scholarly journals Thermosensitive collagen/fibrinogen gels loaded with decorin suppress lesion site cavitation and promote functional recovery after spinal cord injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jacob Matthews ◽  
Sarina Surey ◽  
Liam M. Grover ◽  
Ann Logan ◽  
Zubair Ahmed
Keyword(s):  
Drug Delivery ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Dorsal Column ◽  
Dorsal Root Ganglion Neurons ◽  
Sensory Function ◽  
Adult Rats ◽  
Bovine Collagen ◽  
Cord Injury ◽  
Ganglion Neurons

AbstractThe treatment of spinal cord injury (SCI) is a complex challenge in regenerative medicine, complicated by the low intrinsic capacity of CNS neurons to regenerate their axons and the heterogeneity in size, shape and extent of human injuries. For example, some contusion injuries do not compromise the dura mater and in such cases implantation of preformed scaffolds or drug delivery systems may cause further damage. Injectable in situ thermosensitive scaffolds are therefore a less invasive alternative. In this study, we report the development of a novel, flowable, thermosensitive, injectable drug delivery system comprising bovine collagen (BC) and fibrinogen (FB) that forms a solid BC/FB gel (Gel) immediately upon exposure to physiological conditions and can be used to deliver reparative drugs, such as the naturally occurring anti-inflammatory, anti-scarring agent Decorin, into adult rat spinal cord lesion sites. In dorsal column lesions of adult rats treated with the Gel + Decorin, cavitation was completely suppressed and instead lesion sites became filled with injury-responsive cells and extracellular matrix materials, including collagen and laminin. Decorin increased the intrinsic potential of dorsal root ganglion neurons (DRGN) by increasing their expression of regeneration associated genes (RAGs), enhanced local axon regeneration/sprouting, as evidenced both histologically and by improved electrophysiological, locomotor and sensory function recovery. These results suggest that this drug formulated, injectable hydrogel has the potential to be further studied and translated into the clinic.

scholarly journals Dorsal Root Injury—A Model for Exploring Pathophysiology and Therapeutic Strategies in Spinal Cord Injury

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2185
Author(s):  
Håkan Aldskogius ◽  
Elena N. Kozlova
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Dorsal Root ◽  
Molecular Mechanisms ◽  
Dorsal Root Ganglion Neurons ◽  
Descending Pathways ◽  
In Vivo Models ◽  
Root Injury ◽  
Cord Injury ◽  
Ganglion Neurons

Unraveling the cellular and molecular mechanisms of spinal cord injury is fundamental for our possibility to develop successful therapeutic approaches. These approaches need to address the issues of the emergence of a non-permissive environment for axonal growth in the spinal cord, in combination with a failure of injured neurons to mount an effective regeneration program. Experimental in vivo models are of critical importance for exploring the potential clinical relevance of mechanistic findings and therapeutic innovations. However, the highly complex organization of the spinal cord, comprising multiple types of neurons, which form local neural networks, as well as short and long-ranging ascending or descending pathways, complicates detailed dissection of mechanistic processes, as well as identification/verification of therapeutic targets. Inducing different types of dorsal root injury at specific proximo-distal locations provide opportunities to distinguish key components underlying spinal cord regeneration failure. Crushing or cutting the dorsal root allows detailed analysis of the regeneration program of the sensory neurons, as well as of the glial response at the dorsal root-spinal cord interface without direct trauma to the spinal cord. At the same time, a lesion at this interface creates a localized injury of the spinal cord itself, but with an initial neuronal injury affecting only the axons of dorsal root ganglion neurons, and still a glial cell response closely resembling the one seen after direct spinal cord injury. In this review, we provide examples of previous research on dorsal root injury models and how these models can help future exploration of mechanisms and potential therapies for spinal cord injury repair.

scholarly journals Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models

2019 ◽  
Vol 11 (487) ◽  
pp. eaaw2064 ◽  
Author(s):  
Thomas H. Hutson ◽  
Claudia Kathe ◽  
Ilaria Palmisano ◽  
Kay Bartholdi ◽  
Arnau Hervera ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Histone Acetylation ◽  
Neuronal Activity ◽  
Neuronal Plasticity ◽  
Environmental Enrichment ◽  
Dorsal Root Ganglion Neurons ◽  
Motor Functions ◽  
Cord Injury ◽  
Ganglion Neurons

After a spinal cord injury, axons fail to regenerate in the adult mammalian central nervous system, leading to permanent deficits in sensory and motor functions. Increasing neuronal activity after an injury using electrical stimulation or rehabilitation can enhance neuronal plasticity and result in some degree of recovery; however, the underlying mechanisms remain poorly understood. We found that placing mice in an enriched environment before an injury enhanced the activity of proprioceptive dorsal root ganglion neurons, leading to a lasting increase in their regenerative potential. This effect was dependent on Creb-binding protein (Cbp)–mediated histone acetylation, which increased the expression of genes associated with the regenerative program. Intraperitoneal delivery of a small-molecule activator of Cbp at clinically relevant times promoted regeneration and sprouting of sensory and motor axons, as well as recovery of sensory and motor functions in both the mouse and rat model of spinal cord injury. Our findings showed that the increased regenerative capacity induced by enhancing neuronal activity is mediated by epigenetic reprogramming in rodent models of spinal cord injury. Understanding the mechanisms underlying activity-dependent neuronal plasticity led to the identification of potential molecular targets for improving recovery after spinal cord injury.

The Effects of FK506 on Dorsal Column Axons Following Spinal Cord Injury in Adult Rats: Neuroprotection and Local Regeneration

1999 ◽  
Vol 158 (2) ◽  
pp. 382-393 ◽  
Author(s):  
Seb Bavetta ◽  
Peter J. Hamlyn ◽  
Geoffrey Burnstock ◽  
A.Robert Lieberman ◽  
Patrick N. Anderson
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Dorsal Column ◽  
Adult Rats ◽  
Cord Injury

scholarly journals Artemin promotes functional long-distance axonal regeneration to the brainstem after dorsal root crush

2015 ◽  
Vol 112 (19) ◽  
pp. 6170-6175 ◽  
Author(s):  
Laura Elisabeth Wong ◽  
Molly E. Gibson ◽  
H. Moore Arnold ◽  
Blake Pepinsky ◽  
Eric Frank
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Sensory Function ◽  
Long Distance ◽  
Adult Rats ◽  
Sensory Axons ◽  
Sorting Technique ◽  
Cord Injury

Recovery after a spinal cord injury often requires that axons restore synaptic connectivity with denervated targets several centimeters from the site of injury. Here we report that systemic artemin (ARTN) treatment promotes the regeneration of sensory axons to the brainstem after brachial dorsal root crush in adult rats. ARTN not only stimulates robust regeneration of large, myelinated sensory axons to the brainstem, but also promotes functional reinnervation of the appropriate target region, the cuneate nucleus. ARTN signals primarily through the RET tyrosine kinase, an interaction that requires the nonsignaling coreceptor GDNF family receptor (GFRα3). Previous studies reported limited GFRα3 expression on large sensory neurons, but our findings demonstrate that ARTN promotes robust regeneration of large, myelinated sensory afferents. Using a cell sorting technique, we demonstrate that GFRα3 expression is similar in myelinated and unmyelinated adult sensory neurons, suggesting that ARTN likely induces long-distance regeneration by binding GFRα3 and RET. Although ARTN is delivered for just 2 wk, regeneration to the brainstem requires more than 3 mo, suggesting that brief trophic support may initiate intrinsic growth programs that remain active until targets are reached. Given its ability to promote targeted functional regeneration to the brainstem, ARTN may represent a promising therapy for restoring sensory function after spinal cord injury.

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