What is the major difference between the CNS and the PNS in terms of regeneration?
PNS will regenerate, CNS will not
When damage occurs to a peripheral nerve, which portion of the nerve can regenerate? In which direction?
Proximal portion of the axon can regenerate distally
Is neuronal repair in the PNS full or partial?
Can be full, but is often partial
If a peripheral nerve's cell body is in the CNS, can it still undergo regeneration?
If the axon is damaged in the periphery, the proximal axon can regenerate distally
What happens when neuronal injury occurs in the CNS?
Some neurons die
Some neurons retract processes but can sprout
Glial scars inhibit regrowth
What determines the extent of neuronal repair in the CNS (ie. whether full or partial repair occurs)?
Severity of neuronal injury
Location of injury
What are the three broad differences between the CNS and the PNS that allows the PNS to regenerate, but not the CNS?
Cell types present
Molecules and guidance/repellent cues
Describe the changes that occur in peripheral nerves after injury?
2 weeks post-injury: nucleus moves to the periphery, loss of Nissl substance, Wallerian degeneration, muscle fibre atrophy
3 weeks post injury: Schwann cells proliferate, nucleus moves centrally, growing axons penetrate Schwann cell cord, muscle fibre atrophy
3 months post injury: successful regeneration, muscle fibre regeneration
What is Wallerian degeneration?
Degeneration of axon and myelin sheath below the site of injury
What happens to a neuron if it does not regenerate successfully?
Why might unsuccessful regeneration occur and result in neuroma formation?
Growing axon cannot find right target
Is repair faster if the neuron is cut or crushed? Why?
Faster when crushed, because the Schwann cells and ECM (which act as a guide) remain continuous
More precise alignment allows better recovery and regeneration
What is the main therapeutic approach to PNS injury?
Microsurgery to reattach proximal and distal stumps or a nerve graft
Decsribe the primary injury that occurs in CNS neural injury?
Immediate: Physical damage - cell loss
Describe the secondary injuries that occur in CNS neural injury?
Minutes to hours: ischaemia, Ca influx, lipid peroxidation and free radical production, glutamate excitotoxicity, BBB breakdown
Hours to days/weeks: immune cell infiltration, microglial activation, cytokines, chemokines, metalloproteases
Days/weeks: axonal degeneration, demyelination, apoptosis, astrocytic gliosis and glial scar, cavity formation
What must be achieved in order to effectively repair the CNS?
What broad features inhibit axonal regrowth?
Lack of trophic support
Injury environment inhibiting growth
How can a lack of trophic support be combatted in order to support axonal regeneration?
Provide growth promoting factors eg. neurotrophins
How can the injury environment be altered so that it does not inihibit axonal growth?
Inhibit growth blocking factors: astrocytic gliosis and glial scar, myelin inhibitors, developmental guidance molecules
Describe the difference between axonal plasticity and axonal regeneration?
Plasticity: axons sprout; those near the injured neuron grow extra processes
Regeneration: neuron that was damaged grows a new axon
Describe astrocytic gliosis?
Astrocytes become hypertrophic, proliferate, interdigitate processes, secrete cytokines and growth factors, secrete ECM, upregulate axon guidance molecules
This all leads to glial scar formation
Why can astrocytic gliosis be inhibitory to neuronal regeneration?
Glial scar forms a barrier between undamaged tissue and and injury site
Which techniques targetting astrocytic gliosis have resulted in increased neuronal regeneration?
Blocking of astrocyte ECM
GFAP/Vimentin double knockout
Which molecules in the injury environment inhibit axon regrowth?
Myelin inhibitors on myelin debris
Guidance molecules on actiavted astrocytes
Which particular myelin proteins are inhibitory in the injury environment, and why are they inhibitory?
Nogo, MAG and OMgp
All bind to Nogo receptor, which activates the Rho signalling pathway > inhibits axon growth
How are myelin proteins being targetted to encourage axonal regrowth?
Gene knockouts, Nogo blockers (Anti-Nogo antibody) and Rho inhibitors
What are axon guidance molecules?
Molecules that promote, repel or guide growing axons
Describe why Rho activation inhibits axonal growth?
Causes growth cone to shrink
Compare and contrast the CNS and PNS injury environments?
Describe two strategies for using stem cells to repair the nervous system?
1. Transplant stem cells/neurons
2. Use drugs to activate stem cells already present in NS
What are the two main neurogenic regions in the brain?
Why don't endogenous neural stem cells nromally effectively repair the CNS?
Cells must proliferate, migrate, differentiate, and then survive
What is the most important non-pharmacological form of therapy for functional regeneration?
Physical therapy and muscle/neuronal activity