Regenerative therapies

Question 1

what are some future treatments in comabtting myelin debris?

Answer 1

• Anti-Nogo A antibodies increase axon regeneration in rat spinal cord injury (further away they moved from lesion )

Question 2

what do Anti-Nogo antibodies do in non-human primate SCI?

Answer 2

increase functional recovery and sprouting is seen
( it is currently in phase 2 looking at positive effects of recovery)

Question 3

Explain NogoA knockout experiments?

Answer 3

knockouts have produced variable amounts of axon regeneration after injury.
- one knockout regenerates vigorously
- one regenerates a bit
- one doesn’t regenerate at all

Question 4

what does a triple knockout of NogoA, MAG and OMgp show?

Answer 4

no regeneration after injury

Question 5

what are the main functions of (IN A NORMAL CNS):
- microglia
- astrocytes
- oligodendrocytes

Answer 5

microglia: immune surveillance
astrocytes: neuronal support
oligodendrocytes: continually cycling population

Question 6

what are the major markers/ molecules produced (IN A NORMAL CNS) by :
- microglia
- astrocytes
- oligodendrocytes

Answer 6

microglia: CR3, MCSF and TGFB1
astrocytes: GFAP, CAMs, NGF, FGFs, CNTF, TGFB1
oligodendrocytes: PDGFaR

Question 7

what CS-PGs are expressed (IN A NORMAL CNS) by:
- microglia
- astrocytes
- oligodendrocytes

Answer 7

microglia: none known
astrocytes: Brevican, versican, phosphacan
oligodendrocytes: NG2, versican

Question 8

What happens to glial cells in an injured CNS?

Answer 8

All cells become hyperactive

Question 9

What does an injured CNS do to microglia?

Answer 9

Increases in markers (CR3, MCSF, TGFB1)
New molecules produced: TNFa, IL-1b, IL-6, B7, MHC-I, CAMs, MCSF-R, integrins
Function: antigen recognition, proliferation, hypertrophy

Question 10

what does an injured CNS do to astrocytes?

Answer 10

Increases in markers (GFAP, CAMs, NGF, FGFs, CNTF, TGFB1)
New molecules produced: TNFa, IL-1, IL-6, tenascin
Function: Scar formation, hypertrophy
Increases in CS-PGs expressed (Brevican, versican, phosphacan)

Question 11

what does an injured CNS do to oligodendrocyte precursor cell?

Answer 11

Function: Rapid proliferation, hypertrophy
Increases in expressed CS-PGs (NG2, versican)
Molecules produced: PDGFaR

Question 12

what is Chondroitinase ABC (cABC) ?

Answer 12

an enzyme that digests glycosaminoglycan side chains of CSPGs

Question 13

describe how you can combat glial scar with cABC?

Answer 13

• after rodent spinal cord injury and digestion of glucosaminoglycan side chains with cABC
• no CSPG immunoreactivity detected
• fibres regrew around lesion site better than untreated
• cABC showed more fibres going around the lesion area

Question 14

what is a potential problem of cABC?

Answer 14

regrowth following treatment follows to areas where there is digestion of CSPGs

Question 15

what current treatment could cABC enhance?

Answer 15

rehabilitation

Question 16

how can cABC enhance rehabilitation?

Answer 16

specific forelimb reaching rehabilitation with cABC leads to a dramtic recovery of skilled forelimb function, even with a chronic injury

Question 17

what two experiments are done with rodents to test cABC with rehabilitation ?

Answer 17

• rat trained to reacg for a sugar pellet through a glass window
• staircase task with a sugar pellet on each step

Question 18

what did a combined treatment of cABC and rehabilitation lead to?

Answer 18

a large amount of recovered axons
- improved forepaw reaching
- axonal growth up to 5mm caudal to lesion site

Question 19

within regeneration and repair what five things could cell transplants provide?

Answer 19

1) bridge over/ through scar
2) permissive substrate
3) cell replacement
4) growth factors
5) remyelination

Question 20

name the three common transplant types ?

Answer 20

1) schwann cells
2) olfactory ensheathing cells
3) Stem cells (induced pluripotent, embryonic, multipotent progenitors)

Question 21

Why are olfactory ensheathing cells potential for cell transplants?

Answer 21

• similar to schwann cells
• constantly turned over
• protect olfactory cells
• has regenerative functoion so may help with CNS

Question 22

how does cell transplantation work in parkinson’s disease?

Answer 22

• dissection of ventral mesencephalic tissue (1-8 donor embryos used as a source of tissue)
• transplant preparation (fresh or hibernated tissue is homogenised into cell suspension or small tissue piecec)
• grafting procedure (stereotactic injection in caudate and/ or putamen, 3-8 injection tracts per striatum)
• Immunosuppression (Ciclosporin for 6 months or long-term triple drug therapy to prevent rejection)

Question 23

what the sequential pathway for schwann cell- like OEC?

Answer 23

precursor cell –> astrocyte like OEC –> Intermediate OEC –> Schwann cell-like OEC

Question 24

what can OECs do in regeneration and repair?

Answer 24

• they provide trophic support (neurotrophins)
• can phagocytose debris
• allow cells and axons to integrate through glial scar-rich regions

Question 25

what stem cells are important with regeneration and repair?

Answer 25

- embryonic - Induced Pluripotent (iPSC) - Mesenchymal stem cells

Question 26

what are NSCs?

Answer 26

Human Neural Stem Cells

Question 27

how many clinical trials are currently going on around the world using stem cells in SCI patients?

Answer 27

38

Question 28

what is the importance of biomaterials in repair?

Answer 28

1) Hydrogels that mimic the ECM 2) Provide physical or topographical cues for axonal growth 3) substrate for cell delivery and survival 4) important part of combined therapies (growth factors, cells, etc.)

Question 29

what are CPGs?

Answer 29

Central Pattern Generators - a neural circuit that can produce a rhythmic motor pattern in the absence of descending control: potentially without sensory input)

Question 30

What is epidural stimulation ?

Answer 30

uses electrical stimulation with propriospinal input derived from muscles, bones, and skin that project to the lower spinal cord (to serve as a source of neural control)

Question 31

For quadruped mammals where is it assumed the neural control of locomotion is based?

Answer 31

CPGs within the spinal cord

Question 32

what does the CPGs network generate?

Answer 32

the rhythm and shapes the pattern of bursts of motor neurons

Question 33

what does the rostral spinal cord network control?

Answer 33

forelimb movement

Question 34

what does the specialised neural circuits within the caudal spinal cord organise?

Answer 34

hindlimb locomotor activity

Question 35

what mediates the coordination of circuits within the caudal spinal cord and rostral spinal cord?

Answer 35

propriospinal neurons with long axons, which couple the cervical and lumbar enlargements of the spinal cord

Question 36

name five key things about propriospinal neurons?

Answer 36

- contained entirely within the spinal cord - may have short segmental or multi-segmental projections - may convey supraspinal descending commands and aid in the integration of these commands with sensory feedback from the body - mediate and coordinate rhythmic motor output involving multiple joints and neurons across several spinal segments - they provide a large proportion of the excitatory and inhibitory inputs that the motor neurons recieve

Question 37

give an example of electrical stimulation with rehabilitation

Answer 37

weight-supported locomotor training and epidural stimulation resulted in walking with assistive devices