4. Possible Explanations Reduced Oligodendrocyte Death Enhanced Oligogenesis and Remyelination Does astroglial NF-κB activation contribute to oligodendrocytedeath after injury?
5. Oligodendrocyte Death 1 Week Post-SCI Astroglial NF-κB inactivation reduces oligodendrocyte death 1 week following SCI . (a) Quantification of the number of TUNEL and GSTπ co-labeled cells at 1 week following SCI (n = 3-4). (b) Total GSTπ counts in naïve animals revealed no significant change in total number of oligodendrocytes between WT (n=5) and IκBα-dn (n=4) animals. *, p < 0.05.
6. Fate of oligodendrocytes after spinal cord injury Early mechanism of OL loss - Proteolytic enzymes released from necrotic cells - Free radicals OL particularly vulnerable to oxidative stress - Excitotoxicity(Glu / ATP) - Infiltrating neutrophils and activated microglia (free radicals, cytokines, Glu, and proteases) Chronic OL loss -Wallerian degeneration Almad A. et al. (2011) Neurotherapeutics 8:262-73
23. Combined treatment significantly increases hind limb motor score following SCI. Animals received treatment [vehicle (water), NBQX (30 mg/kg), apocynin (10 mg/kg), or NBQX + apocynin)] 1 hr after injury and daily for 1 week after trauma.
25. Combined inhibition of AMPA receptors and NADPH oxidase reduces descending serotonergic fiber loss after spinal cord injury: 3 mm caudal to lesion epicenter.
26.
27.
28. Astrocyte mediated oligo death is dependent in part upon glutamate-zinc induced NADPH oxidase activity in oligodendrocytes
29.
30. Oligogenesis: what is it, what are the important players, how do we study it? (OPC) CC1+ CC1+/- BrdU: Bromodeoxyuridineis an analog of Thymidine
31. Robust proliferative response 7 weeks post-SCI Serial sections (coronal) Sections are 250mm apart Stereoinvestigator 1 cm Moderate SCI T9 BrdU perfuse and analyze BrdU 6 3 4 5 7 weeks post-SCI 0 1 2 500 mm E 1000 mm -500 mm -1000 mm IkBa-dn Caudal Rostral Sham
34. Microarray Analysis of spinal cords from WT and TG mice following SCI T9 moderate contusion 1.5 cm
35. Lingo-1: Leucine rich repeat and Ig domain containing 1 Lingo-1 is an NgR co-receptor expressed on the surface of oligodendrocytes O/E inhibits oligodendrocyte differentiation and myelination. Mi S. et al. (2005) Nat. Neurosci. 8: 745-751. Lingo-1 antagonists promote CNS remyelination in EAE, Mi S. et al. (2007) Nat. Med. 13: 1228-33. and functional recovery and axonal sprouting in after SCI. Ji B. et al. (2006) Mol. Cell Neurosci. 33: 311-320.
36. Increased cell proliferation and transcriptional activity WT IkBa-dn Ki67 Ki67 marker for cell in cycle SOX-17 : Transcription factor that regulates oligodendrocyte development Sohn J et al. (2006) J. Neuroscience 26: 9722-35 Tcf4 : Oligodendrocyte-related transcription factor Fu H et al. (2009) J. Neurosci29: 11399-408 Sox17 Tcf4
37. Innate immunity-related gene expression WT IkBa-dn CD11b CD11b: Integrin alpha M is a marker expressed by microglia and macrophages. Microglia and mΦ have both destructive and reparative properties after SCI. Jones TB et al. (2005) Curr. Pharm. Des. 11:1223-1236. Macrophage depletion impairs oligodendrocyteremyelination. Kotter MR et al. (2001) Glia 35: 204-212. TLR2 and TLR4 regulate myelin sparing after SCI. Kigerl KA et al. (2007) J Neurochem. 37-50 TLR2 TLR4
51. Evaluate the state of activation of microglia/macrophages between WT and TG mice after SCI by flow cytometry
52.
53. Neurological disorders: Astrocyte dysfunction ? Astrocytes from the contused spinal cord inhibit oligodendrocyte differentiation of adult oligodendrocyte precursor cells Wang Y. et al. (2011) J. Neurosci. 31:6053-58. Transplantation of Specific Human Astrocytes Promotes Functional Recovery after Spinal Cord Injury Stephen J. A. Davies et al. (2011) PLoS One. 6:e17328
