Neural Regeneration Flashcards
What are the peripheral and central projections?
Central > central
Central > peripheral
Peripheral > peripheral
Which projections are together in peripheral nerves?
Central > peripheral
Peripheral > peripheral
Which part of the axon can regenerate when peripheral axons are damaged?
Proximal part regenerates distally
What is the totality of peripheral nerve repair?
Can be full but often partial
What happens when central axons/neurons are damaged?
Some neurons dies
Some neurons retract processes but can sprout and make new local connections
Normally little or no regeneration as glial scar inhibits regrowth
What does a normal neuron’s cell body have?
Central nucleus
Dense Nissl substance
What happens to the neuron two weeks post-injury?
Peripheral nucleus
Chromatolysis
Wallerian degeneration
Muscle fibre atrophy
What happens in Wallerian degeneration?
Degeneration of axon and myelin sheath below site of injury
Debris phagocytosed by macrophages - migrate from peripheral immune system
What is chromatolysis
Nissl substance almost gone
What’s left has moved to edges of cell body
What happens to the neuron three weeks post-injury?
Schwann cells proliferate, forming compact cord
Growing axons penetrate Schwann cell cord
Grow at 0.5-3 mm/day
Muscle fibre atrophy
What happens to the neuron three months post-injury?
Successful regeneration
Electrical activity restored
Muscle fibre regeneration
What happens with unsuccessful regeneration?
Neuroma formation
What happens in neuroma formation?
If regrowing axon can’t find where it has to go
Schwann cells still secreting growing signals
Neuron grows and grows without direction
Can be very painful since neuron is alive and signalling without a target
What are the molecular and cellular responses that promote peripheral nerve regeneration?
1) Injury to peripheral nerve
2)
- Neuron expresses growth-related genes
- Macrophages rapidly remove myelin debris
- Schwann cellrs release axon growth-promoting signals, neurotrophins, and ECM
3)
- Growth cone of axon senses environment and causes axon to grow
- Newly made myelin expresses adhesion molecules detected by growth cone
- Proliferating Schwann cells promote axon regeneration
Is repair fast when an axon is cut, rather than crushed?
No, it’s faster when an axon is crushed
What is the difference in the guide provided by Schwann cells and ECM in distal segments between when a nerve is crushed and cut?
In a crush injury, the guide is continuous
What is the main therapeutic approach to PNS injury?
Microsurgery
Reattach proximal and distal stumps or insert nerve graft
Describe the sequence of events in a crush injury
Crush Dieback - Basal lamina intact - Axons can't get lost along way - Reach appropriate targets Good regrowth
Describe the sequence of events in a cut injury
Cut Dieback Variable growth - Some find right target - Some find wrong targets - Some don't find targets at all
What are the immediate consequences of primary injury to the CNS?
Physical damage
Cell loss
What is the treatment for immediate consequences of primary injury to the CNS?
Minimise extent of primary damage
- Eg: tPA for stroke
Decompression in clinical trials
What happens in the minutes to hours after CNS injury?
Degenerative insults
- Ischaemia
- Ca influx
- Lipid peroxidation and free radical production
- Glutamate excitotoxicity
- BBB breakdown
What is the treatment for the secondary injury that happens in the minutes to hours after CNS injury?
Erythropoietin (Epo) in clinical trials
Active area of research
What happens in the hours to days/weeks after CNS injury?
Immune cell infiltration/microglial activation
Cytokines, chemokines and metalloproteases
What happens in the days/weeks after CNS injury?
Axonal degeneration
demyelination
Apoptosis - neuronal and oligodendroglial
Astrocytic gliosis and glial scar
Syrinx (cavity) formation and meningeal fibroblast migration
What is the treatment for the secondary injury that happens in the days/weeks after CNS injury?
None yet
Many clinical trials
Active area of research
What will it take to effectively repair the CNS?
Neuroprotection Axonal regeneration and functional integration - Regrowth of suriviving neurons - Remyelination Modulate astrocytic gliosis Neural stem cells - Replacement of lost cells - Mobilise endogenous cells - Transplant exogenous cells
What stops axonal regeneration?
Lack of trophic support
Axon regrowth inhibited by injury environment
What can be done to counteract lack of trophic support?
Provide growth promoting factors like neurotrophins
What can be done to counteract axon regrowth inhibition?
Inhibit growth blocking factors
Is axonal plasticity true axon regeneration?
No, since axons close by sprout new branches to innervate area that’s lost it
Don’t get full repair
What happens in astrocytic gliosis?
Upregulate astrocyte cytoskeletal proteins
Hypertrophic
Proliferate
Interdigitate processes
Secrete cytokines and growth factors
Secrete ECM
Upregulate expression of developmental axon guidance molecules
What does astrocytic gliosis lead to?
Glial scar formation - forms barrier between undamaged tissue and injury site
What are the good aspects of astrocytic gliosis?
Wound sealing
BBB repair
Growth factors increase glutamate transporters
What are myelin inhibitors?
Inhibitory molecules in injury environment binding to receptors on regrowing axons/dendrites
Where are myelin inhibitors?
On myelin debris
Where are axon guidance molecules?
On activated astrocytes
What receptor do all myelin proteins bind to?
Nogo receptor
What does binding to the Nogo receptor activate?
Rho signalling pathway
Inhibits axon growth by retracting growth coneIn
What happens when animal models are given Nogo blockers?
Some regeneration
What happens when animal models are given Rho inhibitors?
Some regeneration
What are axon guidance molecules?
Promote, repel, or guide growing axons Many upregulated or re-expressed after injury - Semaphorins - Tenascin - Cell adhesion molecules - Ephrins
In terms of structure, why is the PNS permissive for regrowth and CNS is not?
PNS: relatively simple structure
CNS: complex structure
In terms of degeneration of the distal axon, why is the PNS permissive for regrowth and CNS is not?
PNS: degeneration of distal axon and myelin fast
CNS: degeneration of distal axon and myelin slow
In terms of myelinating cells, why is the PNS permissive for regrowth and CNS is not?
PNS: Schwann cell supports axon regrowth
CNS: oligodendrocyte inhibits axon regrowth
In terms of nerve structure, why is the PNS permissive for regrowth and CNS is not?
PNS: nerve structure often remains largely intact and provides conduit for regrowth
CNS: neural structure destroyed
In terms of phagocytosis, why is the PNS permissive for regrowth and CNS is not?
PNS: macrophages phagocytose debris
CNS: macrophages phagocytose debris and enhance/diminish inflammatory response
In terms of cellular environment, why is the PNS permissive for regrowth and CNS is not?
PNS: Schwann cells and macrophages only cell types present
CNS: complex cellular environment including
- Neuronal cell bodies
- Reactive astrocytes
- Oligodendrocytes
- Macrophages
- Other inflammatory cells
What are the two main regions in the adult brain where neural stem cells live?
Subventricular zone (SVZ) of lateral ventricle Subgranular zone (SGZ) of dentate gyrus in hippocampus
Why don’t endogenous neural stem cells normally effectively repair the nervous system?
Rarely become neurons - often become glial cells
Is monotherapy or a combination of therapies likely to be needed?
Combination of therapies
