CNS Injury And Regrowth Flashcards
What is the difference between PNS and CNS regeneration?
PNS - has Schwann cells which are potent promoters of neurite outgrowth
CNS - central myelin is a potent inhibitor of axon outgrowth
Why are Schwann cells important for nerve regeneration?
Produce growth promoting factors
Contain cell adhesion molecules in their basal laminae that promote axon outgrowth
Form endoneural tubes in which growth cones can act as feelers (not present in CNS)
How do oligodendrocytes prevent regeneration?
Express molecules in the adult that block axon regrowth
White matter is selectively inhibitory for axonal growth
What are the cell adhesion molecules found in Schwann cells?
Laminin
Fibronectin
Name the myelin associated inhibitors
Nogo - Nogo-A NI-250
MAG - myelin associated glycoprotein
OMgp - oligodendrocyte myelin glycoprotein
Where is Nogo found?
In the endoplasmic reticulum of the oligodendrocytes
What are the 3 isoforms of Nogo?
Nogo-A (NI-250) - unique to oligodendria
Nogo-B (NI-35) - absent in myelin
Nogo-C - absent in myelin
What are the two inhibitory domains of Nogo?
Amino Nogo (only in Nogo-A)
Nogo-66
What is MAG?
Myelin associated glycoprotein
A type 1 transmembrane protein with an ectodomain composed of five Ig like domains
Where is the amino-Nogo domain found?
Although it can be detected extracellularly a significant portion is thought to have a cytoplasmic orientation
What is OMgp?
Oligodendrocyte myelin glycoprotein
A member of the leucine rich repeat proteins
Linked to cell surface by a GPI anchor
What receptors are there for prototypic myelin inhibitors?
PirB
NgR1
NgR2
What does PirB bind to?
MAG
Nogo-66
OMpg
What does PirB do?
Signals neuronal growth cones to collapse and neurite outgrowth inhibition in vitro
What does NgR1 bind to?
Nogo-66
MAG
OMgp
What does NgR1 do?
Important for growth cone collapse responses toward acutely presented inhibitors
Form a tripartite receptor complex with Lingo-1 and the death domain containing TNFR superfamily members p75
Describe NgR2
Selective receptor for MAG
Functionally redundant with NgR1
What are CSPGs?
Chondroitin sulphate proteoglycans
A family of molecules with a protein core and negatively charged GAGs attached
What are negatively charged GAGs?
Electrostatically repellent for growth cones
What releases CSPGs?
Hypertrophic reactive phenotypic astrocytes found in the glial scar
Are re-expressed after injury in the brain or spinal cord
What do CSPGs do?
Bind to many receptors
(LAR, PTP sigma, NGR)
Ultimately activating ROCK resulting in actin depolymerisation
Inhibition of axon growth
What happens after injury?
CSGP expression is rapidly upregulated by reactive astrocytes
Forms an inhibition gradient
Highest concentration is at the centre of the lesion (diminishes towards the penumbra of the lesion)
What are the secondary changes after CNS injury?
Astrocytes proliferation
Activation of microglia
Formation of a glial scar
Inflammation
Invasion by immune cells
Proliferation of oligodendrocyte precursor cells
What is the impact of the secondary changes after CNS injury?
Render the environment inhospitable for regeneration
Is environment the only factor affecting CNS nerves from regenerating?
Although a central axon can regenerate in a peripheral nerve, the rate of elongation is inferior to a peripheral axon navigating the same path
This means there are intrinsic factors affecting CNS regeneration
What are the intrinsic factors that also limit CNS regeneration?
Epigenetic changes lead to limited expression of regeneration associated genes (RAGs) upon injury
Most CNS neurons lose growth associated protein 43 - they are retained in the PNS though
High expression of proteins suppressing axonal growth in the CNS neurons
(PTEN, SOCS3, EFA-6)
What do neural grafts do?
Provide a source of depleted substances
Stimulate neuron growth
Promote survival of neurons
Replace lost structure in brain and spinal cord
What materials are needed for neural grafting?
Tissue from the foetal CNS
Tissue from the PNS
peripheral autonomic neurons
Tissue from outside the nervous system
Isolated, cultured, or genetically engineered cells
What is the significance of the foetal CNS tissue?
Foetal tissue develops and integrates within a host organism following grafting
Functional improvements seen in animals with neurological deficits
Potential treatment for Parkinson’s
What are concerns for using foetal CNS tissue?
Number of nerve cells needed - considering the brain size of the recipient
Identification of the region of the foetal brain required for grafting is difficult
Explain the example of using a peripheral nerve graft on the optic nerve
A section of peripheral nerve is attached to the cut end of the optic nerve and the other end is inserted into the superior colliculus
Retinal ganglion axon regenerates and reinnervates the superior colliculus
New functional synapses are formed
(When photoreceptors are activated by light postsynaptic neurons in the colliculus respond)
Administration of growth factors during nerve grafts can enhance regeneration
What are the benefits of peripheral autonomic tissue?
Share common heritage with nervous tissue
Synthesise neurotransmitters and other chemical substances that are similar to those in the CNS
These neurons are easily accessible
They exhibit great potential for regrowth
Describe isolated and cultured cells needed for grafting
Most cells survive a limited time in primary culture
Replicating a limited amount of time or not at all
Some cells continue to replicate - could potentially survive indefinitely
Sustained self propagating cells in culture are called continuous cell lines (CCLs)
How can CCLs lend to neuronal grafting?
Experiments have shown that they can be successfully grafted into the CNS
May attenuate functional problems produced by lesions in the CNS
But! Uncontrolled growth could lead to tumour formation
What are genetically engineered cells?
Cells designed to synthesise a specific chemical substance or to perform a specific function before being implanted into a recipient
What cells can be genetically engineered for grafting?
Foetal CNS tissue cells
The hosts cells
Primary cell cultures
CCLs
Which two non neuronal cells can be genetically engineered for grafting?
Astrocytes
Fibroblasts
What are fibroblasts engineered for?
To synthesise the enzyme important for the production of the brain chemical L-dopa
Which is a precursor of the brain chemical Dopamine
Why are genetically engineered cells used during CNS grafting?
To enhance the survival and growth rates of neurons and improve CNS function
List some clinical trials in place to improve CNS regeneration
Infusion of trophic factors into the injury site
(Neurotrophins NGF, BDNF)
Inhibition of RhoA by cethrin
Insertion of conduits rich in matrix molecules
Schwann cells grafting into the site of injury
Administration of antibodies to the central inhibitory environmental factors to neutralise MAIs
Transplantation of foetal neurons or neural stem cells into site of injury
Immunosuppression
