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?