15 - Neural Regeneration

Question 1

Peripheral and central projections
1
2
3

Answer 1

1) Central to central
2) Central to peripheral
3) Peripheral to peripheral

Question 2

Direction in which damaged peripheral neurons regenerate?

Answer 2

Proximal portion of the axon can regenerate distally.

Partial repair is more common than full repair.

Question 3

Three main things that prevent regeneration in CNS

Answer 3

Structure, cell types, molecules and guidance/repellent cues

Question 4

Normal neuron fibre

Answer 4

Central nucleus.

Dense Nissl substance (ribosomes, rER)

Question 5

Neuron fibre two weeks post-injury

Answer 5

Peripheral nucleus
Loss of Nissl substance (chromolysis/chromatolysis)
Wallerian degeneration
Muscle fibre atrophy

Question 6

Wallerian degeneration

Answer 6

Degeneration of axon and myelin sheath below site of injuty.

Debris phagocytosed by macrophages

Question 7

Neuron fibre three weeks post injury (PNS)

Answer 7

Schwann cells proliferate, forming a compact cord.
Growing axons penetrate the Schwann cell cord
Muscle fibre atrophy

Question 8

Rate at which axons regenerate (PNS)

Answer 8

0.5 - 3mm/day

Question 9

Neuron fibre three months post injury

Answer 9

Successful regeneration.
Electrical activity restored
Muscle fibre regeneration.

Question 10

Potential outcome of improper axon regeneration

Answer 10

Neuroma

Question 11

Molecular, cellular responses that promote peripheral nerve regeneration

Answer 11

Macrophages rapidly remove myelin debris (dead Schwann cells)
Neuron expresses growth-related genes.
Axon growth cone follow neurotrophins, etc.
Regenerating Schwann cells promote axon regeneration

Question 12

Is axon regrowth faster in cut or crushed axons?

Answer 12

Crushed.
Schwann cells and ECM are more continuous in a crush injury.
The more precise the alignment, the better the recovery, regeneration.

Question 13

Main therapeutic approach to PNS injury

Answer 13

Microsurgery

Question 14

Nerve crush versus cut injury.

Answer 14

Get dieback with both types of injury.
Better regrowth with crush.
Only variable regrowth with cut.

Question 15

Example of a treatment for CNS injury

Answer 15

Can administer tissue plasminogen activator for a stroke to break up the clot.

Question 16

Primary CNS injury

Answer 16

Physical damage, cell loss

Question 17

Secondary CNS injury
1
2
3
4
5

Answer 17

Minutes to hours: Degenerative insults
• Ischaemia
• Ca2+ influx
• Lipid peroxidation & free radical production
• Glutamate excitotoxicity
• BBB breakdown

Question 18

Examples of treatments for CNS secondary injury
1
2

Answer 18

1 ) Methylprednisolone in some countries (not Oz)

2) Erythropoietin (Epo) in several clinical trials

Question 19

Secondary CNS injury over hours to days

Answer 19

Hours to days/weeks:
• immune cell infiltration/microglial activation
• cytokines, chemokines, metalloproteases

Question 20

Secondary CNS injury over days to weeks
1
2
3
4
5

Answer 20

• axonal degeneration
• demyelination
• apoptosis
• astrocytic gliosis & glial scar
• also syrinx (cavity) formation, meningeal fibroblast migration

Question 21

Treatments for secondary CNS injuries over days to weeks

Answer 21

None, as of yet.

Question 22

What stops axonal regeneration in the CNS?

Answer 22

1) Lack of trophic support

2) Axon regrowth is inhibited by the injury environment

Question 23

Factors that attract axon growth

Answer 23

Brain derived neurotrophic factor

Question 24

Why do some spinal injuries improve somewhat?

Answer 24

Axonal plasticity (not axonal regeneration). 
Axonal plasticity is where there is axonal sprouting from an uninjured axon.

Question 25

``` Glial scar formation 1 2 3 4 5 ```

Answer 25

1) Astrocytes upregulate astrocyte cytoskeletal proteins (EG: GFAP) 2) Hypertrophy, proliferate 3) Interdigitate processess 4) Secrete ECM (EG: chondroitin sulphate proteoglycans) 5) Upregulate expression of developmental axon guidance molecules, which makes other axons overgrow injury site

Question 26

Ways in which blockage of gliosis might be possible

Answer 26

Chondroitin sulphate proteoglycan inhibition/degradation. | Collagen IV inhibition

Question 27

Way in which CNS regrowing axons are inhibited

Answer 27

Inhibitory molecules in the injury environment bind to receptors on regrowing axons/dendrites (neurites). - Myelin inhibitors on myelin debris - Axon guidance molecules on activated astrocytes

Question 28

Receptor to which all myelin inhibitors bind

Answer 28

Nogo receptor (NgR)

Question 29

Effect of NgR stimulation

Answer 29

Results in Rho signalling pathways activation which inhibits axon growth

Question 30

Example of axon guidance molecules that can be upregulated in adults

Answer 30

Ephrins

Question 31

Potential common mediator of axonal inhibition

Answer 31

Rho kinase

Question 32

*Differences between CNS and PNS in terms of axonal regrowth

Answer 32

PNSVSCNS

Question 33

Two main neurogenic regions in the adult mammalian brain

Answer 33

1. The subventricular zone (SVZ) of the lateral ventricle | 2. The subgranular zone (SGZ) of the dentate gyrus in the hippocampus (memory/learning & anxiety)

Question 34

Response of neurogenic regions to brain injury

Answer 34

Will respond to, migrate to area of injury. Many of these stem cells will become glia instead of neurons. None alive after one month.

Question 35

Replacement of lost cells using transplantation of stem/progenitor cells (experimental)

Answer 35

Use induced pluripotent or embryonic stem cells to make 'neurospheres'. Transplant these into patient CNS.