Week 10 Flashcards
What does trauma include?
Element of Neurotrauma
Brain or spinal cord injury
Where does brain and spinal cord injury occur?
Civilian environment
Military environment
What is the average intervention time?
12-15 minutes
What is the drug discovery and transitional path for development of new treatments?
Basic research Prototype design or Discovery Preclinical development Clinical development - phase 1/phase2/phase3 FDA filling/ Approval and launch
What does a patient who has cervical injury lead to?
Complete tetraplagia
Neurotrauma
Injury of young people from ages 16-35
Primary injury zone
Irreversible
Die in shallow water and break spine
What can primary injury zone be triggered by?
Apoptosis or necrosis
What does damage to the spinal cord trigger?
Loss of cells Loss of axons Degeneration of axons Myelinated fragmented Lots of action of glial cells surrounding area of injury
Secondary injury pathways
Inflammation
Invasion of neutrophils/macrophages
When spinal cord is damaged - break the BBB
Inflammation -local- driven by microglia
Release of many pro-inflammatory cytokines (IL-6, TNF-A and IL-1B)
What is excessive glutamate release defined as?
Excitotoxicity
What does reactive vasospasm lead to?
Hypoxia
Vessels have increased permeability, what does that lead to?
Influx of substances into the brain
What is the consequence of ischemia?
Energy failure
Decreased production of ATP
What can oxidative stress lead to?
Expansion of injury zone
What is time line of SCI (seconds to minutes)?
Vascular alterations
- Hemorhage
- Thrombosis
- Decreased blood flow
- Ischemic necrosis
- Edema
Metabolic disturbances
- Increased sodium, chloride, potassium
- Increase calcium intracellarly
- Increase glucose utilisation
- Decreased ATP
- Acidosis
What is timeline of SCI? (Minutes to hours)?
Biochemical alterations
Lipid periodisation
- Increase free radicals and fatty acid production
- Increase arachidonic acid release
- Increase Eicosanoid synthesis
Neurotransmitter accumulation
- Increase excitotoxic amino acids, catecholamine
- Increase endogenous opioids
What is timeline of SCI? (Hours to weeks)
Cellular reactions
Inflammation
- Increase macrophages
- Increase neutrophils and T cells
- Increase reactive astroglia
Apoptosis
What is timeline of SCI? (seems to months)?
Fibre tract disturbances
- Demyelination
- Wallerian degeneration
- Apoptosis of oligodendrocytes
- Scar formation
What is the features of cervical?
- Smaller and more mobile vertebrae
- Greater diameter
- Highly vascularised
- Susceptible to hemorrhage
- Considerable spontaneous recovery
- Injury interrupts sympathetic innervation to major immune organs
What is the features of Thoracic?
- Larger vertebrae supported by the rib cage
- Smaller diameter
- Reduced vascular supply and greater pedicure coverage
- Less vulnerable to haemorrhage
- Minor spontaneous recovery
- Injuries below T9 do not interrupt sympathetic innervation to major immune organs
What is spinal cord?
Not homogenous
What is the consequence of spinal cord injury?
Paralysed
Can become paraplegic or quadriplegic
What does Quadriplegia control?
Breathing (C1-4), head, neck (C2)
Heart rate (C4-6), shoulder (C5)
Wrist, elbow (C6-7)
Hand, finger (C7-T1)
What does paraplegia control?
Blood pressure Breathing, trunk Sex reflexes Locomotor CPG hip Knee Foot Bladder, bowel
What is Quadriplegia?
Paralysis of all 4 limbs
What is paraplegia?
Paralysis of the legs and lower body
Caused by spinal injury or disease
Quadriplegic
Arms/hand function Sexual function Trunk stability Bladder/Bowel/AD Walking movement Normal sensation Chronic pain
Paraplegic
Sexual function Bladder/bowel/AD Trunk stability Walking movement Chronic pain Normal sensation Arm/hand function
What are therapeutic priorities for SCI?
- Intervene early with neuroprotection
- Regeneration and restoration of circuitry
- Prevent delayed function
- Autonomic dysfunction
- Dysreflexia
What are lesions above T5 level associated with?
Sympathetically-driven intense vasoconstriction triggered by peripheral afferent stimulation below injury level
What is dysreflexia?
Over-activity of the ANS causing abrupt onset of excessively high blood pressure
What can be a trigger of autonomic dysreflexia?
Poo in rectum (sensory stimulation)
Trying to defecate
What does Necrosis destroy?
Spinal cord
What is NeuN immunostaining used for?
3D reconstruction of compression SCI impact
What is Neuraine?
Neuronal antigen which reflects the presence of intact neurons
How can you quantify the expansion of injury zone?
High resolution mri
Expansion of damage zone
Visible 7-10cm
What is secondary injury characterised by?
Inflammation
Excitotoxicity
Hypoxia collapse of energy resources
What are examples of inflammatory compounds?
Anti-integrins
Minocycline
Where are 99% of injury done?
Rodents
Why does quadrapets recover much more than biceps?
They have locomotion pattern generations
How can hind limb score be derived?
Looking at how an animal moved in an open field
What drives oxidation in endangered tissue?
Oxidation of lipids and depletion of antioxidants
What does 4-HNE reflect?
Oxidation of fatty acids in the tissue
Why is there a lot of fatty acids in the tissues?
Brain and spinal cord are full of lipids and phospholipids
What is released after injury?
Pro-inflammatory eicosanoids
(Concentrated in the nervous system - it is an oligo-6 fatty acid)
In the first hour you see a high level of PGF or TXB2
What does a lipid peroxidatjon have?
Decrease oxidative stress
High T bar signal in rats after compression
What is decreased by anti-integrin?
Hydroxyl signal
What does MPO stand for?
Myeloperoxidase
What is MPO?
Enzyme which characterised a neutrophil
What does anti-integrity relieve?
Microglia/macrophage infiltration
What happens after treatment with anti-integrity of myelin?
More spared myelin
Some improvement in the rostral and causal areas
What is combination of injury?
Loss of sensation
Emergence of neuropathic pain
What happens when EPO binds to EPO receptor in the brain?
A host of diverse pathways activated
What is the consequence of injecting EPO?
Induce neuroprotection
What does EPO have the potential to improve?
Neurological outcome
What does carbamylated EPO do?
Reduce lesion volume
