Multiple Sclerosis<br />Gray Matter and White Matter<br />
	Axonal Degeneration and the Pathogenesis of Multiple Sclerosis<br />Bruce Trapp Department of Neuroscience,School of Medi...
Introduction<br />MS is heterogenous disease<br />Axonal loss is a histopathological correlate to neurological disability<...
Mechanisms of Axonal Injury<br />Immune cell-mediated injury<br />Myelin-reactive T cells<br />Macrophages<br />CD8+ T cel...
Neuroprotective Therapeutic Strategies in MS<br />Na+ channel blockers<br />Phenytoinand carbamazepine<br />Animal studies...
Differential accumulation and roles of chondritin sulfate proteoglycans and laminins during de- and remyelination<br />Lor...
Concept<br />Axons covered by thick myelin sheaths<br />Injury causing demyelination<br />Axons covered by shorter and thi...
Concept<br />Developmental Myelination<br />OPCs<br />Oligo<br />Myelin Assembly<br />Cells of Oligo lineage<br />Myelinat...
Presence of inflammatory agents
Damaged/unhealthy axons
Accumulation of ECM components</li></ul>Understanding the complex interplay between inflammatory molecules, ECM components...
ECM molecules in CNS<br />Laminins<br />Important for allowing cells to spread/extend processes(permissive substrate)<br /...
How does expression of laminin and CSPGs correlate with de- and remyelination?<br />
Animal Model<br />% Demyelination<br />14<br />21<br />CSPG and Laminin staining<br />CSPGs increased expression during de...
Where are these ECM molecules coming from?<br />Macrophages/microglia colocalized with CSPGs (Day 7)<br />Laminincolocaliz...
What happens if we block CSPG biological function?<br />Protein Core<br />Xylazide<br />Attachment of GAG chains<br />CSPG...
What happens if we block CSPG biological function?<br />Day 7<br />The is a loss of CSPG ECM deposition<br />Day 21<br />X...
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American Society for Neurochemistry Meeting Santa Fe, NM Presentation

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American Society for Neurochemistry Meeting Santa Fe, NM Presentation

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  8. 8. Multiple Sclerosis<br />Gray Matter and White Matter<br />
  9. 9. Axonal Degeneration and the Pathogenesis of Multiple Sclerosis<br />Bruce Trapp Department of Neuroscience,School of Medicine, Case Western Reserve University, Cleveland, Ohio<br />
  10. 10. Introduction<br />MS is heterogenous disease<br />Axonal loss is a histopathological correlate to neurological disability<br />Axonal loss thought to be due to loss of trophic factors provided by oligodendrocytes<br />Progessive axon loss occurs from the onset of disease<br />
  11. 11. Mechanisms of Axonal Injury<br />Immune cell-mediated injury<br />Myelin-reactive T cells<br />Macrophages<br />CD8+ T cell-mediated cytotoxicity<br />Glutamate excitotoxicity<br />Demyelinated axons require additional AMPA receptors<br />Leads to accumulation of intracellular Na+ and Ca2+ <br />Nitric oxide (NO)-mediated axonal injury<br />NO secreted from inflammatory cells is associated with axonal damage<br />Na+/Ca2+ channel dysfunction<br />Axonal conduction is a continuous energy dependant process<br />Demyelination disrupts this axonal conduction<br />Na+ channels distributed widely to restore conduction<br />This alterated conduction requires even more energy to function<br />Altered electrical neutrality<br />Also leads to changes in Ca2+ homeostasis<br />Ca2+ mediated degenerative responses and cell death<br />
  12. 12. Neuroprotective Therapeutic Strategies in MS<br />Na+ channel blockers<br />Phenytoinand carbamazepine<br />Animal studies show beneficial effect in chronic EAE but withdrawal of these drugs worsens disease<br />Other Na+ channel blockers are being tested<br />Ca2+ channel blockers<br />Increases Ca2+ influx leads to activation of multiple enzymatic processes<br />Calpain– Ca2+ dependant protease that degrades myelin and axonal elements<br />Calpain-inhibitor (eg CYLA) ameliorates axonal breakdown in EAE models<br />Glutamate antagonists<br />Memantine (NMDA antagonist) and NBQX (AMPA antagonist) ameliorates disability in EAE models<br />Insulin-like growth factor-1 (IGF-1)<br />Improve remyelination by promoting oligo function<br />IGF-1 promotes Oligo growth and maturation <br />But results in EAE are conflicting due to variability of EAE models<br />Erythropoietin (Epo)<br />Hemapoietic growth factor widely expressed in CNS<br />Epo in EAE models show anti-inflammatory and neuroprotective effects<br />Epo treated EAE animals show decreased axonal loss<br />
  13. 13. Differential accumulation and roles of chondritin sulfate proteoglycans and laminins during de- and remyelination<br />Lorraine LauUniversity of Calgary<br />
  14. 14. Concept<br />Axons covered by thick myelin sheaths<br />Injury causing demyelination<br />Axons covered by shorter and thinner myelin<br />
  15. 15. Concept<br />Developmental Myelination<br />OPCs<br />Oligo<br />Myelin Assembly<br />Cells of Oligo lineage<br />Myelinationfollowing injury<br /><ul><li>Incorrect expression of growth factors
  16. 16. Presence of inflammatory agents
  17. 17. Damaged/unhealthy axons
  18. 18. Accumulation of ECM components</li></ul>Understanding the complex interplay between inflammatory molecules, ECM components, and proteases is crucial to promoting repair in MS<br />
  19. 19. ECM molecules in CNS<br />Laminins<br />Important for allowing cells to spread/extend processes(permissive substrate)<br />Expression following demyelinating injury is unknown<br />Chondroitin Sulfate Proteoglycans (CSPGs)<br />Common protein core + glycosaminoglycan (GAG) chains<br />Inhibitory in axonal regeneration<br />Expression following demyelinating injury is also unknown<br />
  20. 20. How does expression of laminin and CSPGs correlate with de- and remyelination?<br />
  21. 21. Animal Model<br />% Demyelination<br />14<br />21<br />CSPG and Laminin staining<br />CSPGs increased expression during demyelination but decreased during remyelination<br />Laminins increased expression during demyelination and this expression persists into remyelination phase<br />
  22. 22. Where are these ECM molecules coming from?<br />Macrophages/microglia colocalized with CSPGs (Day 7)<br />Laminincolocalized with GFAP+ astrocytes (Day 21)<br />
  23. 23. What happens if we block CSPG biological function?<br />Protein Core<br />Xylazide<br />Attachment of GAG chains<br />CSPG exocytosis<br />
  24. 24. What happens if we block CSPG biological function?<br />Day 7<br />The is a loss of CSPG ECM deposition<br />Day 21<br />Xylazide treated animals have a decreased lesion size<br />
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  26. 26. Paraclinical Outcome Measures After Acute Optic Neuritis<br />Optic nerve is site of acute localized inflammatory demyelination<br />Common clinical event during MS<br />Structural and functional assessment of optic nerve is useful for quantitative analysis of axonal degeneration in MS<br />
  27. 27. ECM molecules in CNS<br />Divided into 3 divisions:<br />Basement Membrane<br />Surround blood vessels<br />Perineural Nets<br />Stabilizes synaptic plasticity<br />Neural-interstitial Matrix<br />Matrix between neurons and glia<br />Hyaluronanupregulated following demyelination<br />

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