Neuroprotection and secondary damage following spinal cord injury: concepts and methods

Hilton, Brett J.; Moulson, Aaron J.; Tetzlaff, Wolfram

doi:10.1016/j.neulet.2016.12.004

Cited by 82 publications

(55 citation statements)

References 103 publications

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“…After adult injury, astrocytes become reactive and direct the formation of a scar at the injury site by walling off a core of cells, including fibroblasts, macrophages, NG2 glia, pericytes and ependymal cells (Cregg et al, 2014). This response to injury serves an important purpose: in directing scar formation, astrocytes mitigate inflammatory damage and are thus neuroprotective (Faulkner et al, 2004;Hilton et al, 2016b). However, many scar cells inhibit axon growth, typically by physically interacting with the distal tips of axons (Filous et al, 2014) or by secreting ECM molecules such as CSPGs (Burnside and Bradbury, 2014;Cregg et al, 2014;Tan et al, 2011).…”

Section: Astrocytes and The Lesion Site Scarmentioning

confidence: 99%

Can injured adult CNS axons regenerate by recapitulating development?

2017

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In the adult mammalian central nervous system (CNS), neurons typically fail to regenerate their axons after injury. During development, by contrast, neurons extend axons effectively. A variety of intracellular mechanisms mediate this difference, including changes in gene expression, the ability to form a growth cone, differences in mitochondrial function/axonal transport and the efficacy of synaptic transmission. In turn, these intracellular processes are linked to extracellular differences between the developing and adult CNS. During development, the extracellular environment directs axon growth and circuit formation. In adulthood, by contrast, extracellular factors, such as myelin and the extracellular matrix, restrict axon growth. Here, we discuss whether the reactivation of developmental processes can elicit axon regeneration in the injured CNS.

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Section: Astrocytes and The Lesion Site Scarmentioning

confidence: 99%

Can injured adult CNS axons regenerate by recapitulating development?

2017

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“…Since affected individuals are often young adults, the long term social impact of SCI is enormous. Although physical trauma is the initiating event, the final extent of functional loss in SCI is governed by secondary pathophysiological processes which propagate damage radially along the cord from the lesion epicentre [39]. Many deleterious mechanisms are involved in the secondary phase, including neuronal calcium dyshomeostasis, glutamate excitotoxicity, oxidative stress, ischemia/reperfusion, inflammatory cell recruitment and activation, cytoskeletal proteolysis, and both apoptotic and necrotic cell death [40,41].…”

Section: Role Of Lde In Spinal Cord Injurymentioning

confidence: 99%

Carbonyl scavengers as pharmacotherapies in degenerative disease: Hydralazine repurposing and challenges in clinical translation

Burcham

2018

Biochemical Pharmacology

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During cellular metabolism, spontaneous oxidative damage to unsaturated lipids generates many electrophilic carbonyl compounds that readily attack cell macromolecules, forming adducts that are potential drivers of tissue dysfunction. Since such damage is heightened in many degenerative conditions, researchers have assessed the efficacy of nucleophilic carbonyl-trapping drugs in animal models of such disorders, anticipating that they will protect tissues by intercepting toxic lipid-derived electrophiles (LDEs) within cells. This Commentary explores recent animal evidence for carbonyl scavenger efficacy in two disparate yet significant conditions known to involve LDE production, namely spinal cord injury (SCI) and alcoholic liver disease (ALD). Primary emphasis is placed on studies that utilised hydralazine, a clinically-approved "broad-spectrum" scavenger known to trap multiple LDEs. In addition to reviewing recent studies of hydralazine efficacy in animal SCI and ALD models, the Commentary reviews new insights concerning novel lifespan- and healthspan-extending properties of hydralazine obtained during studies in model invertebrate organisms, since the mechanisms involved seem of likely benefit during the treatment of degenerative disease. Finally, noting that human translation of the histoprotective properties of hydralazine have been limited, the final section of the Commentary will address two obstacles that hamper clinical translation of LDE-trapping therapies while also suggesting potential strategies for overcoming these problems.

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“…The pathobiology of SCI can be split into the initial trauma (primary damage) followed by a secondary phase. The secondary phase of injury involves a cascade of ischemia, inflammation, and cell death including, and of importance in this review, oligodendrocytes (Crowe, Bresnahan, Shuman, Masters, & Beattie, 1997;Hilton, Moulson, & Tetzlaff, 2017;Kwon, Tetzlaff, Grauer, Beiner, & Vaccaro, 2004;Norenberg, Smith, & Marcillo, 2004). Oligodendrocytes are susceptive to damage from reactive oxygen species, excitotoxicity, extracellular ATP, and pro-inflammatory cytokines all of which are present following SCI (Crowe et al, 1997;Giacci et al, 2018;Plemel et al, 2014).…”

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confidence: 99%

The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury

Duncan

Manesh

Hilton

et al. 2019

Glia

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Oligodendrocyte progenitor cells (OPCs) are the most proliferative and dispersed population of progenitor cells in the adult central nervous system, which allows these cells to rapidly respond to damage. Oligodendrocytes and myelin are lost after traumatic spinal cord injury (SCI), compromising efficient conduction and, potentially, the long‐term health of axons. In response, OPCs proliferate and then differentiate into new oligodendrocytes and Schwann cells to remyelinate axons. This culminates in highly efficient remyelination following experimental SCI in which nearly all intact demyelinated axons are remyelinated in rodent models. However, myelin regeneration comprises only one role of OPCs following SCI. OPCs contribute to scar formation after SCI and restrict the regeneration of injured axons. Moreover, OPCs alter their gene expression following demyelination, express cytokines and perpetuate the immune response. Here, we review the functional contribution of myelin regeneration and other recently uncovered roles of OPCs and their progeny to repair following SCI.

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Neuroprotection and secondary damage following spinal cord injury: concepts and methods

Cited by 82 publications

References 103 publications

Can injured adult CNS axons regenerate by recapitulating development?

Can injured adult CNS axons regenerate by recapitulating development?

Carbonyl scavengers as pharmacotherapies in degenerative disease: Hydralazine repurposing and challenges in clinical translation

The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury

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