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

2. Department of Neurosciences Newcastle upon Tyne 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. Department of Neurosciences Newcastle upon Tyne 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 > acute traumatic SCI ● Major morbidity = major financial cost ● Social approach = enable disabled people ● Medical approach = overcome physiological barriers imposed by injury

4. Department of Neurosciences Newcastle upon Tyne 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. Department of Neurosciences Newcastle upon Tyne SCI cascade 1. Neuroprotection Attenuate secondary injury cascade 2. Neuroregeneration Promote remyelination and regeneration of axons

6. Department of Neurosciences Newcastle upon Tyne 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. Department of Neurosciences Newcastle upon Tyne 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. Department of Neurosciences Newcastle upon Tyne Methylprednisolone - trials 1. No neurological difference one year post injury Insufficient dose 2. Small but significant improvements in motor scores at one year Lack of standardised assessment of functional outcome, rather than basic motor scores 3. 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. Department of Neurosciences Newcastle upon Tyne alternatives ● 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) ● 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

10. Department of Neurosciences Newcastle upon Tyne 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. Department of Neurosciences Newcastle upon Tyne 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. Department of Neurosciences Newcastle upon Tyne 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. Department of Neurosciences Newcastle upon Tyne Conclusions ● Interesting topic ● Exciting possibilities ● Promising results from animal trials ● Inadequate human trials ● Acute period ● Clinical treatment ● Sub acute period ● Neuroprotective treatment ● Delayed period ● Neuroregenerative treatment ● Endogenous stem cells?

14. Department of Neurosciences Newcastle upon Tyne Any Questions please?