neurotoxin

8/8/2019 neurotoxin

1/42

Intro Neurotoxicity 5/7/04

An Introduction to Toxicologyof the Nervous System

8/8/2019 neurotoxin

2/42

Intro Neurotoxicity 5/7/04A Small Dose of Toxicology

Introduction

You cannot reach your

full genetic potentialwith a damaged nervous

system.S.G. Gilbert

8/8/2019 neurotoxin

3/42


An adverse change in the

chemistry, structure or function

of the nervous system during

development or at maturity,

following exposure to a chemicalor physical agent.

What is Neurotoxicity?

8/8/2019 neurotoxin

4/42


Even minor changes in the

structure or function of the

nervous system may haveprofound consequences for

neurological, behavioral,

and related body functions.

Nervous System Sensitivity

8/8/2019 neurotoxin

5/42


Ancient Awareness

LEAD MAKES THE

MIND GIVE WAYDioscorides - GREEK 2ND BC

8/8/2019 neurotoxin

6/42


The upsurge of interest in recent years

in academia, industry, and government

on the effects of toxic chemicals on thenervous system has created a new

discipline of neurotoxicology.

Peter S. Spencer & Herbert H. Schaumberg, in

Experimental and Clinical Neurotoxicology, 1980

Current Awareness

8/8/2019 neurotoxin

7/42


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

contaminated with TOCP (triorthocresyl

phosphate) causing paralysis in 5,000 with

20,000 to 100,000 affected.

1950s Mercury poisoning

Methylmercury in fish cause death and severenervous system damage in infants and adults.

Historical Events

8/8/2019 neurotoxin

8/42


Case Studies

Lead damages developing brainAlcohol Fetal alcohol syndrome

MPTP similar to Parkinsons disease

8/8/2019 neurotoxin

9/42


Lead In Homes

8/8/2019 neurotoxin

10/42


Nervous Systems Effects

Developmental Neurotoxicity

Reduced IQ

Impaired learning and memory

Life-long effects

Lead Neurotoxicity

8/8/2019 neurotoxin

11/42


Alcohol (ethanol)

CH

H

H

OH

Ethyl Alcohol

C

H

H

8/8/2019 neurotoxin

12/42


Vulnerability of Developing

Nervous System

FAS Fetal Alcohol Syndrome

FAE Fetal Alcohol Effects

What is a save level of

consumption during pregnancy?

Alcohol

8/8/2019 neurotoxin

13/42


8/8/2019 neurotoxin

14/42

Intro Neurotoxicity 5/7/04A Small Dose of ToxicologyFAS Child

8/8/2019 neurotoxin

15/42


MPTP

N

CH3

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

8/8/2019 neurotoxin

16/42


1980s Designer Drug

Caused effects similar toParkinsons disease

Damaged neurons that

secrete dopamine

MPTP Effects

8/8/2019 neurotoxin

17/42


CNS Central Nervous System

PNS Peripheral Nervous System

Blood brain barrier

Neuronal cells

Neurotransmitters & receptors 10-100 billion cells with 1015

connections

Nervous System Biology

8/8/2019 neurotoxin

18/42


Nervous System CNS & PNS

Central Nervous System (CNS) Brain & Spinal Cord

Peripheral Nervous System (PNS)

Afferent (sensory) Nerves Carrysensory information to the CNS

Efferent (motor) Nerves Transmitinformation to muscles or glands

8/8/2019 neurotoxin

19/42


Nervous System

Nervous System

CNS

Central Nervous System

PNSPeripheral Nervous System

Autonomic Somatic

Sympathetic Parasympathetic

8/8/2019 neurotoxin

20/42


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)

8/8/2019 neurotoxin

21/42


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

8/8/2019 neurotoxin

22/42


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)

8/8/2019 neurotoxin

23/42


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

8/8/2019 neurotoxin

24/42


Neuronal Cells

Axon

Myelin (Schwann cell)

Synapse

Dendrite

Cell Body

Nucleus

8/8/2019 neurotoxin

25/42


DopamineTransmitter Cell(Excitatory Neuron)

Dopamine

Receptor Cell(Post-synaptic receptor)

Dopamine

Receptor

Synaptic Cleft

Synaptic Vesicles

Neurotransmission

8/8/2019 neurotoxin

26/42


Neuronal Transmission

+ + - + +

+ + - + +

+ + - + +

+ + - + +

- - + - -- - + - -

- - + - -- - + - -

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

+

+

++

+ + +++ +

+

++

--

-

-

--

----

-K+

K+

Na+

Cl-

-- -

-

-

--

-

- -

InhibitorySynapse

Excitatory

Synapse

+40

0

-40

-70

+40

0-40

-70

Action Potential IPSP

EPSP

Action Potential

No Action Potential

8/8/2019 neurotoxin

27/42


Inhalation (e.g. solvents,

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

Skin (e.g. pesticides, nicotine)

Physical (e.g. load noise)

Exposure Issues

8/8/2019 neurotoxin

28/42


What causes neurotoxicity?

Wide range of agents

chemical and physical

8/8/2019 neurotoxin

29/42


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, DDT

8/8/2019 neurotoxin

30/42


Neurotoxic Injury

Neuron

NormalNeuronopathy

AxonopathyMyelinopathy

Transmission

Axon

Synapse

Myelin

8/8/2019 neurotoxin

31/42


Examples of Neurotoxicology

Diseases

Parkinson's, Alzheimer's, MS, ALS..

Environmental

Lead, Methylmercury, PCBs

Occupational

Solvents, Pesticides

Drugs - ClinicalVincristine, cisplatin

Drugs - Social

Alcohol, cocaine, nicotine

8/8/2019 neurotoxin

32/42


Cognitive Effects- memory, learning, confusion

Motor Effects

- weakness, convulsion, paralysis Sensory Effects

- vision, auditory, touch, balance

Mood and Personality Effects- sleep, depression, irritability, excitability

General Effects- loss of appetite, fatigue

Neurotoxic Effects

8/8/2019 neurotoxin

33/42


Classification of neurotoxicants

by mechanism of action

Temporary inhibition of nerve

function Agents which alter membrane

function

Agents with interfere with synaptic

transmission

8/8/2019 neurotoxin

34/42


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

8/8/2019 neurotoxin

35/42


Structure Long cell requires extensive

intracellular transportBlood-Brain Barrier

Developmental stage

(lead and alcohol)

Physiological Sensitivity

8/8/2019 neurotoxin

36/42


Neurons CANNOT divide and

replace themselves

Neurons CAN repair limitedaxonal damage

Most Recovery

Redundancy of Function

Reversibility of Damage

8/8/2019 neurotoxin

37/42


Classification of neurotoxicants

by mechanism of action

Permanent inhibition of nerve function Agents which cause Anoxia

Anoxic anoxia Ischemic anoxia

Cytotoxic anoxia

Agents which damage myelin formation Oligodendroglia (CNS)

Schwann cells (PNS)

Agents which damage peripheral axons

Agents which damage nerve cell body

Agents which cause localized CNS lesions

8/8/2019 neurotoxin

38/42


ReceptorReceptor

LigandLigand

Cell

Membrane

Cell

Membrane

Signal ProteinSignal Protein

Positive ResponsePositive Response

Outside CellOutside Cell

Inside CellInside Cell

Ligand binds to receptorLigand binds to receptor

11

33

22

Normal Receptor-Ligand Interaction

8/8/2019 neurotoxin

39/42


ToxicantToxicant11

Toxicant

inactivates

receptor

Toxicant

inactivates

receptor

No ResponseNo Response

33

22

Inactivation of Receptor by Toxicant

8/8/2019 neurotoxin

40/42


Toxicant1

No Response

32

Ligand

Toxicant

out competes

normal ligand

Ligand cannot bind

receptor

Competition For Receptor

8/8/2019 neurotoxin

41/42


Who Is Vulnerable?

Young or Old

Male or FemaleGenetics - Individual Diff.

Species

8/8/2019 neurotoxin

42/42


Fetal Nervous System

Developing Nervous System

Mature Nervous System

Aging Nervous System

Vulnerability / Sensitivity

neurotoxin

Documents