NEUROTOKSISITAS.pptx

8/11/2019 NEUROTOKSISITAS.pptx

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Hanif Nasiatul Baroroh

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An adverse change in thechemistry, structure or function

of the nervous system duringdevelopment or at maturity,

following exposure to a chemicalor physical agent.

What is Neurotoxicity?

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Even minor changes in thestructure or function of the

nervous system may haveprofound consequences forneurological, behavioral,

and related body functions.

Nervous System Sensitivity

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CNS Central Nervous System PNS Peripheral Nervous System Blood brain barrier Neuronal cells

Neurotransmitters & receptors

Nervous System Biology

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Nervous SystemCNS & PNS

Central Nervous System (CNS) Brain & Spinal Cord

Peripheral Nervous System (PNS)

Afferent (sensory) NervesCarrysensory information to the CNS

Efferent (motor) NervesTransmitinformation to muscles or glands

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Central Nervous System

Central Nervous System (CNS)(Brain and Spinal Cord)

Peripheral Nervous System(PNS)

Autonomic Somatic

Sympathetic Parasympathetic

Afferent (sensory) Nerves(Carry sensory information to the CNS)

Efferent (motor) Nerves(Transmit information to muscles or glands)

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Peripheral Nervous System

Peripheral Nervous System (PNS) Efferent (motor) Nerves

Transmit information to muscles or glands

Somatic Nervous System Stimulates Skeletal muscles Autonomic Nervous System

Stimulates Glands and Organs (e.g. heart)

Sympathetic- Adrenergic stress response

Parasympathetic- Cholinergic basic functions

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Cells of the Nervous System

Neurons Information conductors

Supporting Cells (Glia cells) Astrocytes (CNS blood brain barrier) Oligodendrocytes (CNS link cells) Schwann cells (PNS wrap cells)

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Blood-brain Barrier

Not an absolute barrier Caffeine (small) Methylmercury cysteine complex

Lipids (brain is a ball of fat)Anatomic Characteristics

Capillary endothelial cells are tightly joined no pores between cells

Capillaries in CNS surrounded by astrocytes Low protein concentration in CNS fluid Active ATP-dependent transporter moves

chemicals into the blood

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Neuronal Cells

Axon

Myelin (Schwann cell)

Synapse

Dendrite

Cell Body

Nucleus

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Neuronal Transmission

+ + - + +

+ + - + +

+ + - + +

+ + - + +

- - + - -- - + - -

- - + - -- - + - -

- - - - -+ + + + +- - - - -+ + + + +

++

++

+ + +++ +

++ +-

--

-

--

-----

K+

K+

Na+

Cl-

-- -

-

-

--

-

- -

InhibitorySynapse

ExcitatorySynapse

+400

-40-70

+400

-40-70

Action Potential IPSP

EPSP

Action Potential

No Action Potential

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Neurotransmission


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Dopamine

Transmitter Cell(ExcitatoryNeuron)

DopamineReceptor Cell(Post-synaptic receptor)

DopamineReceptor

Synaptic Cleft

Synaptic Vesicles

Neurotransmission

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EPSP=EXCITATORY POSTSYNAPTIC

POTENTIAL

Ex : ACETILCHOLINE, NOR ADRENALINE,ADRENALIN E, GLUTAMATE

IPSP=INHIBITORY POSTSYNAPTIC

POTENTIAL

Ex :SEROTONIN, DOPAMIN , GABA, GLISIN,

ASPARTAT.


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Inhalation (e.g. solvents,

nicotine) Ingestions (e.g. lead, alcohol) Skin (e.g. pesticides, nicotine)

Physical (e.g. load noise)

Exposure Issues

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What causes neurotoxicity?

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1930s Ginger-Jake Syndrome During prohibition, an alcohol beverage was

contaminated with TOCP (triorthocresyl

phosphate) causing paralysis in 5,000 with20,000 to 100,000 affected.

1950s Mercury poisoning Methylmercury in fish cause death and sever

nervous system damage in infants and adults.

Historical Events

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Case Studies

Lead damages developing brain

Alcohol Fetal alcohol syndrome MPTP similar to Parkinsons disease

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Nervous Systems Effects

Developmental Neurotoxicity

Reduced IQ Impaired learning and memory

Life-long effects

Lead Neurotoxicity

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Alcohol (ethanol)

CH

H

H

OH

Ethyl Alcohol

C

H

H

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Vulnerability of DevelopingNervous System

FAS Fetal Alcohol SyndromeFAE Fetal Alcohol Effects

What is a save level ofconsumption during pregnancy?

Alcohol

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MPTP

N

CH3

1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine

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1980s Designer Drug Caused effects similar to

Parkinsons disease Damaged neurons that

secrete dopamine

MPTP Effects

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Receptor

Ligand

Cell

Membrane

Signal Protein

Positive Response

Outside Cell

Inside Cell

Ligand binds to receptor

1

3

2

Normal Receptor-Ligand Interaction

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Toxicant1

Toxicantinactivates

receptor

No Response

32

Inactivation of Receptor by Toxicant

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Toxicant1

No Response

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Ligand

Toxicantout competesnormal ligand

Ligand cannot bindreceptor

Competition For Receptor

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Types Of Neurotoxicity

Neuronopathy Cell Death. Irreversible cells not replaced. MPTP, Trimethytin

Axonopathy

Degeneration of axon. Reversible. Hexane, Acrylamide

Myelinopathy Damage to myelin (e.g. Schwann cells) Lead, Hexachlorophene

Transmission Toxicity Disruption of neurotransmission

Organophosphate pesticides, Cocaine, DDT16/12/2011 32


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Neurotoxic Injury

Neuron

Normal

Neuronopathy

Axonopathy

Myelinopathy

Transmission

Axon

Synapse

Myelin

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Neuronopathy Neuronopathy refers to generalized damage to nerve cells,

with the primary damage occurring at the nerve cell bodyMany neurotoxicants produce their effects by promoting

cell death in neurons. Neurons die by one of two processes distinguished by their

morphological and molecular features: apoptosis andnecrosis.

Neurotoxicant-induced cytotoxicity has been associatedwith the pathogenesis of a number of neurodegenerativedisorders, including Alzheimers disease, Parkinsonsdisease, and amyotrophic lateral sclerosis (ALS)

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AxonopathyAxonopathy is a specialized form of neuronal damage,

involving degeneration of the axon, while leaving thecell body intact.

Axonopathy can manifest as defects in sensory ormotor functions, or a combination of the two. For most

neurotoxicants, sensory changes are noticed first,followed by progressive involvement of motor neurons

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Demyelination Neurotoxicants that target the synthesis or integrity of

PNS myelin may cause muscle weakness, poorcoordination, and paralysis.

The former include agents like hexachlorophene,isoniazid, the organotins, cyanide, carbon monoxide,and Inorganic lead

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Toxicant Mediated Alterations in


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Neurotoxicants interfere with signaling processes within

the nervous system by activating or inhibiting receptors, oraltering the amount of neurotransmitter available toactivate receptors.

This type of neurotoxicity is illustrated by the well-

characterized actions of the organophosphates andcarbamates on acetylcholine signaling.

Acetylcholine and its receptors mediate neurotransmissionin sympathetic and parasympathetic autonomic ganglia, inthe effector organs where autonomic nerves terminate, in

neuromuscular junctions, and in the brain and spinal cord. Hyperstimulation of nicotinic receptors in neuromuscular

junctions results in muscle weakness, in rapid, localizedcontractions called fasciculations, and in paralysis

Toxicant-Mediated Alterations inSynaptic Function

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Examples of Neurotoxicology

DiseasesParkinson's, Alzheimer's, MS, ALS..

Environmental

Lead, Methylmercury

Occupational

Solvents, Pesticides

Drugs - Clinical

Vincristine, cisplatin

Drugs - Social

Alcohol, cocaine, nicotine

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Classification of neurotoxicants by


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Classification of neurotoxicants by

mechanism of action

Temporary inhibition ofnerve function

Agents which alter membranefunction

Agents with interfere with synaptic

transmission

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h i l i l S i i i


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Dependence on oxygen Little anaerobic capacity CO less available oxygen Cyanide inability to use oxygen

Dependence on glucose

Sole energy source High metabolic rate

Physiological Sensitivity

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Ph i l i l S i i i


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Structure Long cell requires extensive

intracellular transportBlood-Brain BarrierDevelopmental stage

(lead and alcohol)

Physiological Sensitivity

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Neurons CANNOT divide andreplace themselves

Neurons CAN repair limitedaxonal damage

Most Recovery

Redundancy of Function Plasticity of Organization

Reversibility of Damage

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Neurological and Behavioral Effects of

Exposure to Toxic Substances

Motor Effects - Convulsions, weakness, tremor,, lack ofcoordination, unsteadiness, paralysis, reflex abnormalities,activity changes

Sensory Effects- Equilibrium changes, vision disorders,pain disorders, tactile disorders, auditory disorders

Cognitive Effects- Memory problems, confusion,speech impairment, learning impairment

Mood and personality effects- Sleepdisturbances, excitability, depression, irritability, restlessness,nervousness, tension, delirium, hallucinations

General effects- Loss of appetite, depression ofneuronal activity, narcosis stupor, fatigue, nerve damage

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Mercury


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Mercury

Neurotoxic effects lead to,Paresthesia

AtaxiaNeurastheniaVision and hearing loss- Coma and deathNeurotoxic effects due to focal necrosis of neuronsThe average long-term intake associated withparesthesia calculated to be 300 g/day for an

adultPoisoning therapy utilizes chelators such ascysteine, penicillamine, thiol resins

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Carbon disulfida

Used in the production of viscose rayon, cellophane,

pesticides, as a solubilizer for waxes and oils

Direct interaction with free amine and sulfhydryl groupsMicrosomal activation to reactive sulfur intermediates

that bind macromolecules

Produce neuronal degeneration in CNS; in PNS produce

myelin swelling and fragmentation

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LEAD


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Source is from lead-based paint, contaminated drinkingwater,Encephalopathy occurs at blood lead levels of 80-100g/dL

Symptoms of encephalopathy include lethargy,vomiting, irritability, loss of appetite, and dizzinessProgression of symptoms lead to ataxia, reduced levelof consciousness, which may progress to coma and death

Recovery is often associated with life-long epilepsy,mental retardation, optic neuropathy, blindness

LEAD

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Chronic toxicity affects PNS;Schwanncell degeneration

Mechanisms of toxicity include,Impairment of cell-cell connections,Alterations in neurotransmitter levels,Disrupts calcium metabolism

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NICOTINE


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NICOTINE

Exposure from smokingBinds to nicotinic cholinergic receptors

Increase in HRElevated BPAcute overdose leads to excessive

stimulation of nicotinic receptors leadingto ganglionic paralysis

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DDT, lindane, dieldrinHigh lipid solubility, low degradation rateProduce disturbances in ion transport across

axon leading to increased excitability

ORGANOCHLORINE INSECTICIDES

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ORGANOPHOSPHOROUS PESTICIDES

Malathion, parathion, nerve

gasesInhibits acetylcholinesterase(AChE) leading to continuousstimulationNeurobehavioral, cognitive,neuromuscular disturbances

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NEUROTOKSISITAS.pptx

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