Lecture 9 Toxic Responses of the Nervous System????

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Lecture 9 Toxic Responses of the Nervous
System????
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Organization of the Nervous System

• Two principal divisions
• Central Nervous System?????? (CNS)
• Brain
• Spinal Cord
• Peripheral Nervous System?????? (PNS)
• Sensory system??????
• Motor system ??????

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Central nervous system
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Autonomous Nervous System ??????
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Structure of Neuron???? ???
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Action Potential Conduction
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Neuron

• Fundamental cell consists of
• Cell body
• Axons and dendrites
• for conduction of nerve impulses
• External myelin sheath
• ? velocity of action potential conduction
• Neurotransmitter???? is secreted at the
  synapse??

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Neurotoxicity????

• Any substance capable of producing an adverse
  effect on the structural or functional components
  of the nervous system.
• Nervous system is vulnerable because it has a
  limited capacity for regeneration?? .
• Effects may be immediate, delayed in onset,
  permanent or reversible

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Neurotoxic substances

• Diverse in their chemical structure
• Naturally occuring element e.g. mercury, lead
• Biological compounds (neurotoxins???? e.g.
  botulinum toxin???? , tetrodotoxin????
• Synthetic compounds e.g. pesticides and
  industrial solvents
• Therapeutic drugs and drugs of abuse

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Spectrum of adverse neurological effects

• Motor effects e.g. convulsions, tremors, lack of
  coordination, paralysis and weakness
• Sensory effects e.g. equilibrium changes, and
  visual, tactile and auditory disorders
• Cognitive effects e.g. confusion, memory
  deficits, speech and learning impairments
• Mood and personality effects e.g. depression?? ,
  excitability, irritability, restlessness,
  delirium and hallucinations
• General effects e.g. loss of appetite, fatigue,
  overall depression of neuronal activity

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Adult vs developing fetuses and children

• Developing fetuses?? and children are more
  vulnerable to neurotoxins
• In active growing stage
• blood-brain barrier???? not completely formed
• Metabolic pathways for detoxification are not
  fully developed
• Elderly is also ? sensitivity to neurotoxins
• ? compensation ability of nervous system
• ? hepatic and renal functions

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Classes of Neurotoxic Substances

1. Substances acting on the Neuronal cell membrane
2. Substances acting on Neuronal Structures
3. Substances acting on Glial cells???? and Myelin
4. Substances acting on the Neurotransmitter system

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Substances acting onthe Neuronal cell membrane

• Neuronal cell membrane consists of
• Complex system of pumps, receptors and ion
  channels, for the impulse formation and
  transmission
• Blockage of the ion channels????
• Inability to coordinate muscular movements e.g.
  speaking and swallowing
• Severe situation leads to respiratory paralysis
• Neurotoxins e.g. tetrodotoxin (from puffer fish)
  and saxitoxin????? (from marine alga)

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Substances acting onNeuronal Structures

• Degeneration leads to permanent neuronal damage
• Cerebellum damage e.g.by mercury
• Tremors, difficulty in walking, visual impairment
• Cortex of developing brain e.g. by lead
• Mental retardation
• CPDA (central-peripheral distal axonopathy)
• E.g. by carbon disulfide, hexane, acrylamide
• Loss of sensation in the extremities and muscle
  weakness
• Recovery is possible

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Substances acting onGlial cells and Myelin

• Function of Glial cells
• Maintain the structure of the nervous system
• Form myelin sheath
• Repair damage
• Function of Myelin - ? velocity of signal
  transmission
• Lead to slow degeneration of the cell body and
  axon ? permanent neuronal damage
• E.g. Diphtheria toxin interferes with the cell
  bodies of the myelin producing glial cells
• E.g. hexachlorophene (antiseptic solution)
  interferes with the mitochondria of glial cells.

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Substances acting onthe Neurotransmitter system

• Inhibition of acetylcholinesterase e.g. by
  organophosphorus insecticides
• inappropriately continues impulse conduction.
• ? salivation, lacrimation, sweating, ataxia,
  tremors, muscle convulsions, constriction of
  pupils, brochial constriction, ? peristalsis ?
  nausea, vomiting, abdominal cramps and diarrhea.
  Death due to asphyxiation
• Drug of abuse
• Cocaine ? aggression, paranoia, high blood
  pressure, abnormal heart rhythms

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Occupational Neurotoxicants

• Lead
• Neurotoxic Pesticides
• Organic solvents

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Lead

• In both organic and inorganic forms
• Organic lead degrades quickly in atmosphere and
  body ? small portion of the total
• Inorganic lead is the majority, problem to both
  humans and environment
• Sources of exposure
• Water, food, soil and lead-based paint, leaded
  gasoline, industrial emissions

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Lead (II)

• Absorption and retention is higher in children
  than adults ? store in growing bones, circulating
  blood and soft tissue
• Children is more vulnerable
• blood brain barrier is not completely developed
• Hepatic and renal functions are not fully
  developed.
• US EPA considers 10 to 15 ?g/dL as the maximum
  acceptable lead blood level
• Symptoms nerve dysfunction, ? I.Q., impaired
  muscular coordination to stupor, coma and
  convulsions.

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Neurotoxic Pesticides

• Human exposure to pesticides
• Contaminated drinking water
• Residues in food
• Through the production and use of pesticidal
  products
• Cholinesterase-inhibiting insecticides
• Organochlorine insecticides
• Fumigants??????
• Pyrethroids??????

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Cholinesterase-inhibiting insecticides

• The most common causes of poisonings
  Organophosphorus (OP) and carbamate
• Both inhibit acetylcholinesterase, the enzyme
  breaks down neurotransmitter acetylcholine.
• Acute poisoning symptoms hyperactivity,
  neuromuscular paralysis, visual and breathing
  difficulties, vomiting, diarrhea, weakness,
  convulsions, coma, death.
• Delayed effects irritability, depression, mood
  swings, short-term memory loss

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Organochlorine Insecticides

• Nervous system stimulants
• Potential for chronic toxicity due to
  accumulation in the environment and the body.
  E.g. DDT
• Acute exposure nervous system excitability,
  headache, dizziness, confusion, weakness,
  tremors, coma and death
• Children may suffer persistent behavioral and
  learning disabilities

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Fumigants

• Gases used to kill insects, insect eggs,
  microorganisms, e.g. methyl bromide
• Acute exposure visual and speech disturbances,
  delirium, convulsions
• Chronic exposure progressive peripheral
  neuropathy, loss of motor control, numbness,
  weakness
• Prolonged effects marked personality changes and
  perceptual difficulties

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Pyrethroids

• A group of insecticides, highly toxic to insects,
  less toxic to mammals
• Alteration of the flow of sodium ions through the
  nerve cell membrane ? repeated firing of the
  nerve cell

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Organic solvents

• Used in industrial processes and commercial
  products e.g. paints, paint removers and
  vanishes, adhesive, glues and coatings,
  degreasing and cleaning agents, dyes and inks,
  floor and shoe polishes, agricultural products,
  pharmaceuticals, fuels.
• All solvents are fat soluble ? affect CNS

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Organic Solvents

• Short-term exposure at low toxicity
• Mucous membrane irritation, tearing, nasal
  irritation, headache, and nausea
• Exposure at higher level
• Initial euphoria??????? , followed by confusion,
  motor incoordination, ataxia???? ,
  unconsciousness, death

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Organic Solvent other neurological effects

• Hexane, methyl-n-butyl ketone
• Numbness in the hands and feet, muscle weakness,
  lack of coordination
• Xylene or toluene
• High-frequency hearing loss
• Methylcyclopentane or methylcyclohexane
• Seizures and convulsions
• Trichloroethylene
• Damaged facial nerves and facial numbness
• Styrene
• Impaired perceptual speed, accuracy, memory and
  cognitive performance