Neural Regeneration Flashcards
What is the regenerative response to peripheral neural injury?
[cell body can be in a peripheral ganglion like a DRG or in CNS but nerve is peripheral] the proximal portion can regenerate distally
What is the regenerative response to central neural injury?
do not regenerate well; neurons can die and/or retract processes (but sprout to make new local connections), glial scarring usually inhibits regrowth
What are the general differences between the CNS and PNS that allows PNS regeneration?
general structure; cell types involved; molecular guidance/repellant cues that can inhibit growth of CNS axons
What is the layered structure of peripheral nerves?
SC > dorsal and ventral roots > DRG and VRG > epineurium (around bundles of perineurium) > perineurium (around bundles of endoneurium) > endoneurium (around neurons) > sensory and motor neurons > nerve axons covered in Schwann cells and myelin –> skin and muscle
Normal neuron cell bodies have
central nuclei and dense Nissl substance
What is Nissl substance?
ribosomes which are actively transcribing RNA
Damaged neuron cell bodies show
peripheral nuclei and loss of Nissl substance (chromolysis/chromatolysis)
Up to 2 weeks post injury, peripheral nerves show
peripheral nuclei w/loss of Nissl substance in cell bodies; Wallerian degeneration - degeneration of axon and myelin sheath below site of injury, debris is phagocytosed by macrophages; muscle atrophy
Regeneration of peripheral nerves occurs how soon after injury?
~3weeks
3 weeks post-injury, peripheral nerves display?
nuclei more central; proliferation of Schwann cells forming a compact cord; axon sprouting - hopefully enters Schwann cell cord and grows
About 3 months post-injury, peripheral nerves display
regeneration may be successful - restoration of electrical activity, reforming of synapses, myelin sheath (may be thinner), reversal of muscle atrophy
A neuroma forms when
the axon misses the Schwann cell cord and does not connect to the peripheral nerve segment; this results in continued axon growth and sprouting facilitated by factors released from Schwann cells
What is the impact of myelination by oligodendrocytes in the CNS (vs Schwann cells in the PNS) on regeneration?
Oligodendrocytes are inhibitory of regrowth; Schwann cells are supportive for regrowth
What processes lead to secondary injury in minutes-hours post-injury?
ischaemia: limited blood flow causing hypoxia; Ca2+ influx; lipid peroxidation and production of free radicals (toxic to cells); glutamate excitotoxicity (can’t be mopped up); BBB breakdown
What processes lead to secondary injury in hours to days/weeks post-injury?
activation of immune cells migrated from periphery and of resident microglia releases inflammatory cytokines, chemokines, and metalloproteases
What processes lead to secondary injury in days/weeks post-injury?
ongoing degeneration (inflammatory mediators); axonal degeneration an death; demyelination of remaining axons; oligodendrocyte death; myelin fragments (inhibitory; slowly phagocytosed); astrocytic gliosis and glial scarring inhibits growth; syrinx (cyst) formation; meningeal fibroblast migration
How might neural regeneration be promoted?
neuroprotection (of surviving cells); axonal regeneration & functional integration (regrowth and remyelination); modulation of astrocytic gliosis (important in wound repair and scar formation but scar blocks regeneration); neural stem cell (endogenous activation or exogenous transplantation)
What inhibits axonal regeneration?
lack of trophic support and inhibition by the injury environment
What trophic support is needed in axonal regeneration?
growth promoting factors like neurotrophins (NGF, BDNF)
NGF
nerve growth factor
BDNF
brain-derived neurotrophic factor
What factors of the injury environment inhibit axon regrowth?
astrocytic gliosis and glial scarring; myelin (and oligodendrocte) inhibitors; developmental guidance molecules presenting at the wrong spots
What happens to astrocytes in astrocytic gliosis?
upregulation of astrocyte cytoskeletal proteins (GFAP - glial fibrillary acidic protein); hypertrophy and proliferation of cells; interdigitation of processes; secretion of cytokines and growth factors; secretion of ECM and proteoglycans; upregulation of expression of developmental axon guidance molecules
What is the purpose of glial scar formation?
form a barrier between undamaged tissue and the injury site
How can astrocytic gliosis be modulated to promote neural regeneration?
promote wound healing, BBB repair, secretion of growth factors (NGF, BDNF), increase glutamate transporters; reduce physical and molecular barriers, ECM deposition (CSPG, collagen IV) and cytokines (TNFa, IL-1)
How do myelin inhibitors and axon guidance molecules inhibit axon growth?
axons that encounter myelin debris or guidance molecules (upregulated on astrocytes) will stop growing
What are myelin inhibitors?
myelin proteins Nogo, myelin associated glycoprotein (MAG), and ogliodendrocyte/myelin glycoprotein (OMgp); all of which bind to Nogo receptor on neurons which signals via Rho to inhibit growth
How can myelin inhibitors be blocked to promote axonal regeneration?
antibodies agains proteins eg Anti-Nogo antibody to prevent binding to the Nogo receptor; Rho inhibitors to inhibit Rho signalling that stops growth
What axon guidance molecules are upregulated or re-expressed after injury?
semasphorins, tenascin, cell adhesion molecules (neural-CAM, L1, N-cadherin_, Eph/ephrins (EphA4, ephrinA5)
Why is rho kinase a potential target?
it’s common to the pathways of Ephrin, semaphorin, and CSPG (ECM) which inhibit regeneration; it is what tells the axon to stop growing (growth cone) when it encounters inhibitors in the environment; it also activates astrocytes
How can activation or transplantation of neural stem/progenitor cells promote neural regeneration?
replace neurons or oligodendrocytes (for myelination)
What areas of the brain contain neural stem cells that can make new neurons?
subventricular zone of the lateral ventricle, and the subgranular zone of the dentate gyrus in the hippocampus (memory/learning, anxiety)
