Spinal cord Injury- hope for the future?

Question 1

What are the potential processes that can be targeted for therapy after SCI?

Answer 1

1) sprouting of undamaged pathways and regeneration of damaged pathways- formation of new circuits
2) activation of immunological mechanisms
3) secondary injury: compression, ischemia, sodium/calcium mediated cell injury excitotoxicity
4) spinal reorganization of functional sensorimotor networks

Question 2

What clinical intervention have been done to try and promote sprouting ?

Answer 2

anti-NOGO to foster formation of new circuits

anti-Rho to facilitate axonal growth

Question 3

What clinical interventions have been done to try and activate immunological mechanisms ?

Answer 3

autologous macrophage grafts/vaccines to favour axonal growth

Question 4

What clinical interventions have been done to try and prevent secondary damage?

Answer 4

ST ASCIS trials - early decompression/stabilisation

riluzole trial- targeting sodium/glutamate mediated cell injury

Question 5

What clinical interventions have been done to promote spinal reorganization of functional sensorimotor networks?

Answer 5

locomotor training to rehabilitate remnant sensorimotor functions

Question 6

What happens in the secondary response?

Answer 6

it occurs after the physical damage and it is classified as the inflammatory response
- still unsure as to whether promoting or reducing macrophages is beneficial or not

Question 7

What is reparixin and what did it do ?

Answer 7

1 hour after the operation

• it is an antagonist at receptor of cytokine induced neutrophil chemoattractant - these induce recruitment and activation of neutrophils
• it alleviated symptoms in rats after having clip compression SCI

Question 8

What is a reduced inflammatory response associated with ?

Answer 8

it is associated with improvements and this could be linked to sparing of descending pathways

Question 9

What do antibodies against alpha4beta1 integrin do ?

Answer 9

they reduce autonomic dysreflexia and spare serotonergic axons

Question 10

Why is reducing the secondary response useful?

Answer 10

it reduces the loss of spared descending pathways

Question 11

What did anti-alpha 4 do ?

Answer 11

the descending pathways were better maintained and serotonin onto sympathetic neurones seem to be spared

• there was however little improvement for the VH motoneurones
• does appear to be an effective way of treating autonomic dysreflexia

Question 12

When anti-alpha4 was taken to clinical trials what was the outcome?

Answer 12

3 trials later with 1316 patients trialed and there were huge debates over the following conclusion
“an option in the treatment of patients with acute spinal cord injuries that should be undertaken only with the knowledge that the evidence suggesting harmful side effects is more consistent than any suggestion of clinical benefit”
- huge problem with side effects and no clinical benefits
therefore we are not seeing the follow through to clinical trials

Question 13

What were some of the issues in clinical trials involving macrophages?

Answer 13

many patients drop out of clinical trials and majority failed after pre-screen
in the end only 50 patients after pre-screen
patients had to undergo major surgery again - only 2 weeks after the injury - injected around the lesion site

Question 14

What was the outcome of the clinical trial involving macrophage treatment ?

Answer 14

6 months after the surgery it proved there were no improvements with 41% of the controls staying the same while those that were treated 73% remained asia a therefore this indicated the treatment actually had detrimental effects
12 months after the surgery the treated patients were worse off
neither autonomic or motor effects improved

Question 15

What are some of the conclusions from this clinical trial?

Answer 15

• its difficult to get patients to undergo surgery
• the treatment may have needed to be carried out earlier
• also very difficult to treat just around the target area

Question 16

What is meant by the wrong type of macrophages could have been used?

Answer 16

M1= killer cells and they appear to increase 
M2= beneficial macropages and these seem to decrease

Question 17

What treatment was carried out with macrophages and cultured neurones and what was the outcome?

Answer 17

looking at regeneration of neurones in culture and those treated with M1 demonstrated much less regeneration

Question 18

How was excitotoxicity reduced?

Answer 18

by using a sodium channel blocker - mexiletine, phenytoin and riluzole
excitotoxicity is a consequence of secondary damage due to too much glutamate

Question 19

What was the overall effect of sodium channel blockers?

Answer 19

reduce lesion size

improve motor function scores by 5 and 6 weeks later

Question 20

What is a huge flaw in the sodium channel blocker experiment?

Answer 20

the drugs were administered intraperitoneally immediately following the trauma of weight drop - therefore this is not an appropriate model

Question 21

What was the result of sodium channel blockers in clinical trials?

Answer 21

pinprick scores to assess somatosensory recovery

• there were improvements in the drug treated group indicating improvements in somatosensory function
• greatest improvements were in asia b patients but also improvements in asia a

Question 22

Why was the clinical trial for sodium channel blockers better?

Answer 22

given within 12 hours of injury therefore is feasible

given orally or through a nasogastric tube and scaled from effective animal dose

Question 23

What are myelin associated inhibitory factors?

Answer 23

they are inhibitory factors produced by myelin to stop axon growth so that this process doesn’t continually happen in adults

Question 24

In SCI why would inhibiting myelin associated inhibitory factors be beneficial?

Answer 24

it would help to promote re-growth therefore neutralising inhibitory factors would be beneficial

Question 25

What does ROCK activation cause?

Answer 25

it causes collapse of growth cone

Question 26

What would be a more effective method for inhibiting myelin associated inhibitory factors?

Answer 26

it would be more beneficial to target downstream pathways as they are common to the inhibitory factors and therefore should induce a greater effect

Question 27

What factors are produced by oligodendrocytes?

Answer 27

chondroitin sulfate proteoglycans (CSPGs)
myelin associated glycoprotein (MAG)
oligodendrocyte myelin glycoprotein (OMgp)

Question 28

In pre-clinical studies what happened when Rho was inhibited?

Answer 28

there was growth through the lesion

untreated animals still dragged feet whereas the treated animals could walk much better - improved alternation

Question 29

In a mouse/rodent model how was Rho inhibition carried out?

Answer 29

dripped Rho onto SC therefore surgery was requires

- 3mg was the most effective and results were very promising with many moving from asia a to c or even from a to d

Question 30

What can growth factors do ?

Answer 30

they can nurture growth

Question 31

What experiment was carried out with BDNF?

Answer 31

BDNF was either given on its own or attached to collagen binding domain

• within the glial scar there is lots of collagen so attaching BDNF to collagen binding domain ensures that BDNF will accumulate at the specific site
• there was increased neurofilaments within the area and increased GAP43 +ve neurones indicating significant improvements - it is an indicator of whether they are sending out processes

Question 32

What method was carried out to compensate for loss of descending axons?

Answer 32

stimulating below the lesion site as the neurones have still got receptors - either drug stimulation or electrical stimulation

Question 33

What were the results of drug stimulation in cats?

Answer 33

intact cats walk normally whereas cats after having a massive ventral/ventrolateral cord lesion suffer dragging of feet and abnormal walking

• however 75 minutes after intrathecal injection of serotonin agonist (quipazine) improves weight support and regularity of walking pattern
• the recovery was nearly back to intact condition

Question 34

What happens when a cat is put on a treadmill?

Answer 34

it causes activation of afferent pathways
- this activates CPG to help improve movements and helps to reinforce appropriate movements because you get appropriate circuits reforming= sprouting of appropriate circuits

Question 35

What happened when mice were placed on the treadmill?

Answer 35

mice were made bipedal and it induces activation of afferent feedback
- in the treadmill trained mice there are less neurones activated but there are more appropriate neurones activated

Question 36

What happened when treadmill training was carried out on patients?

Answer 36

improved their well being
these were motor incomplete patients
- had training 3 times a week for 12 months
- aim was to set up CPGs

Question 37

What could be the most effective way of improving recovery in SCI patients?

Answer 37

idea of targetting many different aspects to enhance recovery

• epidural stimulation= electrodes onto surface of SC
• epidural stim + serotonin agonist was better than epidiural stim on its own in treadmill trained rats = the alternation was much better

Question 38

Why is combinatorial therapy not always beneficial?

Answer 38

antibody 11c7 was more beneficial alone than when combined with treadmill training - combination had significantly worse results
similar deleterious effects are observed with combination of methylprednisolone and anti-integrin 4 antibodies

Question 39

What was the ultimate combination for locomotion?

Answer 39

treadmill trainign + then epidural tim at 2 different sites (L2 and S1) - this nearly reached full recovery

Question 40

Other than motor function why else is epidural stimulation + training good?

Answer 40

it helps to restore bladder function

- stimulation of 1Hz provided good bladder function indicating improved autonomic function

Question 41

Why is green tea beneficial?

Answer 41

it is a non-conventional treatment

• motor scores are improved by green tea consumption
• reudced inhibitory effects of NOGO
• growth cone collapse with NOGO does not happen with green tea