CNS Injury & Nerve Regeneration Flashcards
PNS or CNS can regenerate after damage?
PNS can regenerate after damage.
CNS can NOT regenerate after damage.
What occurs during spinal cord injury?
- displacement of vertebral bones
- axons damaged, cannot conduct signals
- damaged neurons release glutamate –> electrotoxicity
- neurotrophin-deprived death
- swelling crushes longitudinal segments and damages white matter
- cytokines form glial scar
- glial scar inhibits regeneration
- myelin has inhibitory factors
neurotrophin
- neuron growth factor
- allows neurons to survive (default w/o this is death)
- allows efficient synapses/paths to continue
-loss of axon transmission causes neurotrophin-deprived death
Ex:
- NGF
- BDNF
- NT-3
what is the greatest source of cell death with a spinal cord injury?
Deprivation of neurotophin.
what triggers formation of glial scar?
cytokines
- released by microglia
- act on neurons. astrocytes
experimental strategies to repair spinal cord
Neuronal survival.
Altering terrain.
Role of inhibitors (inhibit the inhibitors).
Intrinsic capacity for regrowth.
Stem cell regenerative medicine.
Reconnection, training, synaptic plasticity.
neuronal survival
experimental strategy to repair spinal cord
1) reduce swelling
- via methylpredisone
- surgical decompression (break vertebrae to alleviate swelling)
- hypothermia (slows events)
2) apply factors
- NGF (neurotrophin)
- BDNF (neurotrophin)
- NT3 (neurotrophin)
- FGF (fibroblast growth factor)
- artemin (glial derived growth factor
-can apply factors directly, or use engineered cells to deliver
altering terrain
- embryonic grafts (PNS can regenerate, so graft it onto CNS)
- engineered bridges with collagen or secrete factors
- replace myelin and oligodendrocytes (myelin secretes inhibitory factors)
- show significant growth that stops the end of the permissive terrain
inhibitor factors
- Nogo (neurons “no go”)
- MAG: myelin associated glycoprotein
- Receptor for Nogo/MAG: same receptor; cripples motility by affecting cytoskeleton
- Rho: downstream signalling pathway
what increases the intrinsic capacity for regrowth?
- GAP43
- tubulin
- actin
stem cell regenerative medicine
- implant stem cells at site of damage
- cells can differentiate into neurons/glia, release BDNF (in animals)
- cannot control/optimize for differentiation
- clinical trial for safety/functional recovery
reconnection, training, synaptic plasticity
- training paradigms to enhance regeneration (put legs on motorized bike pedals)
- can increase plasticity beyond site of damage and functional recovery
- debate over regeneration vs new sprouting; most likely new sprouting
neuroengineering approaches
- pattern generators
- brain computer interface
- deep brain stimulation to reduce neuropathic pain
- computer controlled exoskeleton/robotics
hope for clinical intervention
- combinational therapies not yet effective
- stem cell therapies, control over differentiation is promising approach
- promise of neuroengineering, robotics, pattern generators
what factors exacerbate severity after spinal cord injury?
1) excitotoxicity
2) swelling w/i vertebral column
3) damage at one vertebral level interrupting transmission at all points below
4) subsequent loss of neurotrophins leading to cell death
what interventions could enhance growth and reconnection after spinal cord injury?
1) preventing swelling (methylprednisone, crack vertebral column)
2) provide permissive substrate for growth
3) block myelin and glial scar based inhibitors
4) provide neurotrophins
5) adding local guideposts
6) stem cells
7) neuroengineering
examples of neurotrophins
- NGF
- BDNF
- NT-3
use of methylprednisone in spinal cord injury
to reduce initial swelling
-prevents some loss of function that would return eventually
what do damaged neurons release? what does that cause?
damaged neurons release GLUTAMATE, which causes EXCITOTOXICITY (cell death)
- glutamate overstimulates local nerve cells
- increases free radicals
where do inhibitory factors reside normally in adults? their function?
reside in myelin, oligodendrocytes
-present to prevent inappropriate sprouting of mature nervous system
receptor for Nogo, MAG is a target for…
receptor for Nogo, MAG is a target for DRUGS to counteract inhibitory factors that prevent axon regrowth
-NAG and Nogo have same receptor
guidance factors
Necessary for correct axon regrowth
-helps get to correct target
swelling crushes
longitudinal segments, damages white matter laterally
how to reduce swelling?
- methylprednisone
- surgical decompression
- hypothermia
