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Neurotoxicology:
Overview:Factors unique to nervous system
Examples of neurotoxicants
TOXC707 Advanced Toxicology (2007)
Cells of the Nervous System
◄ neurons◄ neuroglia (90% of cells)
oligodendrocytes (Schwann cells in PNS) astrocytes microglia gliosis is a marker of gross CNS toxicity
Increased expression of Glial Fibrillary Acidic Protein- (GFAP)
Dopamine: A Brain Neuromodulator
Frontal Cortex
Gyrus Cinguli
Sub. Nigra
Corpus Callosum
Tegmentum
Entorhinal Cortex
Basal Ganglia
Olfactory Tubercle
Nuc. Accumbens
Medial Forebrain Bundle
Hypothalamus
Pituitary
Midbrain}
Types of neuronal connections
Axo-somaticSynapse
Axons
Dendro-dendriticSynapse
Axo-axonalSynapse
Dendrites
Axo-dendriticSynapse
Perikarya
Major Components of Peripheral Nervous System
Peripheral neuron
Three views of myelinating Schwann cell
Nucleus
Compact membrane (Myelin)
Cytoplasmic channel(Schmidt-Lantermann)
Schwann cell cytoplasm
Unwrapped
Longitudinal
Cross-section
Processes of demyelination and remyelination
Susceptibility to neurotoxicants
◄ High metabolic rate and electrical excitability are dependent on membrane integrity and aerobic metabolism
◄ Extended length of axons poses logistical problems associated with transport from cell bodies to terminal fields
◄ Metabolism of some neurotransmitters may produce oxidative stress (e.g., dopamine)
◄ Inability to replace dead or dying cells
Dr. Mailman’s Pet Peeves
◄ Neurotoxin A toxic compound of natural origin
◄ Neurotoxicant A toxic compound
◄ Putative “Generally regarded as such; supposed” (American
Heritage) “Generally thought to be or to exist, whether or not this is
really true” (Cambridge) Does not mean hypothesized or speculated.
Consequences of neuronal characteristics
◄ axonal transport sensitive to toxicants◄ hexanes cause cross-linking of neurofilaments◄ diabetic neuropathy
Neurodevelopmental Toxicology
Unique aspects of the nervous system for neurotoxicology: Neurodevelopment
◄ Massive loss of neurons during vertebrate development has been known for more than a century. Beard (1889) – loss of neuronal populations in fish
(Rohon-Beard Neurons) Collin (1906) – death of many sensory and motor neurons
in the chick embryo
Clarke, Rogers & Cowan J. Comp. Neurol. 167: 125 (1976)
~50% of Post-mitotic neurons die during normal development
Apoptotic neuronal death in the developing substantia nigra
R. Burke. Cell Tiss. Res. 2004
Victor Hamburger: Peripheral Targets Regulate Cell Death
led to NGF discovery
Transcriptional regulation of apoptotic cell death
Summary
◄ There is massive death of neurons, neuroprogenitors, and oligodendroglia in normal vertebrate development.
◄ This is largely regulated by access to limiting supplies of exogenous survival-promoting trophic factors.
◄ Survival is promoted largely by activation of Akt as well as Erks, and involves blockade of death pathways at multiple points.
◄ Developmental neuron death is transcription dependent. ◄ Induction of death involves multiple pro-apoptotic signaling
pathways, some of which converge on induction of BH3-domain proteins.
Impact of neurodevelopment on toxicology
◄ The effects of toxicological insults may be temporally delayed, being expressed as a variety of alterations in development.
◄ The effects of toxicant exposure will be markedly affected not only by dose/concentration, but also by timing.
◄ Insults by the same dose/concentration at different times during development may result in markedly different sequelae.
◄ Extrapolation from animal models present an even greater challenge than usual because of species differences in developmental patterns.
◄ This will be discussed later re. Fetal Alcohol Syndrome and solvents.
Toxicant Access and Metabolism
Unique aspects of the nervous system for neurotoxicology: Blood-brain barrier
◄ The choroid plexus separates the blood from the cerebrospinal fluid, whereas the blood-brain barrier limits the influx of circulating substances into the immediate brain interstitial space.
◄ Blood brain barrier limits influx of circulating substances from capillaries into interstitial space
◄ Brain capillaries, unlike those in other tissues, are not fundamentally porous. Tight junctions between adjacent capillary endothelial cells Processes from adjacent cells (astrocytic end feet). A microperoxidase (molecular mass 1800 daltons) that is readily transverses
capillaries in other tissues will not pass through capillaries in the brain. ◄ Carrier-mediated transport systems exist for entry of certain required
molecules (e.g., hexoses, carboxylic acids, amino acids (separate ones for neutral, basic, and acidic amino acids), amines, and inorganic ions
Breaching the barrier
◄ Generalizations for healthy brain Large molecules (large peptides and proteins) are excluded Polar molecules are excluded; nonpolar lipid-soluble molecules can
penetrate more easily e.g., increased absorption of dimethyl mercury vs. inorganic mercury
(Minamata disease) e.g., MPP+ (toxic metabolite of MPTP) does not cross the BBB
Specific transport systems may facilitate toxicant passage e.g., elemental mercury forms complex with cysteine and is recognized by
amino acid transporters as methionine
◄ Alterations in BBB substances that alter membrane function (organic solvents) brain edema bacterial meningitis
Unique aspects of the nervous system for neurotoxicology: Toxicant metabolism
◄ Although some xenobiotic metabolic capacity exists in brain, the relative concentration is low compared to the liver or other tissues.
◄ Detoxification mechanisms in CNS have much lower capacity and diversity than in periphery.
◄ Can be important for specific toxicants. 2,4,5‑trihydroxyphenylalanine is activated MPTP is activated
Unique aspects of the nervous system for neurotoxicology: Plasticity
◄ The nervous system has a unique capacity to accommodate to change.
◄ These changes may sometimes mask, or even be caused by, neurotoxic insult.
◄ Interesting phenomena include: Desensitization Sensitization Up- and down-regulation Long-term potentiation and other types of synaptic plasticity Sprouting
Neurotransmission
Neurotransmission
◄ Relies on separation of positive and negative charges across membrane
◄ Ionic gradient depends on ATP-linked Na+/K+ pump at rest, interior more negatively charged following sufficient stimulus in dendritic region, unidirectional impulse
flow along axon occurs role of ion channels
voltage gated sodium voltage-gated potassium channels
◄ Electrochemical neurotransmission vs. electrical transmission
Synapse
◄ Specialized structure for releasing and sensing small amounts of neurotransmitters
◄ Neurotransmitters vs. neuromodulators◄ Importance to toxicologists
toxicants may act directly at synaptic loci toxicants may indirectly alter synaptic function
Synaptic Structure
1
4
2
Na+
transmitter synthesis Precursor
5
6
3
Second messenger events
8
PresynapticCell
PostsynapticCell
ImpulseFlow
etc.
mRNA
Nucleus
(in perikaryon)
7
adenylate cyclaseG protein
GTPcAMPATP
GDPGTPcAMPATP
GDP
Synaptic targets for toxicants
◄ Neurotransmitter synthesis◄ Neurotransmitter storage◄ Neurotransmitter inactivation or degradation◄ Neurotransmitter receptor binding◄ Receptor-linked second messenger events◄ Pumping or transport of ions◄ Downstream cellular function (e.g., nucleic acid
synthesis)
Mechanisms of toxicity:Receptors
Receptors and Signal Transduction
2 Ion
R R
ligand 1
E2
R E1
ligand
ligand
nucleus
R
R
3 ligand
E
R R
4
P
P
P
P
R R
Toxicants acting directly on receptors
◄ morphine and codeine alkaloids of the opium poppy that causes acute analgesic, antitussive, euphoric,
emetic/antiemetic effects◄ mescaline
derivative of peyote cactus mescaline is believed to cause central actions via interactions with serotonin receptors
◄ ergot alkaloids LSD (ergot-contaminated grain and medieval European cities and the Salem witch
trials??). ◄ methylxanthines
caffeine; theophylline are found in coffee and tea Adenosine receptor ligands plus phosphodiesterase inhibitors
◄ reserpine – VMAT2 ligand blocks vesicular monamine transporter in dopamine and serotonin neurons initial effect is massive release later effect is long term depletion
Cholinergic toxins
◄ Snake neurotoxins -bungarotoxin
blocks nicotinic acetylcholine receptor (binds irreversibly)◄ Belladonna alkaloids
atropine; scopolamine derived from “deadly nightshade” (Belladonna sp.) competitively blocks muscarinic cholinergic receptors also used as antidote for muscarinic agonists/ACh overactivity
◄ nicotine nAChR agonist
◄ Cholinesterase inhibitors solanine and chaconine (Solanum sp., tomoato, potato) Huperzine A physostigmine (eserine) from Calabar bean
Clostridium Indirect Actions
◄ Tetanus Cl. tetani produces 70,000 KDa protein called tetanospasmin Blocks inhibitory synaptic input on spinal motor neurons, resulting in
spastic paralysis. moved through nerve cells via retrograde axonal transport until it
binds, or is fixed, to gangliosides in the brain stem or cord. Ricin also retrogradely transported.
◄ Botulism Cl. botulinum produces a series of neurotoxins Bind to presynaptic cholinergic nerve terminals
◄ Gas gangrene Cl. perfringens
Amino acid receptors
◄ strychnine blocks glycine receptors in spinal cord predominantly effects due to blockade of normal inhibitory influence of
glycine receptor complex
◄ monosodium glutamate (MSG) sodium salt of amino acid glutamate can be actively transported into brain
Ion channel ligands
◄ Alteration in sodium channel activity tetrodotoxin (isolated from puffer fish) and saxitoxin (dinoflaggelate
phytoplankton) binds to voltage-dependent sodium channel and blocks increases in
conductance disrupts generation of action potentials
veratridine steroidal alkaloid (found in Veratrum and Zygadenus species) depolarizes
nerve membranes. grayanotoxins (plant alkaloids from leaves of Ericaceae family)
causes reversible increase in Na+ channel permeability
◄ Ouabain inhibits Na+K+ ATPase by high affinity binding to a site on the
enzyme interferes with maintenance of electrical potential across membrane
Agents that disrupt calcium homeostasis
◄ In addition to effects on Na+ channels, pyrethroid insecticides target Ca2+/Mg2+ ATPase and calmodulin inhibition of these enzymes increases intracellular calcium excessive intracellular calcium is linked to a variety of deleterious
effects
◄ Among other effects, a variety of heavy metals (lead, mercury, aluminum) are associated with increased intracellular calcium actions may derive from competition for binding sites on various types
of calcium binding proteins
Agents that alter intracellular signaling
◄ Mercury has ubiquitous effects e.g., interferes with synthesis of tubulin and other proteins mechanism my be its ability to couple to cysteine and other thiol-
containing groups, promoting binding to many proteins
◄ Aluminum competes with iron for cellular uptake due to similar coordination
chemistry participates in redox cycling and oxygen radical formation promotes aggregation of certain proteins
has been linked to pathogenesis of Alzheimer’s disease (AD) presence of aluminum in neurofibrillary tangles may be a consequence, not
a cause of AD
Agents that cause hypoxia
◄ Any agent that derives CNS of oxygen is neurotoxic◄ Neuronal subpopulations with very metabolic activity are
particularly susceptible (e.g., hippocampus, neocortex)◄ Sequelae of hypoxia are similar to excitotoxicity◄ Anoxic hypoxia (compromised oxygen supply to brain despite
adequate blood flow) carbon monoxide
◄ Ischemic hypoxia (block of blood supply to brain) any agent causing cardiovascular failure (digitalis glycosides)
◄ Cytotoxic hypoxia (interference with cellular respiration) cyanide azide
Agents that affect membranes
◄ Organic and inorganic lead damage membranes probably occurs via disruption of ion channels results in ultrastructural damage to mitochondria,
breakdown of active transport, damage to myelin-containing membranes
◄ Copper can participate in formation of reactive oxygen species and lipid peroxidation
◄ Solvents and vapors are lipid soluble and can alter membrane fluidity
Indirect effects on neurotransmission
◄ activation of neurotransmitter release latrotoxin (black widow venom) releases vesicle-bound
neurotransmitters amphetamine, methamphetamine, ephedrine release
catecholamines methylmercury neurotransmitter release occurs secondary
to altered calcium homeostasis
◄ inhibition of neurotransmitter reuptake or metabolism organophosphates inhibit acetylcholinesterase
Agents that interfere with oxidative phosphorylation
◄ Classical inhibitors of oxidative phosphorylation dinitrophenol cyanide hydrogen sulfide
◄ Lead, mercury and other metals indirectly compromise oxidative phosphorylation by mitochondrial insult
◄ MPTP directly inhibits oxidative phosphorylation
Agents that damage myelin
◄ Some demyelinating agents do not cross BBB and demyelinate only in periphery
◄ Other agents of capable of CNS and PNS effects Hexachlorophene Isoniazid Tellurium Organotins
Protection from oxidative damage
◄ Brain has highest rate of oxidative activity of any organ◄ Endogenous oxygen-derived radicals are thought to be
important in pathogenesis of many neurodegenerative diseases◄ Both neurons and glia contain protective mechanisms; neurons
benefit from secreted enzymes manufactured in glia e.g., glutathione is distributed ubiquitously--chelates transition metals
and prevents redox cycling events glutathione peroxidase and superoxide dismutase are present in
astrocytes catalase is found in oligodendrocytes
◄ The cytochrome P450 isozymes found in brain purported to have a role in Parkinson’s disease
Translational Medicine (Buzzzzzzz):
How can we assess neurotoxicity?
Discussion
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