Flashcards in Spinal cord Injury- hope for the future? Deck (41):
What are the potential processes that can be targeted for therapy after SCI?
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
What clinical intervention have been done to try and promote sprouting ?
anti-NOGO to foster formation of new circuits
anti-Rho to facilitate axonal growth
What clinical interventions have been done to try and activate immunological mechanisms ?
autologous macrophage grafts/vaccines to favour axonal growth
What clinical interventions have been done to try and prevent secondary damage?
ST ASCIS trials - early decompression/stabilisation
riluzole trial- targeting sodium/glutamate mediated cell injury
What clinical interventions have been done to promote spinal reorganization of functional sensorimotor networks?
locomotor training to rehabilitate remnant sensorimotor functions
What happens in the secondary response?
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
What is reparixin and what did it do ?
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
What is a reduced inflammatory response associated with ?
it is associated with improvements and this could be linked to sparing of descending pathways
What do antibodies against alpha4beta1 integrin do ?
they reduce autonomic dysreflexia and spare serotonergic axons
Why is reducing the secondary response useful?
it reduces the loss of spared descending pathways
What did anti-alpha 4 do ?
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
When anti-alpha4 was taken to clinical trials what was the outcome?
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
What were some of the issues in clinical trials involving macrophages?
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
What was the outcome of the clinical trial involving macrophage treatment ?
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
What are some of the conclusions from this clinical trial?
- 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
What is meant by the wrong type of macrophages could have been used?
M1= killer cells and they appear to increase
M2= beneficial macropages and these seem to decrease
What treatment was carried out with macrophages and cultured neurones and what was the outcome?
looking at regeneration of neurones in culture and those treated with M1 demonstrated much less regeneration
How was excitotoxicity reduced?
by using a sodium channel blocker - mexiletine, phenytoin and riluzole
excitotoxicity is a consequence of secondary damage due to too much glutamate
What was the overall effect of sodium channel blockers?
reduce lesion size
improve motor function scores by 5 and 6 weeks later
What is a huge flaw in the sodium channel blocker experiment?
the drugs were administered intraperitoneally immediately following the trauma of weight drop - therefore this is not an appropriate model
What was the result of sodium channel blockers in clinical trials?
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
Why was the clinical trial for sodium channel blockers better?
given within 12 hours of injury therefore is feasible
given orally or through a nasogastric tube and scaled from effective animal dose
What are myelin associated inhibitory factors?
they are inhibitory factors produced by myelin to stop axon growth so that this process doesn't continually happen in adults
In SCI why would inhibiting myelin associated inhibitory factors be beneficial?
it would help to promote re-growth therefore neutralising inhibitory factors would be beneficial
What does ROCK activation cause?
it causes collapse of growth cone
What would be a more effective method for inhibiting myelin associated inhibitory factors?
it would be more beneficial to target downstream pathways as they are common to the inhibitory factors and therefore should induce a greater effect
What factors are produced by oligodendrocytes?
chondroitin sulfate proteoglycans (CSPGs)
myelin associated glycoprotein (MAG)
oligodendrocyte myelin glycoprotein (OMgp)
In pre-clinical studies what happened when Rho was inhibited?
there was growth through the lesion
untreated animals still dragged feet whereas the treated animals could walk much better - improved alternation
In a mouse/rodent model how was Rho inhibition carried out?
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
What can growth factors do ?
they can nurture growth
What experiment was carried out with BDNF?
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
What method was carried out to compensate for loss of descending axons?
stimulating below the lesion site as the neurones have still got receptors - either drug stimulation or electrical stimulation
What were the results of drug stimulation in cats?
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
What happens when a cat is put on a treadmill?
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
What happened when mice were placed on the treadmill?
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
What happened when treadmill training was carried out on patients?
improved their well being
these were motor incomplete patients
- had training 3 times a week for 12 months
- aim was to set up CPGs
What could be the most effective way of improving recovery in SCI patients?
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
Why is combinatorial therapy not always beneficial?
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
What was the ultimate combination for locomotion?
treadmill trainign + then epidural tim at 2 different sites (L2 and S1) - this nearly reached full recovery
Other than motor function why else is epidural stimulation + training good?
it helps to restore bladder function
- stimulation of 1Hz provided good bladder function indicating improved autonomic function