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Multimodality treatment of spinal cord injury: Endogenous stem cells and other magic bullets

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Department of Neurosciences. Newcastle upon Tyne. Spinal cord injury stats. ... Department of Neurosciences. Newcastle upon Tyne. Endogenous stem cells. From ... – PowerPoint PPT presentation

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Title: Multimodality treatment of spinal cord injury: Endogenous stem cells and other magic bullets


1
Multimodality treatment of spinal cord injury
Endogenous stem cells and other magic bullets
Horn E. M., et al. Barrow Quarterly. Vol 23, no.
1 2007
  • Dr Andrea Whitehead
  • SHO Neurosurgery

2
Background
  • Choice of paper
  • Personal interest, BMedSci
  • Acute traumatic spinal core injury (SCI)
  • Severity linked to force / mechanism of injury
  • Complex cascade of inflammation ischemia ? scar
    formation ? inhibition to regeneration
  • Injury at multiple levels multimodal approach
    to treatment required (neuroprotective
    neuroregenerative)
  • Promising new techniques inc. endogenous stem
    cells for promoting neuroregeneration

3
Spinal cord injury stats.
  • 10,000 14,000 p.a. in US
  • Mean age 30 years
  • Prevalence 150,000 300,000 living with
    disabilities from SCI
  • Complete paralysis mild myelopathy depending on
    mechanism of injury
  • Degenerative spinal disease gt acute traumatic SCI
  • Major morbidity major financial cost
  • Social approach enable disabled people
  • Medical approach overcome physiological
    barriers imposed by injury

4
spinal cord injuries
  • Initial trauma
  • High impact trauma
  • Low impact - degeneration, tumours
  • Shearing, laceration disruption of neurons,
    axons supporting tissues,
  • Scar formation
  • Barrier to repair
  • Ideal treatment
  • 1. Realignment of spinal column to minimise
    further physical cord trauma decompress to
    relieve subsequent ischemia from secondary
    cascade
  • 2. Promote neural regeneration

5
SCI cascade
  • Neuroprotection
  • Attenuate secondary injury cascade
  • Neuroregeneration
  • Promote remyelination and regeneration of axons

6
Research
  • Animal models
  • neuroprotective agents to limit toxicity and
    membrane breakdown
  • Few human trials
  • Main problem of ischemia
  • Disruption of the vasculature ? physical barrier
    to tissue perfusion ? reduced delivery of
    pharmacological agents to injury

7
Neuroprotection
  • High-dose methylprednisolone (Glucocorticoid)
  • stabilise cell membranes
  • reduce vasogenic oedema
  • enhance spinal cord blood flow
  • alter electrolyte concentrations at injury site
  • inhibits endorphin release
  • Scavenge free radicals
  • Limit inflammatory response post injury

8
Methylprednisolone - trials
  • No neurological difference one year post injury
  • Insufficient dose
  • Small but significant improvements in motor
    scores at one year
  • Lack of standardised assessment of functional
    outcome, rather than basic motor scores
  • Greatest benefit within the first 3hours
  • Remains only an option in SCI
  • complications
  • increased incidence of infection
  • Gastrointestinal problems
  • Pulmonary issues
  • Long-term effects
  • Mixed evidence

9
alternatives
  • 4AP
  • K channel antagonist
  • Stabilises axonal membranes during acute injury
    only
  • Riluzole
  • Sodium channel antagonist
  • Improved outcome in animal models
  • Approved for treatment of amyotrophic lateral
    sclerosis
  • Attenuation of inflammatory response
  • COX-2, NSAIDS, tetracycline, erythropoeitin
  • Improved functional recovery
  • Naloxone
  • opiate antagonist
  • No clinical benefit
  • Tiirilazad
  • 21-aminosteriod
  • No benefit
  • No true placebo group
  • GM-1
  • Ganglioside
  • Two randomised trials
  • Improvement in smaller trial not detected in
    larger one
  • Remains an option
  • Other agents with no benefit
  • Thyrotropin-releasing hormone
  • Gacyclidine (NMDA-receptor antagonist)
  • Nimodipine (calcium channel antagonist)

10
Neuroregeneration
  • Scar tissue ? Inhibitors of axonal growth
  • Activated macrophages (Phase II trials)
  • Injected into site injury
  • Reduces concentration of inhibitors
  • Clean cellular debris and damage myelin
  • C3 transferase (Phase II trials)
  • Rho antagonist, applied at surgery
  • Inhibition of degenerating axons, allowing
    regeneration and functional recovery (animal
    models)
  • Stem cell transplantation or stimulation
  • Limited human work ethical dilemma (embryonic
    stem cells)
  • bone marrow stimulation of endogenous stem cells

11
Endogenous stem cells
  • From bone marrow
  • Activation and promotion
  • Animal models endogenous neural progenitor
    cells up-regulated
  • Mostly near ependyma of central canal
  • Induced 3-7days after injury
  • Most ? non-neuronal cells ? inhibition of
    neuroregeneration
  • Can be promoted to develop into cell types which
    help injured axon survival and help regain
    function
  • 2 million new cells at injury site during first
    month after injury

12
Endogenous stem cells
  • Adult stem cell differentiation process
    undefined
  • Agents to control stem cell differentiation
  • Away from astrocytic pathway
  • towards oligodentrocytic pathway
  • Shh (protein)
  • Early neuronal differentiation
  • Increases number of neuronal progenitor cells in
    spinal cord after demyelination (rats)
  • When administered with oligodendroctye precursors
    ?reduced cellular damage improved functional
    recovery (after SCI in rats)
  • bFGF (protein)
  • Increased expression (in rats) after SCI
  • Causes differentiation into neuronal phenotypes

13
Conclusions
  • Acute period
  • Clinical treatment
  • Sub acute period
  • Neuroprotective treatment
  • Delayed period
  • Neuroregenerative treatment
  • Endogenous stem cells?
  • Interesting topic
  • Exciting possibilities
  • Promising results from animal trials
  • Inadequate human trials

14
Any Questions please?
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