SCI regeneration Flashcards
What are the seminal experiments for extrinsic differences with CNS/PNS?
Tello (1910) and Aguayo (1980)
Aguayo (1980)
demonstrated that at least some mature CNS neurons retain their ability to regenerate on permissive PNS grafts, whilst they cannot regenerate in their native environment.
What are the 2 major classes of molecules that inhibit regeneration?
Myelin-associated inhibitors and chondroitin sulfate proteoglycans.
Name 3 MAIs
- Nogo-A
- Myelin associated glycoprotein
- Oligodendrocyte myelin protein
What do all the MAIs interact with?
Nogo-66 receptor
Schwab (1990)
Myelin injected into mouse, Abs generated against an inhibitory factor in the myelin, so that regeneration of axons in the corticospinal tract was observed.
What makes rodent CST not a good model for human CST?
CST axons lie at the base of dorsal columns and terminate in the dorsal horn. Cutting the CST means you also have to cut the dorsal columns.
Lee (2009)
Nogo deletion mutant that is null for all known isoforms of Nogo. Analyses failed to reveal any enhanced CST regeneration after experimental SCI.
What are the molecules involved in Nogo-related axon regeneration
Rho A and ROCK.
Murinson (2005)
Selective rhizotomy in the rat showing that schwann cells of degenerating efferents incorporated 3H thymidine, whose myelinating intact sensory axons did not. Suggest diffusible mitogen induces non-myelinating SCs to enter cell cycle but axonal contact can block this response.
What do SCs form?
bands of Bugner within basal laminar of the nerve- rich in laminin, encouraging axonal growth.
Suigara (2000)
LIF KO mice show delayed macrophage migration into the injured nerve and delayed myelin clearance during Wallerian degeneration. LIF released from SCs.
Vaughn and Pease (1970)
Early EM studies showing enucleation of the eye resulted in survival of 60-70% of OCs in quiescent state- only a small number appear to phagocytose myelin.
Why is the CNS inaccessible to leukocytes
Entire length of PN becomes accessible to heamatogenous macrophages, BBB only disrupted at site of injury.
Kim (2003)
substantially improved regeneration found in Nogo-A/B mouse knockout after SCI, with associated locomotor recovery.
Critique of Kim (2003)
- Hard to prove regeneration and not plasticity
- Mouse model of SCI not a good model for human.
Sorfroniew (2016)
Prevented astrocyte scar formation through ganciclovir inducible destruction of astrocytes- in mouse model of SCI - weight drop. Mice without astrocyte activity failed to form scars, exhibited larger areas of damage. CSPGs produced by other cells? Also showed that local delivery of hydrogel depots containing axon growth factors encouraged axon regrowth, but inhibiting scar formation reduced regrowth.
Zhao (2013)
Combination treatment with anti-Nogo-A and chondroitinase ABC in rat dorsal column lesion model promoted significant recovery in a forelimb reaching task.
Zhao (2013) critique
Partial lesion model not gold standard. Different makeup of the rat spinal cord, not a good model for humans.
Why are DRG neurons good models for SCI?
Pseudounipolar with axons that extend in peripheral process to receptors in periphery and central process to spinal cord.
Neumann and Woolf (1999)
A peripheral conditioning lesion allows regeneration of subsequently injured central branch, a process that is transcription dependent. Effects of peripheral conditioning injury can be replicated by numerous factors such as cAMP therefore crucial signal.
Bomze (2001)
co-expression of GAP-43 and CAP-23, two major growth cone proteins in adult DRG neurons increases their regenerative capacity
Franssen (2015)
Genetic knockdown experiments in mice with fluorescently labelled integrins demonstrated role of ARF6 in regulating reterograde trafficking of integrins away from axon. Developmental activation of gene may be responsible for lack of regenerative capacity. Overexpression of ACAP-GTPase involved in anterograde integrin trafficking shows axon growth restored.
Mishra (2016)
Blocked astrocyte clacium elevations in cortical brain slices with BAPTA. Reduction in dilation of capillaries - no effect on arterioles.
Kraft (2013)
Transgenic mouse line with GPAP and VIM intermediate filament proteins for astrocyte activation deleted - on model AD background (APP/PS1). Gene deletions increased the amyloid plaque load.
Liu (2017)
cKO in LRP1 in astrocytes on amyloid model - therefore clear role of astrocytic LRP1 in brain Abeta clearance. ApoE also a ligand for LRP1 , therefore may compete with Abeta for cellular uptake into astrocytes.
