiosis of the brain.
Hexachlorophene
causes intramyelinic edema that leads to segmental demyelination
Hexachlorophene
_____________ causes increased intracranial pressure, axonal degeneration, along with degeneration of
photoreceptors in the retina
(Hexachlorophene)
Swelling of the brain
Characterized by weakness, confusion, and seizures, which may progress to coma or death
Hexachlorophene
- No effects in humans have been reported
- It can alter the synthesis of the myelin lipids in Schwann cells in young rats, because of various lipid abnormalities
- As biochemical changes occur, lipids accumulate in Schwann cells, which eventually lose their ability to maintain myelin in the PNS.
Tellurium
- Exposure in animals results in a peripheral neuropathy with
prominent segmental demyelination - In young children, acute massive exposures can result in severe cerebral edema
> Children absorb lead more readily, and the very
young do not have the protection of the blood–brain barrier
Lead
Chronic ____________ intoxication in adults results in peripheral
neuropathy, gastritis, colicky abdominal pain, anemia, & the prominent deposition of lead in particular anatomical sites, creating lead lines in the gums and in the epiphyses of long bones in children.
lead
Lead in the peripheral nerve of humans _______ nerve conduction
slows
The basis of lead encephalopathy is unclear, although an effect on the membrane structure of myelin and myelin membrane fluidity has been shown (t or f)
T
_________ perform and regulate a wide range of physiologic functions in the CNS
- primary means of defense in the CNS following
exposure to neurotoxicants - These are spatial buffering systems for osmotically active ions,
and as a depot for the sequestration and metabolic processing
of endogenous molecules and xenobiotics.
Astrocytes
- high CNS concentrations: produces seizures, resulting from its
depolarizing action on cell membranes - lower concentrations: produces stupor and coma, consistent with its hyperpolarizing effects.
Ammonia
can cause astrocytic swelling and morphological changes
Ammonia
↑ intracellular ammonia
- inhibition of neuronal
glutamate precursor
- diminished glutamatergic
neurotransmission - changes in neurotransmitter uptake:
glutamate - changes in receptor-mediated metabolic
responses of astrocytes to neuronal signals
↑ intracellular ammonia
- Organic nitrates, Dinitrobenzenes (DNB), Metronidazole
Nitrochemicals
used for peripheral vasodilatation and reduction of blood pressure (nitroglycerine) in treatment of cardiovascular disease
(Nitrochemicals)
Organic nitrates
- important synthetic intermediates in the industrial production of dyes, plastics, and explosives.
- neurotoxic compound: 1,3-dinitrobenzene
(Nitrochemicals)
DNB
produce gliovascular lesions target
astrocytes in the gray matter of the
brainstem and deep cerebellar roof nuclei
DNB
- antimicrobial, antiprotozoal agent that is commonly used for the treatment of a wide variety of infections.
- Prolonged treatment is associated with a peripheral neuropathy characterized by paraesthesias,dysaesthesias, headaches, glossitis, urticaria, and pruritus
(Nitrochemicals)
Metronidazole
- irreversible inhibitor of astrocyte-specific enzyme glutamine synthase
Methionine sulfoximine (MSO)
- Ingestion of large amounts leads to neuronal cell loss in the hippocampal fascia dentata and pyramidal cell layer, in the
short association fibers and lower layers of the cerebral
cortex, and in cerebellar Purkinje cells
Methionine sulfoximine
- Can cause large increases of glycogen levels, primarily within astrocytic cell bodies, as well as swollen and damaged astrocytic mitochondria
Methionine sulfoximine
The Krebs cycle inhibitor _________ and its precursor ___________are preferentially taken up by glia
Fluorocitrate; Fluoroacetate
occurs naturally in a number of plants, and is available commercially as a rodenticide (Compound 1080)
Fluoroacetate
Exposure to FA may also occur via exposure to the anticancer drug ______________
5 fluorouracil
Ingestion of large amounts of FA results in _____________,
with onset of seizures within minutes of consumption; those
surviving these episodes frequently die later on due to ___________ or ___________.
ionic convulsions; respiratory arrest or heart failure
The actions of FC and FA have been attributed both to the ________________ through the Krebs cycle and to _____________
disruption of carbon flux; impairment of ATP production.
- A wide variety of naturally occurring toxins, as well as
synthetic chemicals, alter specific mechanisms of intercellular communication - Can affect the neurotransmitter or the receptors where the
neurotransmitters would bind. It can also affect the reuptake of the neurotransmitters - Although neurotransmitter associated actions may be well understood for some agents, the specificity of the mechanisms should not be assumed
NEUROTRANSMISSION-ASSOCIATED NEUROTOXICITY
binds to nicotinic cholinergic receptor
nicotine
rapid rise after acute OD → excessive stimulation of
nicotinic receptors → ______________
(nausea, rapid heart rate, perspiration, somnolence, coma)
ganglionic paralysis
accelerate heart rate, elevate blood pressure, and
constrict blood vessels within the skin as a
stimulation of the ganglionic sympathetic nervous system
smoking/nicotine
_________ poisoning with nicotine fortunately is uncommon; however, exposure to lower levels for longer duration is very
common.
Acute
An increased propensity for platelets to aggregate is seen in smokers, and this platelet abnormality correlates with the level
of nicotine. (t or f)
T
- blocks dopamine (DA), norepinephrine, and
serotonin reuptake at the nerve terminal in the CNS; causes release of dopamine from storage vesicles
Cocaine
accumulation of dopamine leads to
cerebrovascular defects, stroke, intracranial
hemorrhage, cerebral atrophy
is the primary event responsible for the
addictive properties and euphoric feeling when
intoxicated is a block on the dopamine reuptake
transporter
cocaine
Cerebrovascular resistance has also been found to
be higher in cocaine abusers (t or f)
T
catecholamine neurotransmission in the CNS and damage monoaminergic cells directly
Amphetamines
have become popular with young adults in recent decades due to the belief that it is a “safe” drug, and its ability to increase energy and sensation in adults
MDMA, or “ecstasy”
Similar to cocaine, the most pronounced effect of
amphetamines is on the __________, but they
can also damage _________ and axon terminals.
DAergic neurons; 5HT axons
Dopamine is oxidized to produce free radicals, and
acute use can affect superoxide dismutase and
catalase balance in rodents. (t or f)
F (chronic)
_____________ and certain other acidic amino acids are excitatory
neurotransmitters.
glutamate
The toxicity of glutamate can be blocked by certain glutamate antagonists, and the concept has emerged that the toxicity of excitatory amino acids may be related to such conditions as
hypoxia, epilepsy, and neurodegenerative diseases.
is the main excitatory neurotransmitter of the brain, and its effects are mediated by several subtypes of receptors
called excitatory amino acid receptors (EAARs)
glutamate
two major subtypes of glutamate receptors are those that are ligand-gated directly to ion channels ________________, and those that are coupled with G proteins _______________
ionotropic; metabotropic
Ionotropic receptors may be further subdivided by their specificity for binding _________, ___________,
__________________, and ____________
- kainate
- quisqualate
- α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)
- N-methyl-D-aspartate (NMDA)
The entry of glutamate into the CNS is regulated at the
blood–brain barrier, and glutamate exerts its effects in the ______________ of the brain in which the blood–brain barrier is least developed.
circumventricular organ
Within this site of limited access, glutamate injures neurons, apparently by opening glutamate-independent ion channels,
ultimately leading to neuronal swelling and neuronal cell death. (t or f)
F (dependent)
The only known related human condition is the ________________ in which consumption of large amounts of monosodium glutamate (MSG) as a seasoning may lead to a
burning sensation in the face, neck, and chest.
“Chinese restaurant syndrome,”
MODELS OF NEURODEGENERATIVE DISEASE
- MPTP
- MANGANESE (Mn)
contaminant formed during meperidine synthesis,
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
MPTP
produces over hours to days the signs and symptoms of
irreversible Parkinson’s disease.
MPTP
Autopsy studies have demonstrated marked degeneration of dopaminergic neurons in the ____________, with
degeneration continuing many years after exposure
substantia nigra
MPTP is metabolized by three 3-electron oxidation reactions to the pyridinium ion, MPP+, which enters the dopaminergic neurons of the substantia nigra, resulting in their deaths by
blocking mitochondrial respiration at complex I. (t or f)
F (two)
Although not identical, MPTP neurotoxicity and Parkinson’s disease produce symptomatology of masked facies, difficulties in initiating and terminating movements, resting
- “pill-rolling” tremors
- rigidity
- bradykinesias
- essential trace metal found in all tissues
- required for normal metabolism of amino acids, proteins, lipids, and carbohydrates, acting as a cofactor of synthesis enzymes
MANGANESE (Mn)
The most common commercial sources of Mn
-the fuel additive methylcyclopentadienyl manganese tricarbonyl
(MMT)
- pesticides such as Maneb
- steel factories, welding
- mining plants
Mn toxicity causes a loss of DA neurons in the substantia nigra,
and as in Parkinson’s disease, oxidative stress appears to play
a significant role in the disorder (t or f)
T
basic processes that occur in specific spatial and temporal patterns and underlie development of the NS.
Replication, migration, differentiation, myelination, and synapse formation
during pregnancy, it can result in abnormalities in
the fetus, including abnormal neuronal migration and facial development, and diffuse abnormalities in the development of neuronal processes, especially the dendritic spines
ethanol exposure
-leads to developmental disabilities, including
cerebral palsy, mental retardation, and seizures, in many children at birth
- utero show widespread
neuronal loss, disruption of cellular migration,
profound mental retardation, and paralysis
meHg
- decreased birth weights
attention deficit disorders are more common in
children whose mothers smoke cigarettes during
pregnancy, - lead to analogous neurobehavioral abnormalities in
animals exposed prenatally to nicotine.
nicotine
- able to cross the placental barrier and the fetal
blood–brain barrier, and also causes reduced blood flow in the
uterus
Cocaine
- In severe events at large doses taken by the mother,
the fetus may develop hypoxia = higher rate of birth defects. - use leads to low–birth weight and behavioral defects, including a decreased awareness of the surroundings and altered response to stress and pain sensitivity
Cocaine
- These persistent pollutants produce endocrine disruptions, cognitive deficits, and changes in activity levels in exposed offspring; however, the specific outcomes depend on the congener or mixture tested as well as the timing of exposure
- Changes in estrogen or thyroid hormone,
neurotransmitter function, and second messenger
systems have been proposed as cellular bases for PCB toxicity
polychlorinated biphenyls (PCBs) and/or dioxins.
- have shown similarities in altering thyroid hormone metabolism and cholinergic function, and it has thus been proposed that this chemical class would also be developmentally neurotoxic.
polybrominated
diphenyl ethers (PBDEs)
