Oligodendrocyte-protection and remyelination post-spinal cord injuries: A review Mina Mekhail a,1 , Guillermina Almazan b,2 , Maryam Tabrizian a,c, * a Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada b Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada c Faculty of Dentistry, McGill University, Montreal, Quebec, Canada Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 2. Oligodendrocyte myelination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 3. Demyelination, dysmyelination and remyelination post-SCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 3.1. Oligodendrocyte necrosis and apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 3.2. Dysmyelination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 Progress in Neurobiology 96 (2012) 322–339 A R T I C L E I N F O Article history: Received 24 July 2011 Received in revised form 9 January 2012 Accepted 19 January 2012 Available online 28 January 2012 Keywords: Spinal cord injuries Remyelination Oligodendrocyte Biomaterials Molecular therapies Drug delivery systems A B S T R A C T In the past four decades, the main focus of investigators in the field of spinal cord regeneration has been to devise therapeutic measures that enhance neural regeneration. More recently, emphasis has been placed on enhancing remyelination and providing oligodendrocyte-protection after a spinal cord injury (SCI). Demyelination post-SCI is part of the cascading secondary injury that takes place immediately after the primary insult; therefore, therapeutic measures are needed to reduce oligodendrocyte death and/or enhance remyelination during the acute stage, preserving neurological functions that would be lost otherwise. In this review a thorough investigation of the oligodendrocyte-protective and remyelinative molecular therapies available to date is provided. The advent of new biomaterials shown to promote remyelination post-SCI is discussed mainly in the context of a combinatorial approach where the biomaterial also provides drug delivery capabilities. The aim of these molecular and biomaterial-based therapies is twofold: (1) oligodendrocyte-protective therapy, which involves protecting already existing oligodendrocytes from undergoing apoptosis/necrosis; and (2) inductive remyelination, which involves harnessing the remyelinative capabilities of endogenous oligodendrocyte precursor cells (OPCs) at the lesion site by providing a suitable environment for their migration, survival, proliferation and differentiation. From the evidence reported in the literature, we conclude that the use of a combinatorial approach including biomaterials and molecular therapies would provide advantages such as: (1) sustained release of the therapeutic molecule, (2) local delivery at the lesion site, and (3) an environment at the site of injury that promotes OPC migration, differentiation and remyelination. ß 2012 Elsevier Ltd. All rights reserved. Abbreviations: SCI, spinal cord injuries; OPCs, oligodendrocyte precursor cells; CNS, central nervous system; MP, methylprednisolone; LIF, leukemia inhibitory factor; LIFR, leukemia inhibitory factor receptor; p75 NTR , p75 neurotrophin receptor; NT-3, neurotrophin 3; BDNF, brain derived neurotrophic factor; NGF, neural growth factor; IGF-1, insulin-like growth factor 1; TNF, tumor necrosis factor; IFN-g, interferon gamma; PR, progesterone; MAG, myelin associated glycoprotein; MBP, myelin basic protein; PLP, proteolipid protein; MOG, myelin oligodendrocyte glycoprotein; GalC, galactocerebroside; GR, glucocorticoid receptor; cIAP2, cellular inhibitor of apoptosis 2; PKA, protein kinase A; Akt, protein kinase B; MAPK, mitogen-activated protein kinases; PI3K, phosphatidylinositol 3-kinases; Olig1, oligodendrocyte transcription factor 1; Olig2, oligodendrocyte transcription factor 2; Nkx-2.2, homeobox protein; BAD, Bcl-2 antagonist of cell death; FKHRL-1, forkhead transcription factor; Bcl-2, B-cell lymphoma 2; RhoA, Ras homolog gene family member A; cAMP, cyclic adenosine monophosphate; PARP, Poly (ADP-ribose) polymerase; PDE4, phosphodiesterase type 4 inhibitor; TrK, tyrosine kinase; CREB, cAMP response element-binding protein. * Corresponding author at: Department of Biomedical Engineering, 3775 University Street - Duff Medical Building, Room 313, McGill University, Montreal, Quebec H3A 2B4, Canada. Tel.: +1 514 398 8129; fax: +1 514 398 7461. E-mail addresses: mina.mekhail@mail.mcgill.ca (M. Mekhail), guillermina.almazan@mcgill.ca (G. Almazan), maryam.tabrizian@mcgill.ca (M. Tabrizian). 1 Department of Biomedical Engineering, 740 Penfield – Genome Building, Room 4300, McGill University, Montreal, Quebec H3A 1A4, Canada. 2 Department of Pharmacology and Therapeutics, 3655 Promenade Sir William Osler – McIntyre Building, Room 1321/1323, McGill University, Montreal, Quebec H3G 1Y6, Canada. Contents lists available at SciVerse ScienceDirect Progress in Neurobiology jo u rn al ho m epag e: ww w.els evier .c om /lo cat e/pn eu ro b io 0301-0082/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2012.01.008