Lecture 32- Repairing the nervous system Flashcards
What was the situation regarding neural injuries?
-Life expectancy following SCI remained ~2 weeks until after WWII
What will it take to effectively repair the CNS?
-Neuroprotection: protect surviving cells
-Axonal regeneration and functional integration:
- Regrowth of surviving neurons
- Remyelination
-Modulate astrocytic gliosis:
- Wound repair & scar formation
- Blocks axonal regeneration
-Neural stem cells:
- Replacement of lost cells
- Mobilise endogenous cells
- Transplant exogenous cells
What stops axonal regeneration and what can be done about it?
1.
Stops it: Lack of trophic support
What can be done: Encourage axons to regrow – Provide growth promoting factors • Neurotrophins (eg NGF, BDNF) • Some clinical trials • Adverse effects e.g. neuropathic pain
2.
Stops it: Axon regrowth inhibited by the injury environment
What can be done: – Inhibit growth blocking factors -Astrocytic gliosis & glial scar -Myelin inhibitors -Developmental guidance molecules -Active and increasing area of research, Several clinical trials
What are the types of reconnections after axonal damage?
- direct would be the ideal way
- relayed connection: the axon cannot find the right neuron but finds one via which can get teh path
- re-routed: just connect in a different bit, get past the injury site
- alternative pathway: connect to neuron that wasn’t affected by the injury, can compensate by sprouting
How does astrocytic gliosis affect regeneration?
- astocytic gliosis is one of the main inhibitors of regeneration
- people have tried a number of things to do this, no increased regeneration when block TGFbeta
- genetically modified mice made with knockout of one of the markers expressed after injury= GFAP
- also tried to kill al the astrocytes, axons could get through but the mice didn’t do well the injury wasn’t proper, increased inflammation etc.
What were the trials to counteract astrocytic gliosis?
-Preclinical research to modulate astrocytic gliosis= No increased regeneration
- blocking of TGFb= Increased regeneration:
- blocking of astrocyte ECM – Chondroitin Sulphate Proteoglycan inhibition – collagen IV inhibition
- GFAP/Vimentin double knockout mice
- astrocyte ablation – GFAPp-HSV-TK mice + Gancyclovir – kills reactive astrocytes – but: increased tissue destruction and degeneration, increased inflammation, inhibited Blood-Brain-Barrier repair
What do you need to balance well in astrocytic gliosis?
- Wound sealing BBB repair Growth factors -NGF/BDNF increase glutamate transporters
- Physical barrier, Molecular barrier ECM -CSPG, collagen IV Cytokines -TNFa, IL-1…
What do myelin inhibitors and axon guidance molecules do in the injury environment?
- Inhibitory molecules in the injury environment bind to receptors on (re)growing axons/dendrites (neurites)
- myelin inhibitors on myelin debris
- axon guidance molecules on activated astrocytes
What do axon guidance molecules do?
- Promote, repel or guide growing axons
- Many upregulated or re-expressed after injury in the adult – Semaphorins – Tenascin – Cell Adhesion Molecules (N-CAM, L1, N-Cadherin) – Eph/ephrins
- EphA4 • ephrinA5 No clinical trials to date – preclinical research in animal models
What happens to EPhA4 and GFAP after injury?
-increased expression in both
What happens if you block EphA4 after injury has occured?
- Blocking EphA4 promotes regeneration
- it promotes regeneration of the lesion site
- and the astrocytic gliosis is decreased
- fewer astrocytes around the lesion site and less GFAP expression around the lesion
- it also enhances axonal regrowth in the mice with EphA4 blocked
- axonal regeneration across injury site
- there is also functional improvement in walking and climbing (this shows the neurons are functional!)
• Functional improvement • walking • climbing • Effective in mice and rats
What sort of studies have there been looking at the myelin inhibitors and regeneration?
-Nogo blockers= antibody discovered that blocks Nogo, and these are now in clinical trials, this seems to allow axons to regrow -
Rho inhibitors also effective, and in clinical trials
-Animal studies
- Gene knockouts – minimal & variable regeneration
- Nogo blockers – some regeneration
- Rho inhibitors – some regeneration
-Clinical trials are underway for Anti-Nogo antibody (Phase I/II) Novartis
What are the differences in regeneration capability in the neonatal and adult brain?
- if you cause a lesion in a neonatal mice, these neurons will adapt and sprout and help re-innervate the other side of the spinal cord
- in adult this doesn’t happen
- if you add the Nogo inhibitor more similar to the neonatal situation
Rho kinase as a common mediator of inhibition?
- Rho pathway is the common pathway to most of these inhibitors so targeting that one may be
- Rho is also activated in injury, activates the astrocytes, so theoretically blocking Rho could dampen the astrocyte response
- Clinical trial underway: BioAxone’s recombinant Rho inhibitor (C3) plus a fibrin sealant (Cethrin) applied during spinal stabilization surgery (Phase I/II)
How can we use stem cells to repair the nervous system after injury or disease?
- Transplant stem cells/neurons grown in tissue culture
- Use drugs to “activate” stem cells already present in the adult nervous system – promote neurogenesis
-can grow cells in a culture and then transplant or activate the stem cells in the brain
What is neurogenesis like in the SVZ?
- in between the ependymal cells and the layer above are the neural stem cells (express astrocyte markers)
- Type B are the stem cells
- generate Type C the transit amplifying cells that can generate many progenitors
- these are then the Type A that are the differentiated neuroblasts
What is neurogenesis like in the SGZ?
- important in humans in day to day life
- Type 1- Type 2 to Type 3
What is another way to repair injury?
- replace the lost cells via transplantation of stem/progenitor cells
- these can come from embryonic stem cells (ESC), from adult non neural stem cells and induce them (iPSC)
- clinical trials underway
