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Semina
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devel
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neurot
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Submitted to Dr, kps gowda sir Hod and asso professorDept of pharmacology
DEVELOPMENTAL NEUROTOXICITY
Contents :Introduction.Syndrome of neurotoxicity.Sign of central and peripheral
neuropathy.Why is the Brain Particularly
Vulnerable to Injury.Causes of neurotoxicity.Types.Neurotoxicology of heavy metal.
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)
Developmental neurotoxicity (DNT) is probably the least tested health effect of chemicals: only about 150 substances have been subjected to the internationally agreed guideline studies.The lack DNT data for almost all chemicals, including environmental pollutants, industrial chemicals, drugs, consumer .
Epidemiological studies in this field can hardly prove causal
relationships unless effects are dramatic; only a handful of compounds, therefore, have been established as definitive DNToxicants in man methyl mercury, lead, arsenic, toluene, and ethanol. This group was recently expanded to include six additional developmental neurotoxicants – manganese, fluoride, chlorpyrifos, dichlorodiphenyltrichloroethane,
• Brain in children and fetuses is much more vulnerable to chemical perturbation than the adult brain, leads to major concerns about deficient DNT data. The high sensitivity of the developing brain is due to the still immature blood/brain-barrier, increased absorption versus low body weight, and diminished ability to detoxify exogenous chemicals
Moreover, CNS development is a complex process involving many different events, such as differentiation of progenitor cells, proliferation and cell migration, synaptogenesis, myelination, cell death, synthesis of neurotransmitters, and formation of receptors. these events occur within strictly controlled timeframes and, therefore, each event creates a different window of vulnerability to xenobiotic exposure
Once neurodevelopment is disturbed there is little potential for repair
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
Many substances go directly to the brain via inhalation
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
brain.
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
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? Chemical
Physical
Toxicants and Exposure
Inhalation (e.g. solvents CS2 , 1,1,1‐trichloroethane, nicotine, nerve gases)
Ingestions (e.g. lead, alcohol, drugs such as MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
Skin (e.g. pesticides, nicotine). Physical (e.g. load noise, trauma).
Types Of Neurotoxicity
Neuropathies Axonopathies Myelinopathies Neurotransmission-associated
abnormalities
NEURONOPATHIES
Injury or death to neurons. Irreversible loss. Initial injury followed by apoptosis or
necrosis. Caused by CO, ethanol, carbon
tetrachloride, methyl mercury, lead.
AXONOPATHIES
Primary site of toxicity is axon Degeneration of axon, surrounding
myelin, but cell body remains intact Irreversible in CNS, but reversible in
PNS Caused by CS2, acrylamide, gold,
organophosphorus esters
PATHWAY OF AXOPATHOPATHIES
MYELINOPATHIES
Intramyelinic edema Demyelination Remyelination in CNS occurs to a limited
extent Remyelination in PNS done by Schwann
cells Caused by amiodarone, disulfiram,Pb
NEUROTRANSMISSION-ASSOCIATED ANOMALITIES
Interruption of impulse transmission Blockade of transsynaptic
communication Inhibition of neurotransmitter uptake Interference with second-messenger
systems Caused by nicotine, amphetamines,
cocaine
Neurotoxicology
Heavy Metals Lead – environmental exposure
(paint, fuels) Mercury – exposure via diet
(bioaccumulation in fish
Lead Neurotoxicity Developmental Neurotoxicity Reduced IQ Impaired learning and memory Life-long effects Related to effects on calcium
permeable channels (NMDA, Ca++ channels)
Overview of Glutamate and Excitotoxicity
Lead neurotoxicity 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
Toxicity of Mercury
Organic mercury (methylmercury) is the form in fish tuna and swordfish, 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.
References
Google .com Slideshare.com Authorstream.com Lena s, Helena T. Marcel L , and
Thomas H. Developmental Neurotoxicity – Challenges
in the 21st Century and In Vitro Opportunities.2014 altrex :page 129-156.