MODULE 5 (PART 5): TARGET ORGAN TOXICITY - TOXIC RESPONSE OF THE NERVOUS SYSTEM

1. Central or CNS

2. Peripheral

Major division of Nervous System? (2)

Central or CNS

Protected by adverse effects of many potential toxicants by anatomical blood brain barrier.

Brain and spinal cord

Central or CNS includes? (2)

Peripheral

Nerves connecting CNS to muscles and organs that allow us to move our body.

Motor neurons

Present in Peripheral division

1. Nucleus

2. dendrite

3. dendritic spine

4. mitochondrion

5. axon

6. schwann cell

7. presynaptic terminal

Parts of the Neuron (7)

1. dendrite

2. dendritic spine

3. mitochondrion

Upper portion cell body of the Neuron (3)

1. Axon

2. Schwann cell

3. Presynaptic terminal

Lower portion of the Neuron (3)

Upper portion cell body having the dendrite, dendritic spine, mitochondrion.

Nerve cell has to have energy and undergo certain metabolism with the presence of oxygen thus spending the energy.

axon

protected by the schwann cell.

Schwann cell

make the myelin sheath.

Presynaptic terminal

connected to postsynaptic terminal.

presynaptic terminal

During incidence that happens in neuromuscular junction (NMJ), before synaptic cleft is the?

1. BLOOD BRAIN BARRIER

2. ENERGY REQUIREMENT

3. AXONAL TRANSPORT

4. AXONAL DEGENERATION

5. MYELIN FORMATION AND MAINTENANCE

6. NEUROTRANSMISSION

7. DEVELOPMENT OF THE NERVOUS SYSTEM

8. ENVIRONMENTAL FACTORS

FACTORS AFFECTING THE PROGRESS OF NEUROTOXICANTS IN THE BODY (8)

endothelial cells and xenobiotic transporters

The BBB consists of (2)

TRUE

TRUE OR FALSE

BBB is highly lipophilic, hence, lipophilic neurotoxicants enter readily.

endothelial cells

Hydrophilic substances when they enter the BBB, they are being transported back into the blood because of the presence of?

TRUE

TRUE OR FALSE

Endothelial cells in the brain is thicker than the other parts of the body.

Xenobiotic transporters

transports foreign substance back in the blood.

Tight junction

is compact which makes the BBB selective.

tight seal of cells

BBB contain?

TRUE

TRUE OR FALSE

Neurons need aerobic metabolism to maintain proper ion gradients.

1. protein

2. amino acids

Body creates energy through the breakdown of what? (2) in the presence of oxygen.

ENERGY REQUIREMENT

The brain is extremely sensitive to brief interruptions in oxygen.

ENERGY REQUIREMENT

Neurons need aerobic metabolism to maintain proper ion gradients.

1. carbon monoxide

2. cyanide

Agents such as what? (2) inhibit aerobic respiration and produce hypoxia to cells.

combined 2 hemoglobin forming carboxyhemoglobin. It can decrease the carrying capacity.

MOT Cyanide

Cherry red skin

Clinical manifestation of cyanide toxicity?

Axonal transport

is the mechanism through which the neuron provides the distal axon with its complement of functional and structural proteins.

AXONAL TRANSPORT

Impulse should be transmitted rapidly that allows an organized response to be carried out a specific site.

1. Anterograde transport

2. Retrograde transport

In the axon, there is two types of transport. (2)

Anterograde transport

transfer materials along in microtubules mediated by kinesin. Usually from cell body to presynaptic terminal.

Retrograde transport

transfer along a microtubule is mediated by cytoplasmic dynein. Going back from presynaptic terminal to cell body.

kinesin

Anterograde transport transfer materials along in microtubules mediated by?

cytoplasmic dynein

Retrograde transport transfer along a microtubule is mediated by?

TRUE OR FALSE.

TRUE OR FALSE

Whatever protein or materials that reached their lifetime in presynaptic terminal are recycled as they reach the cell body.

AXONAL TRANSPORT

Since cells are elongated and may extend up to 1 meter long, they require ATP in order to meet these demands.

Neuronopathy

is characterized by the loss of the cell body and all of its processes, with no potential for regeneration.

Axonopathy

the primary site is the axon.

1. Neuronopathy

2. Axonopathy

types of axonal degeneration (2)

Neuropathy

axon is destroyed while the cell body is still intact.

1. axolemma

2. axoplasm

After an axon dies, active proteolysis digests? (2)

schwann cells

act as protective layer decreasing the synthesis of myelin lipids and downregulating the genes encoding for myelin.

TRUE

TRUE OR FALSE

axons in the PNS regenerate while axons in the CNS do not.

Phase 1: Acute response to injury

Phase 2: Lag between injury and onset of Wallerian degeneration

Phase 3: Execution of Wallerian degeneration

How does the axon respond to injury? (3)

Phase 1: Acute response to injury

There is a cutting of a part of an axon.

Phase 2: Lag between injury and onset of Wallerian degeneration

Defense response to inflammatory and immune response.

Phase 2: Lag between injury and onset of Wallerian degeneration

Elevated expression of cytokine, growth factor, chemokine and hormone

Wallerian Degeneration

Phase II is known as?

Phase 3: Execution of Wallerian degeneration

Transition to homeostasis.

Neuronopathy

permanent damage, all parts of neurons are damages.

Axonopathy

some parts or axon is the damage but cell body is still intact.

Myelinopathy

there is demyelination, some schwann cells does not integrity anymore causing myelin sheath to be damaged.

Transmission

at some point signal is lost in the cell body going to the presynaptic terminal. Communication between cells and axon is damaged.

oligodendrocytes

Myelin is formed by the __________ in the CNS.

Schwann cells

Myelin is formed by the _______ in the PNS.

intramyelinic edema and/or demyelination

Exposure to toxicants can result to?

Intramyelinic edema

refers to the separation of myelin lamellae.

Demyelination

is the loss of myelin.

Multiple sclerosis

Ex of manifestation of demyelination

Remyellination

in the CNS happens in a very limited extent while greater chance of remyelination in the PNS.

1. In the CNS, there may be low growth inhibiting proteins.

2. There is a slower debris clearance.

3. After damage, it may result to astroglial scar in the CNS.

4. Glial cells and macrophages are only present in the CNS (pero sabi niya we do not find it in the CNS?????).

Why do neurons in CNS not regenerate? (4)

Waste products

may alter or retard the growth of nerves in CNS.

thickened cells

Scar means?

1. Axon is slightly wrapped around myelin or schwann cells.

2. Initial wrapping of axon by the schwann cell.

3. There is progressive multiple wrapping by schwann cell.

4. Has integral or more defined myelin sheath.

MYELIN FORMATION (4)

NEUROTRANSMISSION

It is achieved in the nervous system through a synapse.

Synapse

space or synaptic cleft.

Neurotransmitters

released from one neuron acts as the first messenger, followed by the modulation of an ion channel or activation of secondary messenger system leading to changes in responding cell.

First messenger

release of ACh and ACh traverses the synaptic cleft going to post synaptic terminal.

Second messenger

happens at the post synaptic terminal. Once the Ach binds to the gate, it opens causing the influx of sodium ions -> depolarization -> action potential.

Repolarization

Calcium channel enters = ?

Replication, migration, differentiation, myelination and synapse formation

are the basic process that underlie the development of the nervous system.

Myelination

begins in utero and continuous through childhood.

10-12 years

Myelination takes about how many years to complete the myelin formation?

DEVELOPMENT OF THE NERVOUS SYSTEM

The slow formation of the BBB and lack of enzymes may influence sensitivity.

Ethanol

exposure during pregnancy may result in abnormalities in the fetus characterized by mental retardation, with malformations of the brain and delayed myelination.

Fetal alcohol syndrome

because of abnormal neural migration.

1. mental retardation

2. unusual face features

3. lower than average heights

4. poor coordination

Fetal alcohol syndrome effects (4)

1. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

2. Aluminum in dialysate

ENVIRONMENTAL FACTORS (2)

parkinsonism

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes?

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

Dopaminergic neurotoxic compound and an herbicide.

Aluminum in dialysate

Can cause dialysis dementia and alzheimer’s disease.

Aluminum

is absorbed in the GIT, normally excreted in the kidney in the form of urine.

dialysis encephalopathy or dialysis dementia

In px with damage kidney (CRF), accumulation of aluminum in tissues can cause?

1. NEUROPATHY

2. AXONOPATHY

3. MYELINOPATHY

4. ASTROCYTES

5. NEUROTRANSMISSION-ASSOCIATED NEUROPATHY

TOXIC RESPONSES (5)

1. Doxorubicin

2. Methylmercury

3. Dopamine

4. 6-hydroxytryptamine

5. catecholamine

NEUROPATHY (5)

1. Gamma diketones

2. Carbon disulfide

3. IDPN and DMHD

4. Acrylamide

5. Organophosphates

6. Pyrdinethione

7. Microtubule-associated

AXONOPATHY (7)

1. Hexachlorophene

2. Tellurium

3. Lead

MYELINOPATHY (3)

1. Ammonia

2. Nitrochemicals

ASTROCYTES (2)

1. Nicotine

2. Cocaine and amphetamines

3. Excitatory amino acids

NEUROTRANSMISSION-ASSOCIATED NEUROPATHY (3)

DOXORUBICIN

It is an antineoplastic drug affecting neurons in the PNS.

interference with DNA transcription.

DOXORUBICIN MOT

1. DOXORUBICIN

2. METHYLMERCURY

3. DOPAMINE, 6- HYDROXYTRYPTAMINE, CATECHOLAMINE

4. GAMMA DIKETONES

5. CARBON DISULFIDE

6. IDPN

8. ACRYLAMIDE

9. DMHD

10. ORGANOPHOSPHATES

11. PYRIDINETHIONE

12. MICROTUBULE-ASSOCIATED COMPOUNDS

13. HEXACHLOROPHENE

14. TELLURIUM

15. LEAD

16. AMMONIA

17. NITROCHEMICALS

18. EXCITATORY AMINO ACIDS

NEUROTOXIC AGENTS (18)

METHYLMERCURY

Impairs glycolysis, nucleic acid biosynthesis and aerobic respiration.

fishes

METHYLMERCURY CAN BE FOUND IN?

methylmercury

If a pregnant woman ingests lots of fish, ______________ will be absorbed more by the placenta which can cause fetal abnormalities in the brain.

H2O2

Cathecolamines yield a toxic metabolite, ____ which is a cytotoxic metabolite.

2,5- hexenedione

n-hexane yields what? which is diketone.

GAMMA DIKETONES

The metabolite reacts with amino acid to form pyrrole.