Axonal Thinning and Extensive Remyelination without Chronic Demyelination in Spinal Injured Rats (original) (raw)
Related papers
Experimental Neurology, 1998
We previously observed that the transient developmental suppression of myelination or disruption of mature myelin, by local intraspinal infusion of serum complement proteins along with a complement-fixing, myelin-specific antibody (e.g., anti-Galactocerebroside), facilitated avian brainstem-spinal axonal regeneration after spinal transection. We now report the effects of similar immunological protocols on axonal regeneration in the injured adult rat spinal cord. After a lateral hemisection injury of the T10 spinal cord, infusion of the above reagents, over 14 days at T11, facilitated the regeneration of some brainstem-spinal axons. The hemisection lesion enabled comparisons between the retrograde labeling within an injured brainstem-spinal nucleus and the uninjured contralateral homologue. The brainstem-spinal nucleus examined in detail was the red nucleus (RN), chosen for its relatively compact descending pathway within the dorsolateral cord. Comparing the number of labeled neurons within each RN, of an experimentally myelin suppressed animal, indicated that approximately 32% of injured rubrospinal projections had regenerated into the caudal lumbar cord. In contrast, controltreated animals (e.g., PBS vehicle alone, GalC antibody alone, or serum complement alone) showed little or no axonal regeneration. We also examined the ultrastructural appearance of the treated cords. We noted demyelination over 1-2 segments surrounding the infusion site (T11) and a further two segments of myelin disruption (delamination) on either side of the demyelinated zone. The demyelination is an active process (F3 days) with microglia and/or macrophages engulfing myelin. Thus, the facilitation of axonal regeneration through the transient suppression of CNS myelin may be fundamental to all higher vertebrates. 1998 Academic Press
Experimental Neurology, 2016
This article reviews all historical literature in which rodent-derived myelinating cells have been engrafted into the contused adult rodent spinal cord. From 2,500 initial PubMed citations identified, human cells grafts, bone mesenchymal stem cells, olfactory ensheathing cells, nonmyelinating cell grafts, and rodent grafts into hemisection or transection models were excluded, resulting in the 67 studies encompassed in this review. Forty five of those involved central nervous system (CNS)-derived cells, including neural stem progenitor cells (NSPCs), neural restricted precursor cells (NRPs) or oligodendrocyte precursor cells (OPCs), and 22 studies involved Schwann cells (SC). Of the NSPC/NPC/OPC grafts, there was no consistency with respect to the types of cells grafted and/or the additional growth factors or cells co-grafted. Enhanced functional recovery was reported in 31/45 studies, but only 20 of those had appropriate controls making conclusive interpretation of the remaining studies impossible. Of those 20, 19 were properly powered and utilized appropriate statistical analyses. Ten of those 19 studies reported the presence of graft-derived myelin, 3 reported evidence of endogenous remyelination or myelin sparing, and 2 reported both. For the SC grafts, 16/21 reported functional improvement, with 11 having appropriate cellular controls and 9/11 using proper statistical analyses. Of those 9, increased myelin was reported in 6 studies. The lack of consistency and replication among these preclinical studies are discussed with respect to the progression of myelinating cell transplantation therapies into the clinic.
Clinical implications of myelin regeneration in the central nervous system
Expert review of neurotherapeutics, 2018
Amongst strategies to repair the brain, myelin repair offers genuine cause for optimism. Myelin, which sheaths most axons in the central nervous system (CNS), is vital for normal neurological function, as demonstrated by the functional deficits that accrue when it is absent in a range of debilitating myelin diseases. Following demyelination, post-mortem and imaging studies have shown that extensive regeneration of myelin is possible in the human brain. Over recent decades preclinical research has given us a strong understanding of the biology of myelin regeneration, opening up several exciting therapeutic opportunities that are on the cusp of clinical translation. Areas covered: This review discusses diseases that compromise the function of myelin, the endogenous capacity of the CNS to regenerate myelin, and why this sometimes fails. We then outline the extensive progress that has been made towards therapies that promote the regeneration of myelin. Expert commentary: Finally, a comm...
Myelin repair strategies: a cellular view
Current Opinion in Neurology, 2008
Purpose of review-The development of successful myelin repair strategies depends on the detailed knowledge of the cellular and molecular processes underlying demyelination and remyelination in the CNS of animal models and in patients with multiple sclerosis (MS). Based on the complexity of the demyelination and remyelination processes, it should be expected that effective therapeutic approaches will require a combination of strategies for immunomodulation, neuroprotection, and myelin replacement. This brief review highlights recent cellular and molecular findings and indicates that future therapeutic strategies to enhance remyelination may also require combinatorial treatment to accomplish.
Myelin damage and repair in pathologic CNS: challenges and prospects
Frontiers in Molecular Neuroscience, 2015
Alizadeh A, Dyck SM and Karimi-Abdolrezaee S (2015) Myelin damage and repair in pathologic CNS: challenges and prospects. Front. Mol. Neurosci. 8:35. signify the importance of remyelination as a mechanism for improving functions in CNS injuries. In this review, we provide an overview on: (1) the precise organization of myelinated axons and the reciprocal axo-myelin interactions that warrant properly balanced physiological activities within the CNS; (2) underlying cause of demyelination and the structural and functional consequences of demyelination in axons following injury and disease; (3) the endogenous mechanisms of oligodendrocyte replacement;
Remyelination after spinal cord injury: Is it a target for repair?
Progress in Neurobiology, 2014
After spinal cord injury (SCI) there is prolonged and dispersed oligodendrocyte cell death that is responsible for widespread demyelination. To regenerate this lost myelin, many investigators have transplanted myelin-producing cells as a treatment for contusive SCI. There are several documented examples of cellular transplantation improving function after injury, with the degree of myelin regeneration correlating with functional recovery. On the basis of these findings, remyelination is hypothesized to be a beneficial strategy to promote recovery after injury. As cellular transplantation is now entering clinical trials for treatment of SCI, it is important to dissect carefully whether accelerating remyelination after SCI is a valid clinical target. In this review we will discuss the consequences of demyelination and the potential benefits of remyelination as it relates to injury. Prolonged demyelination is hypothesized to enhance axonal vulnerability to degeneration, and is thereby thought to contribute to the axonal degeneration that underlies the permanent functional losses associated with SCI. Currently, strategies to promote remyelination after SCI are largely limited to cellular transplantation. This review discusses those strategies as well as new, and largely untested, modes of therapy that aim to coax endogenous cells residing adjacent to the injury site to differentiate in order to replace lost myelin.
Brain Research Reviews, 2001
Injuries of the spinal cord often result in an irretrievable loss of motor and sensory functions of all body parts situated below the lesion site. Functional recovery is restricted mainly due to the limited regeneration and plasticity of injured axons in the adult central nervous system. Over the last few years different experimental approaches have led to axonal growth and functional benefits in animal models. This review focuses on the effects of the neutralization of myelin-associated neurite growth inhibitors, in particular Nogo-A, using the monoclonal antibody IN-1. Acute mAb IN-1 treatment of adult CNS lesioned rats results in extensive plastic changes of neuronal connections and regenerative fiber growth. In two different lesion paradigms (i.e. pyramidal tract lesion and incomplete spinal cord lesion in adult rats), the mAb IN-1-treated animals always showed a higher degree of recovery in various behavioral tests. These observations, together with electrophysiological results, suggest that neuronal CNS circuits of mAb IN-1-treated animals can be rearranged, and that sprouting and regenerating axons form functionally meaningful connections.