Neural Regeneration Flashcards
What happens when peripheral nerve axons are injured?
The proximal part is able to regenerate distally (often only partially), regardless of whether the cell body is in a peripheral ganglion or the CNS
What happens when central axons or neurons are damaged?
Some neurons die, some retract their processes but others are able to “sprout” and make new local connections in an attempt to compensate; regeneration is limited or non-existent
Give a timeline of structural changes in PNS injury and regeneration
Before injury: central nucleus, dense Nissl substance
Up to 2 weeks post-injury: peripheral nucleus, chromolysis, Wallerian degeneration (rapid degeneration of distal axon and myelin sheath and phagocytosis by macrophages), muscle fibre atrophy
3 weeks post-injury: Schwann cell proliferation (forms compact cord), penetration of cell cord by growing axons (0.5-3mm growth/day)
3 months post-injury: restoration of electrical activity, muscle fibre regeneration
What happens if neural regeneration in the PNS is unsuccessful?
The growing axon forms a bundle of fibres called a neuroma, which can be painful or cause unwanted sensation
Why is neural regeneration more effective in crushed vs. cut peripheral nerves?
Because the Schwann cells and ECM in the distal segments of a crushed nerve provide a continuous guide for the growing axon
What is the main therapeutic approach used to treat PNS injury?
Microsurgery, where proximal and distal stumps are reattached or a nerve graft is inserted
What treatments for CNS neural injury are used to reduce the extent of the damage caused by the primary injury?
Tissue plasminogen activator (TPA) to dissolve the blood clot in stroke, decompression for SCI (e.g. removing vertebra if crushing the cord)
What processes contribute to the secondary injury occurring within minutes to hours in SCI?
Ischaemia Ca2+ influx Lipid peroxidation and free radical production Glutamate excitotoxicity BBB breakdown
What processes contribute to the secondary injury occurring within hours to days/weeks in SCI?
Immune cell infiltration/microglial activation
Influx of cytokines, chemokines, metalloproteinases
What processes contribute to the secondary injury occurring within days/weeks in SCI?
Axonal degeneration
Demyelination
Apoptosis (neuronal and oligodendroglial)
Astrocytic gliosis and glial scar
Syrinx (fluid-filled cavity or cyst) formation, meningeal fibroblast migration
What are 4 requirements for effective CNS repair and what does each involve?
Neuroprotection: protecting surviving cells
Axonal regeneration and functional integration: regrowing and remyelinating surviving neurons
Astrocytic gliosis modulation: preventing wound repair and scar formation from blocking axonal regeneration
Neural stem cells: replacing lost cells (either by mobilising endogenous cells or transplanting exogenous cells)
How can a lack of trophic support for axonal regeneration be overcome?
Neurotrophins (e.g. NGF, BDNF) can be provided
Give an example of an adverse effect of neurotrophin administration in SCI
Neuropathic pain
List 6 processes that occur in astrocytic gliosis.
Upregulation of astrocyte cytoskeletal proteins (e.g. GFAP)
Astrocyte hypertrophy and proliferation
Development of interdigitate processes
Secretion of cytokines and GFs
Secretion of ECM (e.g. chondroitin sulphate proteoglycans, CSPGs)
Upregulation of expression of developmental axon guidance molecules
What processes occurring in astrocytic gliosis aid axonal regeneration?
Wound sealing
BBB repair
GFs
Increased glutamate transporters
What processes occurring in astrocytic gliosis hinder axonal regeneration?
Physical barrier
Molecular barrier
ECM deposition (CSPG, collagen IV)
Cytokines (including TNF-a, IL-1)
What effect does astrocyte ablation have on axonal regeneration?
Outcome is worse than no inhibition; there is increased tissue destruction and degeneration, increased inflammation, and inhibition of BBB repair
What effect do myelin debris and axon guidance molecules have on axonal growth?
Myelin inhibitors on myelin debris and axon guidance molecules on activated astrocytes bind to receptors on regrowing axons/dendrites and have an inhibitory effect
Give some examples of myelin inhibitor molecules. What receptor do they bind to? What effect does this have?
Nogo, MAG (myelin-associated glycoprotein) and OMgp (oligodendrocyte/myelin glycoprotein) all bind to the Nogo receptor (NgR) on neurons to activate a Rho signalling pathway and inhibit axon growth
What is the role of axon guidance molecules?
They are normally expressed during development and promote, repel or guide growing axons; however, many are upregulated or re-expressed after injury in adulthood
Give 4 examples of axon guidance molecules
Semaphorins
Tenascin
Cell adhesion molecules (e.g. N-CAM, L1, N-Cadherin)
Eph/ephrins (e.g. EphA4, ephrinA5)
Identify 2 effects rho kinase has on neurons
When the growth cone of a neuron contacts rho kinase, it retracts
Activates astrocytes
List 7 characteristics of the PNS that are conducive to regrowth after injury
Simple structure
Quick degeneration of distal axon and myelin
Myelinating cell (Schwann cell) supports regrowth
Nerve structure often remains intact and provides a conduit for growth
Macrophages phagocytose debris
Schwann cells and macrophages only cell types present
Neurons survive (cell body intact)
List 7 characteristics of the CNS that are inhibitive to regrowth after injury
Complex structure
Slow degeneration of distal axon and myelin
Myelinating cell (oligodendrocyte) inhibits regrowth
Neural structure often destroyed
Macrophages phagocytose debris and also enhance or diminish inflammatory response
Complex cellular environment (neuronal cell bodies, reactive astrocytes, oligodendrocytes, macrophages, other inflammatory cells)
Neurons often die (necrosis and apoptosis at the primary injury site)
What are the 2 main neurogenic regions in the adult mammalian brain?
Subventricular zone (SVZ) of the lateral ventricle Subgranular zone (SGZ) of the dentate gyrus in the hippocampus
What is the difference between neurons in the SVZ and SGZ in terms of their response to injury?
Neurons in the SGZ can proliferate in response to injury within the hippocampus; neurons in the SVZ can migrate to the site of an injury and proliferate there
What kind of stem cells can be used to replace lost neurons in the CNS?
iPSCs, ESCs (transplanted first or differentiated before being transplanted)
Other stem cell types including bone marrow, haematopoietic, mesenchymal (don’t become neurons but can secrete beneficial factors)
