Systemic administration of epothilone D improves functional recovery of walking after rat spinal cord contusion injury

Ruschel, Jörg; Bradke, Frank

doi:10.1016/j.expneurol.2017.12.001

Cited by 47 publications

(46 citation statements)

References 45 publications

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“…Other therapeutic approaches targeted to reduce fibrotic and glial scar formation include suppression of TGF-beta, an upstream regulator of fibroblast proliferation; iron chelation to decrease fibrotic ECM formation; and epothilone B and D treatment to limit pericyte and fibroblast proliferation and migration [29,32,97,98]. Of these, the iron chelator, deferoxamine, and epothilone D have viable safety profiles in humans; however, further work is likely required for both agents to understand their mechanisms of action in SCI.…”

Section: Spinal Cord Injury Therapies Targeting the Glial And Fibrotimentioning

confidence: 99%

Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

2018

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Deficits in neuronal function are a hallmark of spinal cord injury (SCI) and therapeutic efforts are often focused on central nervous system (CNS) axon regeneration. However, secondary injury responses by astrocytes, microglia, pericytes, endothelial cells, Schwann cells, fibroblasts, meningeal cells, and other glia not only potentiate SCI damage but also facilitate endogenous repair. Due to their profound impact on the progression of SCI, glial cells and modification of the glial scar are focuses of SCI therapeutic research. Within and around the glial scar, cells deposit extracellular matrix (ECM) proteins that affect axon growth such as chondroitin sulfate proteoglycans (CSPGs), laminin, collagen, and fibronectin. This dense deposition of material, i.e., the fibrotic scar, is another barrier to endogenous repair and is a target of SCI therapies. Infiltrating neutrophils and monocytes are recruited to the injury site through glial chemokine and cytokine release and subsequent upregulation of chemotactic cellular adhesion molecules and selectins on endothelial cells. These peripheral immune cells, along with endogenous microglia, drive a robust inflammatory response to injury with heterogeneous reparative and pathological properties and are targeted for therapeutic modification. Here, we review the role of glial and inflammatory cells after SCI and the therapeutic strategies that aim to replace, dampen, or alter their activity to modulate SCI scarring and inflammation and improve injury outcomes.

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Section: Spinal Cord Injury Therapies Targeting the Glial And Fibrotimentioning

confidence: 99%

Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

2018

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“…This distal dynamic pool potentially creates free microtubule plus‐ends to allow the polymerization of new microtubules. Accordingly, the microtubule‐disrupting drug nocodazole converts a growth cone into a retraction bulb, whereas moderate stabilization of microtubules using drugs such as taxol, at concentrations that allow microtubule stability in the axon shaft but still some dynamics in the axon tip, leads to the formation of growth cone‐like structures in vitro in DRG neuron cultures (Erturk et al, ) and increased axon regeneration in vivo in adult rats, after either spinal cord injury (Hellal et al, , Ruschel et al, , Ruschel and Bradke, ) or optic nerve injury (Sengottuvel et al, ). It has been suggested that instead of inducing the formation of a normal dynamic growth cone, taxol might promote axon regeneration by enabling the axon tip to become more forceful (Baas and Ahmad, ).…”

Section: The Local Modulation Of Microtubule Dynamics Is Crucial Formentioning

confidence: 99%

Neuronal Intrinsic Regenerative Capacity: The Impact of Microtubule Organization and Axonal Transport

Murillo

Sousa

2018

Developmental Neurobiology

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In the adult vertebrate central nervous system, axons generally fail to regenerate. In contrast, peripheral nervous system axons are able to form a growth cone and regenerate upon lesion. Among the multiple intrinsic mechanisms leading to the formation of a new growth cone and to successful axon regrowth, cytoskeleton organization and dynamics is central. Here we discuss how multiple pathways that define the regenerative capacity converge into the regulation of the axonal microtubule cytoskeleton and transport. We further explore the use of dorsal root ganglion neurons as a model to study the neuronal regenerative ability. Finally, we address some of the unanswered questions in the field, including the mechanisms by which axonal transport might be modulated by injury, and the relationship between microtubule organization, dynamics, and axonal transport. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 00: 000-000, 2018.

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“…It serves as the major track for vesicular transport through the axon shaft, provides structural support to the axon, and, in the distal region of the axon, polymerizing MTs play a critical role in promoting axon elongation and in steering the growth cone in response to environmental cues [1,2]. Given its role in regulating axonal growth, targeting the MT cytoskeleton to enhance axon regeneration after nerve injury has been proposed as a potential therapeutic strategy [3][4][5][6][7][8][9][10][11]. This proposition is supported by studies demonstrating that modulation of MT dynamics in the axon can promote regeneration and attenuate degeneration: for example, multiple studies have found that low doses of MT stabilizing drugs (taxol and epothilones) promote axon regeneration and improve recovery of locomotor function after spinal cord injury (SCI) in rats [5][6][7]11].…”

Section: Introductionmentioning

confidence: 99%

“…Given its role in regulating axonal growth, targeting the MT cytoskeleton to enhance axon regeneration after nerve injury has been proposed as a potential therapeutic strategy [3][4][5][6][7][8][9][10][11]. This proposition is supported by studies demonstrating that modulation of MT dynamics in the axon can promote regeneration and attenuate degeneration: for example, multiple studies have found that low doses of MT stabilizing drugs (taxol and epothilones) promote axon regeneration and improve recovery of locomotor function after spinal cord injury (SCI) in rats [5][6][7]11]. Increasing the density of dynamic MTs in the axon by knocking down the MT severing enzyme fidgetin was also shown to promote axon regeneration after dorsal root crush in rats [9].…”

Section: Introductionmentioning

confidence: 99%

Fidgetin-like 2 is a novel negative regulator of axonal growth and can be targeted to promote functional nerve regeneration after injury

Baker

Tar

Villegas

et al. 2020

Preprint

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The microtubule (MT) cytoskeleton plays a critical role in axon growth and guidance. Here, we identify the MT severing enzyme fidgetin-like 2 (FL2) as a negative regulator of axonal regeneration and a potential therapeutic target for promoting neural regeneration after injury.Genetic knockout of FL2 in cultured adult dorsal root ganglion (DRG) neurons resulted in longer axons and attenuated growth cone retraction in response to inhibitory molecules. Given the axonal growth-promoting effects of FL2 depletion in vitro, we tested whether the enzyme could be targeted to promote regeneration in a rodent model of peripheral nerve injury. In the model used in our experiments, the cavernous nerves (CN) are either crushed or transected, mimicking nerve injury caused by radical prostatectomy (RP). As with patients, CN injury results in erectile dysfunction, for which there are presently poor treatment options. At the time of injury, FL2-siRNA or control-siRNA was applied to the site using nanoparticles or chondroitin sulfate microgels as delivery agents. Treatment significantly enhanced functional nerve recovery, as determined by cavernosometry (measurements of corporal blood pressure in response to electrostimulation of the nerve). Remarkably, following complete bilateral nerve transection, visible and functional nerve regeneration was observed in 7 out of 8 animals treated with FL2-siRNA. In contrast, no control-siRNA treated animals showed regeneration. These observations suggest a novel therapeutic approach to treat peripheral nerve injury, particularly injuries resulting from surgical procedures such as RP, where treatments depleting FL2 could be applied locally at the time of injury.

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Systemic administration of epothilone D improves functional recovery of walking after rat spinal cord contusion injury

Cited by 47 publications

References 45 publications

Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

Neuronal Intrinsic Regenerative Capacity: The Impact of Microtubule Organization and Axonal Transport

Fidgetin-like 2 is a novel negative regulator of axonal growth and can be targeted to promote functional nerve regeneration after injury

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