LECTURE 25 - CNS response to trauma Flashcards
What is CNS trauma?
Acute
- TBI and traumatic spinal cord injury (SCI) can be result of a physical insult to the CNS e.g. road accidents, strokes, neurotoxins
Chronic
- degenerative disease -AlzD, PD etc., brain tumours, ALS, alcohol and drug abuse
What pathophysiological changes can occur from both chronic and acute insults?
- cerebral oedema
- inflammation
- cytotoxicity
- loss of cerebral auto regulation
- apoptosis
What damage can occur after pathophysiological changes?
Secondary neuronal damage in the:
- limbic system
- basal ganglia
- brain stem
- forebrain
- cerebellum
- cerebral cortex
What neuropsychiatric disorders can arise after secondary neuronal damage?
- memory/cognitive deficits
- sleep disruptions
- mental and emotional symptoms
- impaired psychomotor and neuromotor functions
What is common feature of all CNS injuries?
- leads to severe detrimental effefcts
- mammalian CNS does not regenerate, has a limited capacity for repair, neuronal loss and cell death results in permanent functional cell death
How are injuries to the spinal cord split up?
- C4 injury
- C6 injury
- T6 injury
- L1 injury
What is a C4 injury?
- Quadriplegia/ Tetraplegia
- results in complete paralysis below the neck
What is a C6 injury?
- results in partial paralysis of hands and arms as well as lower body
What is a T6 injury?
- Paraplegia
- results in paralysis below the chest
What is an L1 injury?
- Paraplegia
- results in paralysis below the waist
How prevalent are TBIs and SCIs?
TBI
- over 1M people in UK living with TBI
- in 2016-2017, there were 348,453 UK admissions with brain injury and 155,919 for head injury
- men are 1.5x more likely to be admitted for head injury
SCI
- more than 50,000 people in UK and Ireland living with paralysis caused by SCI
- every day, 3 people are told they will never walk again
- more than 2.5 million worldwide live with paralysis caused by SCI
What are the consequences of CNS injury?
- functional deficits
- CNS neurones do not regenerate
What prevents regeneration of CNS neurones? - injury response
- inhibitory environments (characterised by glial scar and up-regulation of inhibitory molecules such as CSPG, MAG and Nogo-A)
- lack of trophic support
- loss of cells
What are the mechanisms of damage and inhibition of regeneration as we’ll as the permissive and reparative mechanisms?
Mechanical insult
–>
Primary damage: mechanical failure; BBB/BSCB breakdown, necrosis
–> (EITHER)
Secondary damage: inflammation, excitotoxicity, ischemia, free radicals, oedema, apoptosis
WHICH LEADS TO
- repair attempts; increased neurogenesis, angiogenesis (blood vessel formation), increase in beneficial ECM proteins (extracellular matrix) - helps cells move around
–> (OR (reparative))
initial glial response; phagocytosis; decreased excitotoxicity, sequester injury site
WHICH LEADS TO
long-term glial scar; inhibits neurone outgrowth/regeneration
ALL OCCURS ALONGSIDE EACH OTHER
What happens when the blood brain barrier (BBB) breaks down?
- -> lesion cavity expands due to inflammation
- -> inflammatory cells interact with reactive glial cells
- -> reactive astrocytes seal off the BBB
- -> to retain tissue integrity and reduce the inflammatory response (scar formation)
- scarring is associated with upregualtion of inhibitory molecules and ECM deposition
- injured CNS is non-permissive for axonal regeneration and dystrophic neurones develop
What cellular interactions does CNS injury response lead to?
- dystrophic neurones
- severed axons and axonal sprouting
- highly active structures which are stalled without functional growth
- neuronal death
- lack of neurotrophic support (cells lack nutrients to stay alive)
- production of inhibitory molecules (oligos/myelin)
- demyelination
- glial scar - barrier to regeneration
How can the PNS regenerate with full restoration of function?
Schwann cells (myelinate a single axon)
- permissive for growth
- align longitudinally
- release growth promoting factors
Neurons can regenerate:
- fusion of cut axonal membrane
- proximal axon retraction and growth cone, regrowth, re-innervation
- axon myelination
- re-innervation of target tissues
Why can CNS neurones not grow after injury?
Oligodendrocytes (myelinate multiple axons)
- do not form guidance path for sprouting axons
- express inhibitory molecules
Astrocytes
- release factors to promote scar deposition
- release inhibitory molecules (CSPGs etc.)
Myelin debris
- is not cleared and expresses inhibitory molecules (Nogo, myelin-associated glycoprotein (MAG), Oligodendrocyte Myelin Glycoprotein (OMgp)
–> end up with regenerative failure
What are the features of CNS injury?
CNS axons have some intrinsic capacity for regenerating BUT are prevented by the inhibitory environment
- lack of neurotrophic factors
- neuronal death
- demyelination
- glial scars (CSPGs/ECM)
- inhibitory molecules
What in vitro research into neurotrauma is being conducted?
- culture cells and neurones in a dish and transfect with various agents and treatments to cause injury and measure with and without treatments any growth
- genetic labelling
- RNA sequencing
- immunopanning
- in vitro assays/ imaging
- develop in vitro models of TBI like injuries by stretching brain, can measure lots of things we know occur e.g. inflammatory cascade and cellular disruption
What in vivo research into neurotrauma is being conducted?
- fluid cushion injuries
- blast injuries
- cortical impacts
- penetrating injuries
- weight drop models
- optic models to look at CNS injury, less invasive
measured outcomes - RGC (retinal ganglial cells) survival
- neurite outgrowth
- glial response
- apoptosis
Treatment given via intravitreal injection
(all done on rats/mice)
What are the main research areas into CNS injury and strategies to repair?
- inhibit the inhibitory molecules –> promote axonal regeneration (chABC = enzyme that digests chondroitin sulphate proteoglycans (CSPG) => stop inhibitory molecules. Also convert antibodies to Nogos)
- promote neurite outgrowth (e.g. silencing RhoA –> siRhoA)
- prevent cell death (neuroprotection - inhibit apoptosis, research into CASPases)
- endogenous stem cells (neurogenesis, endogenous NSCs)
- cell therapies (e.g. dental pulp stem cells (autologous cells), replace dead cells, create favourable permissive environments)
Why do spinal cord axons not regenerate?
Inactive growth program
- neurones may posses program for regeneration nut not have it switched on
Lack of growth factors
- neurotrophins can increase and guide axon growth, without them axons wither
Myelin
- myelin contains Nogo, MAG and OMgp that inhibit axon growth
Lesion cavity
- neurones do not grow well through empty spaces
Extracellular matrix
- framework between cells has surface molecules that can inhibit axon growth, especially after injury
What are the main treatment approaches for injury to axons
- bridge the lesions: scaffolds/ hydrogels
- remodel the glial scar: chondroitinase ABC
- replace damaged/ lost cells: cell therapies
- promote neural plasticity: physical rehabilitation, cell therapies
- promote neuroprotection: Riluzole, growth factors
- tame myelin inhibition: anti-NOGO, RhoA antagonists
- modulate inflammation: methylprednisolone, minocycline
