15 - Neural Regeneration Flashcards
Peripheral and central projections
1
2
3
1) Central to central
2) Central to peripheral
3) Peripheral to peripheral
Direction in which damaged peripheral neurons regenerate?
Proximal portion of the axon can regenerate distally.
Partial repair is more common than full repair.
Three main things that prevent regeneration in CNS
Structure, cell types, molecules and guidance/repellent cues
Normal neuron fibre
Central nucleus.
Dense Nissl substance (ribosomes, rER)
Neuron fibre two weeks post-injury
Peripheral nucleus
Loss of Nissl substance (chromolysis/chromatolysis)
Wallerian degeneration
Muscle fibre atrophy
Wallerian degeneration
Degeneration of axon and myelin sheath below site of injuty.
Debris phagocytosed by macrophages
Neuron fibre three weeks post injury (PNS)
Schwann cells proliferate, forming a compact cord.
Growing axons penetrate the Schwann cell cord
Muscle fibre atrophy
Rate at which axons regenerate (PNS)
0.5 - 3mm/day
Neuron fibre three months post injury
Successful regeneration.
Electrical activity restored
Muscle fibre regeneration.
Potential outcome of improper axon regeneration
Neuroma
Molecular, cellular responses that promote peripheral nerve regeneration
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
Is axon regrowth faster in cut or crushed axons?
Crushed.
Schwann cells and ECM are more continuous in a crush injury.
The more precise the alignment, the better the recovery, regeneration.
Main therapeutic approach to PNS injury
Microsurgery
Nerve crush versus cut injury.
Get dieback with both types of injury.
Better regrowth with crush.
Only variable regrowth with cut.
Example of a treatment for CNS injury
Can administer tissue plasminogen activator for a stroke to break up the clot.
Primary CNS injury
Physical damage, cell loss
Secondary CNS injury 1 2 3 4 5
Minutes to hours: Degenerative insults • Ischaemia • Ca2+ influx • Lipid peroxidation & free radical production • Glutamate excitotoxicity • BBB breakdown
Examples of treatments for CNS secondary injury
1
2
1 ) Methylprednisolone in some countries (not Oz)
2) Erythropoietin (Epo) in several clinical trials
Secondary CNS injury over hours to days
Hours to days/weeks:
• immune cell infiltration/microglial activation
• cytokines, chemokines, metalloproteases
Secondary CNS injury over days to weeks 1 2 3 4 5
- axonal degeneration
- demyelination
- apoptosis
- astrocytic gliosis & glial scar
- also syrinx (cavity) formation, meningeal fibroblast migration
Treatments for secondary CNS injuries over days to weeks
None, as of yet.
What stops axonal regeneration in the CNS?
1) Lack of trophic support
2) Axon regrowth is inhibited by the injury environment
Factors that attract axon growth
Brain derived neurotrophic factor
Why do some spinal injuries improve somewhat?
Axonal plasticity (not axonal regeneration). Axonal plasticity is where there is axonal sprouting from an uninjured axon.
Glial scar formation 1 2 3 4 5
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
Ways in which blockage of gliosis might be possible
Chondroitin sulphate proteoglycan inhibition/degradation.
Collagen IV inhibition
Way in which CNS regrowing axons are inhibited
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
Receptor to which all myelin inhibitors bind
Nogo receptor (NgR)
Effect of NgR stimulation
Results in Rho signalling pathways activation which inhibits axon growth
Example of axon guidance molecules that can be upregulated in adults
Ephrins
Potential common mediator of axonal inhibition
Rho kinase
*Differences between CNS and PNS in terms of axonal regrowth
PNSVSCNS
Two main neurogenic regions in the adult mammalian brain
- The subventricular zone (SVZ) of the lateral ventricle
2. The subgranular zone (SGZ) of the dentate gyrus in the hippocampus (memory/learning & anxiety)
Response of neurogenic regions to brain injury
Will respond to, migrate to area of injury. Many of these stem cells will become glia instead of neurons.
None alive after one month.
Replacement of lost cells using transplantation of stem/progenitor cells (experimental)
Use induced pluripotent or embryonic stem cells to make ‘neurospheres’. Transplant these into patient CNS.
