What is the difference in CNS structure compared to PNS?
-CNS is much more complex, many connection
-neurons in different and very specific positions (in different layers)
-more than one sort of neurons in one place, eg. excitatory and inhibitory intertwined
What are the causes of CNS injury?
• Spinal cord injury – traffic accidents, diving into shallow water, rugby/football, falls, (gunshot wounds, shrapnel)
• Brain injury – traffic accidents, falls, football & boxing (repeated concussion), (explosions, gunshot wounds etc) – stroke – degenerative disease
What is the incidence of neural injury?
• Acquired brain injury (~440,000/year in Australia)*
– traumatic brain injury(~22,000/year in Australia)
– stroke (~60,000 new strokes/year in Australia)
– disease (eg Parkinson’s, MS, Alzheimer’s...) – other (eg infection, alcohol abuse, tumour)
• Spinal cord injury (~250/year in Australia)**
What are the common components of neural injury types?
• Different causes but common components – neuronal and glial cell death – neuronal damage and loss of connections – ongoing disability
• physical, cognitive, emotional impairments • often young people with long lifespan
What is the biology of CNS injury?
-In the PNS it is macrophages and Schwann cells that affect the regrowth
-in the CNS much more than that How is the CNS more complex than the PNS?
-all these types of cells in the CNS
-A much more complex environment than the PNS
What is the primary injury?
-the actual injury, most often also damage cell body, so cell loss at the same time, if that happens most often dies
-if damage is very contained people can recover, the problem is not necessarily the primary injury
-there is not much you can do in terms of primary damage
-Immediate: Physical damage - cell loss
-Treatment: minimise extent of primary damage e.g. decompression in clinical trials -Immediate: Physical damage - cell loss
What is the secondary injury?
-Minutes to hours: Degenerative insults
• Ca2+ influx
• lipid peroxidation & free radical production
• glutamate and neurotransmitter excitotoxicity
• Blood-Brain-Barrier breakdown
-an ongoing process, starts minutes to hours after the primary injury occurs
-extends often far away from the site of injury -many things going on, get metabolic breakdown (ischemia= closing of blood vessels so even more damage)
-glutamate release causes other neurons to fire and causes other neurons to die as only can sustain life if the right level present
-blood barrier breakdown then lets in more proteins and big problems
What is the treatment for secondary neural injury?
• Methylprednisolone in some countries (not Oz)
• Erythropoietin (Epo) in several clinical trials
• Active area of research
-cool the body to 33 degrees, in ambulances they have ice cold saline
What is the secondary injury more long term?
-the injury progresses
-release of cytokines, etc. = inflammatory response
-leads to apoptosis of both the neural and glial cells
• immune cell infiltration/microglial activation
-Hours to days/weeks: • immune cell infiltration/microglial activation • cytokines, chemokines, metalloproteases
-Days/weeks: • axonal degeneration - slow • demyelination - slow • apoptosis – neuronal and oligodendroglial -the debris doesn’t get taken away
What happens in the secondary injury days/weeks after?
• axonal degeneration - slow
• demyelination - slow
• astrocytic gliosis & glial scar
• also syrinx (cavity) formation, meningeal fibroblast migration
-astrocytic gliosis= become active and secrete a range of things and can stop axons growing
-fluid filled cavity forms= syrinx
-Treatment: None yet – many clinical trials underway
• Active area of research
What are the types of CNS injury?
-the type will to a point determine what happens molecularly
-penetrating= will have fibroblasts
-concussion= the abrupt stop causes axons to tear (axonal shearing)
• Spinal cordinjury – compressed, severed, penetrating
• Brain injury – axonal shearing – penetrating – blunt compressive – +/- hypoxia (lack of oxygen) – injury or stroke – often a combination of above
– severe injury effects obvious but mild injury effects also cause degenerative damage
What happens to the brain if it is exposed to concussions too often?
-see neurodegeneration very early (45 years old)
-problem in Australia as well, have cognitive tests they have to do before going back on the field
-several concussions close together are incredibly brain damaging
What is axon plasticity/sprouting?
-doesn’t really happen in the CNS but common in the PNS
-instead of the damaged axon regrowing, the neuron next to the damage will grow another axon to connect the gap
What causes the inhibitory environment in the CNS?
-Things that stop surviving neurons from regenerating axons:
• Inhibitory molecules in myelin debris – Nogo,MAG
• Astrocytic gliosis and the glial scar
• Upregulation of developmental axon guidance molecules – Semaphorins,Tenascin,CAMs – Eph/ephrin family
-these are the main factors but there are many more (MAG= myelin associated glioprotein)
-normally during development it is guided by a variety of molecules, once development is finished these molecules are downregulated, in injury it is upregulated again and “confuses” the axons that cannot get past
What is the cellular response to injury in the CNS?
-inhibitory signals disrupt axon extension
What are the macrophages that invade post injury in the CNS?
-the macrophages here don’t do a very good job of clearing the debris
-hundreds of different types of macrophages, broadly anti inflammatory or inflammatory (much more complicated than in the body and the PNS)
-Macrophages also infiltrate a CNS injury site – but not all macrophages are the same
What is the reaction of the three major classes of glia in the CNS to local tissue damage?
-more astrocytes, oligodendrocytes as well as microglia in CNS site of injury
-increase in complexity
What is astrocytic gliosis?
-the cells become hypetrophic (enlarged) -become reactive and form a wall a barrier at the site of the injury, secrete a number of factors
• Upregulate astrocyte cytoskeletal proteins eg GFAP (glial fibrillary acidic protein)
• Interdigitate processes
￼￼￼• Secrete cytokines & growth factors
• Secrete extracellular matrix - e.g. chondroitin sulphate proteoglycans (CSPGs)
• Upregulate expression of developmental axon guidance molecules =leads to Glial Scar Formation – forms a barrier between undamaged tissue and injury site
What is the cellular response of the CNS to injury and the proteins involved?
-3 proteins in myelin that are inhibitory: Nogo A, MAG, OMgp
-their normal function is to keep axons from sprouting aberrantly, but in injury it prevents regeneration
-various ligands etc. that affect the regeneration process
-Also upregulation of developmental axon guidance molecules: Eph/ephrins, semaphorins,
What are the myelin inhibitors?
Myelin proteins – Nogo – MAG (myelin-associated glycoprotein) – OMgp (Oligodendrocyte/ myelin glycoprotein)
All bind to Nogo receptor (NgR) – associates with p75/LINGO and/or TROY/LINGO
Results in Rho signalling pathway activation which inhibits axon growth
How are the myelin proteins inhibitory?
-bind to the same receptor on the neuron, TROY/LINGO and p75
-this receptor’s pathway is the Rho pathway (activation of Rho inhibits growth)
What is the CNS/PNS environment after injury?
What can be targeted to promote repair and regeneration of the CNS?
• block molecules that inhibit axon regeneration
- myelin inhibitors
- developmental guidance molecules
• block/modify astrocytic reactivity and glial scar formation
• grow new neurons from neural stem cells
- endogenous (activation of own stem cells in brain)
- transplanted (from tissue culture sources)