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Therapeutic Strategies to Spinal Cord Injury
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Therapeutic Strategies to Spinal Cord Injury

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 April 2018) | Viewed by 93685

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Assoc. Prof. Pavla Jendelova

E-Mail Website
Guest Editor
Institute of Experimental Medicine, Academy of Sciences of the Czech, Republic, Vídeňská 1083, Prague 142 20, Czech Republic
Interests: spinal cord injury; neuroregeneration; axonal growth; cell therapy; inhibitory molecules; growth factors; astrogliosis; remyelination; neuroinflammation; biomaterials

Special Issue Information

Dear Colleagues,

Traumatic spinal cord injury (SCI) results in an immediate loss of motor and sensory function below the injury site and is associated with a poor prognosis. The inhibitory environment that develops in response to the injury is mainly due to local expression of inhibitory factors, scarring and the formation of cystic cavitations, all of which limit the regenerative capacity of endogenous cells. Current treatment modalities are focused on minimizing secondary injury and maximizing residual function via rehabilitation. Strategies that demonstrate promising results are performed in areas such as cellular therapy, growth factors (BDNF), inhibitory molecules, fibroglial scar, gene therapies, etc. Other promising experimental treatments focus on neuroprotection with hypothermia and pharmacologic therapies, regeneration facilitation via biomaterial transplantation, and rewiring with electrical stimulation. Some strategies have provided encouraging results by themselves; others have been tested as a combination, showing an improved outcome after SCI. Experimental evidence suggests that it is possible to obtain better results with a combination of strategies, which justifies further research for therapeutic approaches. This Special Issue intends to provide the most relevant information about available up-to-date therapeutic strategies that are administered alone or in combination with others, and have offered the best results in neural regeneration after spinal cord injury.

Assoc. Prof. Pavla Jendelova
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • spinal cord injury
  • neuroregeneration
  • axonal growth
  • plasticity
  • cell therapy
  • inhibitory molecules
  • growth factors
  • astrogliosis
  • remyelination
  • neuroinflammation

Published Papers (15 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 164 KiB  
Editorial
Therapeutic Strategies for Spinal Cord Injury
by Pavla Jendelova
Int. J. Mol. Sci. 2018, 19(10), 3200; https://doi.org/10.3390/ijms19103200 - 16 Oct 2018
Cited by 21 | Viewed by 5225
Abstract
n/a Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)

Research

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16 pages, 3309 KiB  
Article
Modified Methacrylate Hydrogels Improve Tissue Repair after Spinal Cord Injury
by Aleš Hejčl, Jiří Růžička, Kristýna Kekulová, Barbora Svobodová, Vladimír Proks, Hana Macková, Kateřina Jiránková, Kristýna Kárová, Lucia Machová Urdziková, Šárka Kubinová, Jiří Cihlář, Daniel Horák and Pavla Jendelová
Int. J. Mol. Sci. 2018, 19(9), 2481; https://doi.org/10.3390/ijms19092481 - 22 Aug 2018
Cited by 27 | Viewed by 4429
Abstract
Methacrylate hydrogels have been extensively used as bridging scaffolds in experimental spinal cord injury (SCI) research. As synthetic materials, they can be modified, which leads to improved bridging of the lesion. Fibronectin, a glycoprotein of the extracellular matrix produced by reactive astrocytes after [...] Read more.
Methacrylate hydrogels have been extensively used as bridging scaffolds in experimental spinal cord injury (SCI) research. As synthetic materials, they can be modified, which leads to improved bridging of the lesion. Fibronectin, a glycoprotein of the extracellular matrix produced by reactive astrocytes after SCI, is known to promote cell adhesion. We implanted 3 methacrylate hydrogels: a scaffold based on hydroxypropylmethacrylamid (HPMA), 2-hydroxyethylmethacrylate (HEMA) and a HEMA hydrogel with an attached fibronectin (HEMA-Fn) in an experimental model of acute SCI in rats. The animals underwent functional evaluation once a week and the spinal cords were histologically assessed 3 months after hydrogel implantation. We found that both the HPMA and the HEMA-Fn hydrogel scaffolds lead to partial sensory improvement compared to control animals and animals treated with plain HEMA scaffold. The HPMA scaffold showed an increased connective tissue infiltration compared to plain HEMA hydrogels. There was a tendency towards connective tissue infiltration and higher blood vessel ingrowth in the HEMA-Fn scaffold. HPMA hydrogels showed a significantly increased axonal ingrowth compared to HEMA-Fn and plain HEMA; while there were some neurofilaments in the peripheral as well as the central region of the HEMA-Fn scaffold, no neurofilaments were found in plain HEMA hydrogels. In conclusion, HPMA hydrogel as well as the HEMA-Fn scaffold showed better bridging qualities compared to the plain HEMA hydrogel, which resulted in very limited partial sensory improvement. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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12 pages, 1545 KiB  
Article
Level-Specific Differences in Systemic Expression of Pro- and Anti-Inflammatory Cytokines and Chemokines after Spinal Cord Injury
by James Hong, Alex Chang, Mohammad-Masoud Zavvarian, Jian Wang, Yang Liu and Michael G. Fehlings
Int. J. Mol. Sci. 2018, 19(8), 2167; https://doi.org/10.3390/ijms19082167 - 25 Jul 2018
Cited by 31 | Viewed by 6133
Abstract
While over half of all spinal cord injuries (SCIs) occur in the cervical region, the majority of preclinical studies have focused on models of thoracic injury. However, these two levels are anatomically distinct—with the cervical region possessing a greater vascular supply, grey-white matter [...] Read more.
While over half of all spinal cord injuries (SCIs) occur in the cervical region, the majority of preclinical studies have focused on models of thoracic injury. However, these two levels are anatomically distinct—with the cervical region possessing a greater vascular supply, grey-white matter ratio and sympathetic outflow relative to the thoracic region. As such, there exists a significant knowledge gap in the secondary pathology at these levels following SCI. In this study, we characterized the systemic plasma markers of inflammation over time (1, 3, 7, 14, 56 days post-SCI) after moderate-severe, clip-compression cervical and thoracic SCI in a rat model. Using high-throughput ELISA panels, we observed a clear level-specific difference in plasma levels of VEGF, leptin, IP10, IL18, GCSF, and fractalkine. Overall, cervical SCI had reduced expression of both pro- and anti-inflammatory proteins relative to thoracic SCI, likely due to sympathetic dysregulation associated with higher level SCIs. However, contrary to the literature, we did not observe level-dependent splenic atrophy with our incomplete SCI model. This is the first study to compare the systemic plasma-level changes following cervical and thoracic SCI using level-matched and time-matched controls. The results of this study provide the first evidence in support of level-targeted intervention and also challenge the phenomenon of high SCI-induced splenic atrophy in incomplete SCI models. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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9 pages, 3231 KiB  
Communication
Application of a Novel Anti-Adhesive Membrane, E8002, in a Rat Laminectomy Model
by Kiyoshi Kikuchi, Kentaro Setoyama, Takuto Terashi, Megumi Sumizono, Salunya Tancharoen, Shotaro Otsuka, Seiya Takada, Kazuki Nakanishi, Koki Ueda, Harutoshi Sakakima, Ko-ichi Kawahara, Ikuro Maruyama, Gohsuke Hattori, Motohiro Morioka, Eiichiro Tanaka and Hisaaki Uchikado
Int. J. Mol. Sci. 2018, 19(5), 1513; https://doi.org/10.3390/ijms19051513 - 18 May 2018
Cited by 6 | Viewed by 3794
Abstract
Neuropathic pain after spinal surgery, so-called failed back surgery syndrome, is a frequently observed common complication. One cause of the pain is scar tissue formation, observed as post-surgical epidural adhesions. These adhesions may compress surrounding spinal nerves, resulting in pain, even after successful [...] Read more.
Neuropathic pain after spinal surgery, so-called failed back surgery syndrome, is a frequently observed common complication. One cause of the pain is scar tissue formation, observed as post-surgical epidural adhesions. These adhesions may compress surrounding spinal nerves, resulting in pain, even after successful spinal surgery. E8002 is an anti-adhesive membrane. In Japan, a clinical trial of E8002 is currently ongoing in patients undergoing abdominal surgery. However, animal experiments have not been performed for E8002 in spinal surgery. We assessed the anti-adhesive effect of E8002 in a rat laminectomy model. The dura matter was covered with an E8002 membrane or left uncovered as a control. Neurological evaluations and histopathological findings were compared at six weeks postoperatively. Histopathological analyses were performed by hematoxylin–eosin and aldehyde fuchsin-Masson Goldner staining. Three assessment areas were selected at the middle and margins of the laminectomy sites, and the numbers of fibroblasts and inflammatory cells were counted. Blinded histopathological evaluation revealed that adhesions and scar formation were reduced in the E8002 group compared with the control group. The E8002 group had significantly lower numbers of fibroblasts and inflammatory cells than the control group. The present results indicate that E8002 can prevent epidural scar adhesions after laminectomy. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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18 pages, 3260 KiB  
Article
The Effect of Human Mesenchymal Stem Cells Derived from Wharton’s Jelly in Spinal Cord Injury Treatment Is Dose-Dependent and Can Be Facilitated by Repeated Application
by Petr Krupa, Irena Vackova, Jiri Ruzicka, Kristyna Zaviskova, Jana Dubisova, Zuzana Koci, Karolina Turnovcova, Lucia Machova Urdzikova, Sarka Kubinova, Svatopluk Rehak and Pavla Jendelova
Int. J. Mol. Sci. 2018, 19(5), 1503; https://doi.org/10.3390/ijms19051503 - 17 May 2018
Cited by 48 | Viewed by 6000
Abstract
Human mesenchymal stem cells derived from Wharton’s jelly (WJ-MSCs) were used for the treatment of the ischemic-compression model of spinal cord injury in rats. To assess the effectivity of the treatment, different dosages (0.5 or 1.5 million cells) and repeated applications were compared. [...] Read more.
Human mesenchymal stem cells derived from Wharton’s jelly (WJ-MSCs) were used for the treatment of the ischemic-compression model of spinal cord injury in rats. To assess the effectivity of the treatment, different dosages (0.5 or 1.5 million cells) and repeated applications were compared. Cells or saline were applied intrathecally by lumbar puncture for one week only, or in three consecutive weeks after injury. Rats were assessed for locomotor skills (BBB, rotarod, flat beam) for 9 weeks. Spinal cord tissue was morphometrically analyzed for axonal sprouting, sparing of gray and white matter and astrogliosis. Endogenous gene expression (Gfap, Casp3, Irf5, Cd86, Mrc1, Cd163) was studied with quantitative Real-time polymerase chain reaction (qRT PCR). Significant recovery of functional outcome was observed in all of the treated groups except for the single application of the lowest number of cells. Histochemical analyses revealed a gradually increasing effect of grafted cells, resulting in a significant increase in the number of GAP43+ fibers, a higher amount of spared gray matter and reduced astrogliosis. mRNA expression of macrophage markers and apoptosis was downregulated after the repeated application of 1.5 million cells. We conclude that the effect of hWJ-MSCs on spinal cord regeneration is dose-dependent and potentiated by repeated application. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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19 pages, 3460 KiB  
Article
Combined Transcriptomics, Proteomics and Bioinformatics Identify Drug Targets in Spinal Cord Injury
by Jure Tica, Elizabeth J. Bradbury and Athanasios Didangelos
Int. J. Mol. Sci. 2018, 19(5), 1461; https://doi.org/10.3390/ijms19051461 - 14 May 2018
Cited by 21 | Viewed by 5460
Abstract
Spinal cord injury (SCI) causes irreversible tissue damage and severe loss of neurological function. Currently, there are no approved treatments and very few therapeutic targets are under investigation. Here, we combined 4 high-throughput transcriptomics and proteomics datasets, 7 days and 8 weeks following [...] Read more.
Spinal cord injury (SCI) causes irreversible tissue damage and severe loss of neurological function. Currently, there are no approved treatments and very few therapeutic targets are under investigation. Here, we combined 4 high-throughput transcriptomics and proteomics datasets, 7 days and 8 weeks following clinically-relevant rat SCI to identify proteins with persistent differential expression post-injury. Out of thousands of differentially regulated entities our combined analysis identified 40 significantly upregulated versus 48 significantly downregulated molecules, which were persistently altered at the mRNA and protein level, 7 days and 8 weeks post-SCI. Bioinformatics analysis was then utilized to identify currently available drugs with activity against the filtered molecules and to isolate proteins with known or unknown function in SCI. Our findings revealed multiple overlooked therapeutic candidates with important bioactivity and established druggability but with unknown expression and function in SCI including the upregulated purine nucleoside phosphorylase (PNP), cathepsins A, H, Z (CTSA, CTSH, CTSZ) and proteasome protease PSMB10, as well as the downregulated ATP citrate lyase (ACLY), malic enzyme (ME1) and sodium-potassium ATPase (ATP1A3), amongst others. This work reveals previously unappreciated therapeutic candidates for SCI and available drugs, thus providing a valuable resource for further studies and potential repurposing of existing therapeutics for SCI. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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19 pages, 15813 KiB  
Article
Perineuronal Nets in Spinal Motoneurones: Chondroitin Sulphate Proteoglycan around Alpha Motoneurones
by Sian F. Irvine and Jessica C. F. Kwok
Int. J. Mol. Sci. 2018, 19(4), 1172; https://doi.org/10.3390/ijms19041172 - 12 Apr 2018
Cited by 27 | Viewed by 6604
Abstract
Perineuronal nets (PNNs) are extracellular matrix structures surrounding neuronal sub-populations throughout the central nervous system, regulating plasticity. Enzymatically removing PNNs successfully enhances plasticity and thus functional recovery, particularly in spinal cord injury models. While PNNs within various brain regions are well studied, much [...] Read more.
Perineuronal nets (PNNs) are extracellular matrix structures surrounding neuronal sub-populations throughout the central nervous system, regulating plasticity. Enzymatically removing PNNs successfully enhances plasticity and thus functional recovery, particularly in spinal cord injury models. While PNNs within various brain regions are well studied, much of the composition and associated populations in the spinal cord is yet unknown. We aim to investigate the populations of PNN neurones involved in this functional motor recovery. Immunohistochemistry for choline acetyltransferase (labelling motoneurones), PNNs using Wisteria floribunda agglutinin (WFA) and chondroitin sulphate proteoglycans (CSPGs), including aggrecan, was performed to characterise the molecular heterogeneity of PNNs in rat spinal motoneurones (Mns). CSPG-positive PNNs surrounded ~70–80% of Mns. Using WFA, only ~60% of the CSPG-positive PNNs co-localised with WFA in the spinal Mns, while ~15–30% of Mns showed CSPG-positive but WFA-negative PNNs. Selective labelling revealed that aggrecan encircled ~90% of alpha Mns. The results indicate that (1) aggrecan labels spinal PNNs better than WFA, and (2) there are differences in PNN composition and their associated neuronal populations between the spinal cord and cortex. Insights into the role of PNNs and their molecular heterogeneity in the spinal motor pools could aid in designing targeted strategies to enhance functional recovery post-injury. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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17 pages, 31926 KiB  
Article
A Single Dose of Atorvastatin Applied Acutely after Spinal Cord Injury Suppresses Inflammation, Apoptosis, and Promotes Axon Outgrowth, Which Might Be Essential for Favorable Functional Outcome
by Katarina Bimbova, Maria Bacova, Alexandra Kisucka, Jaroslav Pavel, Jan Galik, Peter Zavacky, Martin Marsala, Andrea Stropkovska, Jana Fedorova, Stefania Papcunova, Jana Jachova and Nadezda Lukacova
Int. J. Mol. Sci. 2018, 19(4), 1106; https://doi.org/10.3390/ijms19041106 - 07 Apr 2018
Cited by 21 | Viewed by 3892
Abstract
The aim of our study was to limit the inflammatory response after a spinal cord injury (SCI) using Atorvastatin (ATR), a potent inhibitor of cholesterol biosynthesis. Adult Wistar rats were divided into five experimental groups: one control group, two Th9 compression (40 g/15 [...] Read more.
The aim of our study was to limit the inflammatory response after a spinal cord injury (SCI) using Atorvastatin (ATR), a potent inhibitor of cholesterol biosynthesis. Adult Wistar rats were divided into five experimental groups: one control group, two Th9 compression (40 g/15 min) groups, and two Th9 compression + ATR (5 mg/kg, i.p.) groups. The animals survived one day and six weeks. ATR applied in a single dose immediately post-SCI strongly reduced IL-1β release at 4 and 24 h and considerably reduced the activation of resident cells at one day post-injury. Acute ATR treatment effectively prevented the excessive infiltration of destructive M1 macrophages cranially, at the lesion site, and caudally (by 66%, 62%, and 52%, respectively) one day post-injury, whereas the infiltration of beneficial M2 macrophages was less affected (by 27%, 41%, and 16%). In addition, at the same time point, ATR visibly decreased caspase-3 cleavage in neurons, astrocytes, and oligodendrocytes. Six weeks post-SCI, ATR increased the expression of neurofilaments in the dorsolateral columns and Gap43-positive fibers in the lateral columns around the epicenter, and from day 30 to 42, significantly improved the motor activity of the hindlimbs. We suggest that early modulation of the inflammatory response via effects on the M1/M2 macrophages and the inhibition of caspase-3 expression could be crucial for the functional outcome. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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13 pages, 5903 KiB  
Article
Localized Intrathecal Delivery of Mesenchymal Stromal Cells Conditioned Medium Improves Functional Recovery in a Rat Model of Spinal Cord Injury
by Dasa Cizkova, Veronika Cubinkova, Tomas Smolek, Adriana-Natalia Murgoci, Jan Danko, Katarina Vdoviakova, Filip Humenik, Milan Cizek, Jusal Quanico, Isabelle Fournier and Michel Salzet
Int. J. Mol. Sci. 2018, 19(3), 870; https://doi.org/10.3390/ijms19030870 - 15 Mar 2018
Cited by 46 | Viewed by 5374 | Correction
Abstract
It was recently shown that the conditioned medium (CM) of mesenchymal stem cells can enhance viability of neural and glial cell populations. In the present study, we have investigated a cell-free approach via CM from rat bone marrow stromal cells (MScCM) applied intrathecally [...] Read more.
It was recently shown that the conditioned medium (CM) of mesenchymal stem cells can enhance viability of neural and glial cell populations. In the present study, we have investigated a cell-free approach via CM from rat bone marrow stromal cells (MScCM) applied intrathecally (IT) for spinal cord injury (SCI) recovery in adult rats. Functional in vitro test on dorsal root ganglion (DRG) primary cultures confirmed biological properties of collected MScCM for production of neurosphere-like structures and axon outgrowth. Afterwards, rats underwent SCI and were treated with IT delivery of MScCM or vehicle at postsurgical Days 1, 5, 9, and 13, and left to survive 10 weeks. Rats that received MScCM showed significantly higher motor function recovery, increase in spared spinal cord tissue, enhanced GAP-43 expression and attenuated inflammation in comparison with vehicle-treated rats. Spared tissue around the lesion site was infiltrated with GAP-43-labeled axons at four weeks that gradually decreased at 10 weeks. Finally, a cytokine array performed on spinal cord extracts after MScCM treatment revealed decreased levels of IL-2, IL-6 and TNFα when compared to vehicle group. In conclusion, our results suggest that molecular cocktail found in MScCM is favorable for final neuroregeneration after SCI. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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16 pages, 6763 KiB  
Article
FM19G11 and Ependymal Progenitor/Stem Cell Combinatory Treatment Enhances Neuronal Preservation and Oligodendrogenesis after Severe Spinal Cord Injury
by Ana Alastrue-Agudo, Francisco Javier Rodriguez-Jimenez, Eric López Mocholi, Francesca De Giorgio, Slaven Erceg and Victoria Moreno-Manzano
Int. J. Mol. Sci. 2018, 19(1), 200; https://doi.org/10.3390/ijms19010200 - 09 Jan 2018
Cited by 13 | Viewed by 4978
Abstract
Spinal cord injury (SCI) suffers from a lack of effective therapeutic strategies. We have previously shown that individual therapeutic strategies, transplantation of ependymal stem/progenitor cells of the spinal cord after injury (epSPCi) or FM19G11 pharmacological treatment, induce moderate functional recovery after SCI. Here, [...] Read more.
Spinal cord injury (SCI) suffers from a lack of effective therapeutic strategies. We have previously shown that individual therapeutic strategies, transplantation of ependymal stem/progenitor cells of the spinal cord after injury (epSPCi) or FM19G11 pharmacological treatment, induce moderate functional recovery after SCI. Here, the combination of treatments has been assayed for functional and histological analysis. Immediately after severe SCI, one million epSPCi were intramedullary injected, and the FM19G11 compound or dimethyl sulfoxide (DMSO) (as the vehicle control) was administrated via intrathecal catheterization. The combination of treatments, epSPCi and FM19G11, improves locomotor tasks compared to the control group, but did not significantly improve the Basso, Beattie, Bresnahan (BBB) scores for locomotor analysis in comparison with the individual treatments. However, the histological analysis of the spinal cord tissues, two months after SCI and treatments, demonstrated that when we treat the animals with both epSPCi and FM19G11, an improved environment for neuronal preservation was generated by reduction of the glial scar extension. The combinatorial treatment also contributes to enhancing the oligodendrocyte precursor cells by inducing the expression of Olig1 in vivo. These results suggest that a combination of therapies may be an exciting new therapeutic treatment for more efficient neuronal activity recovery after severe SCI. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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Review

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17 pages, 764 KiB  
Review
Translational Regenerative Therapies for Chronic Spinal Cord Injury
by Kyriakos Dalamagkas, Magdalini Tsintou, Amelia Seifalian and Alexander M. Seifalian
Int. J. Mol. Sci. 2018, 19(6), 1776; https://doi.org/10.3390/ijms19061776 - 15 Jun 2018
Cited by 47 | Viewed by 8098
Abstract
Spinal cord injury is a chronic and debilitating neurological condition that is currently being managed symptomatically with no real therapeutic strategies available. Even though there is no consensus on the best time to start interventions, the chronic phase is definitely the most stable [...] Read more.
Spinal cord injury is a chronic and debilitating neurological condition that is currently being managed symptomatically with no real therapeutic strategies available. Even though there is no consensus on the best time to start interventions, the chronic phase is definitely the most stable target in order to determine whether a therapy can effectively restore neurological function. The advancements of nanoscience and stem cell technology, combined with the powerful, novel neuroimaging modalities that have arisen can now accelerate the path of promising novel therapeutic strategies from bench to bedside. Several types of stem cells have reached up to clinical trials phase II, including adult neural stem cells, human spinal cord stem cells, olfactory ensheathing cells, autologous Schwann cells, umbilical cord blood-derived mononuclear cells, adult mesenchymal cells, and autologous bone-marrow-derived stem cells. There also have been combinations of different molecular therapies; these have been either alone or combined with supportive scaffolds with nanostructures to facilitate favorable cell–material interactions. The results already show promise but it will take some coordinated actions in order to develop a proper step-by-step approach to solve impactful problems with neural repair. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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36 pages, 766 KiB  
Review
Activity-Based Physical Rehabilitation with Adjuvant Testosterone to Promote Neuromuscular Recovery after Spinal Cord Injury
by Dana M. Otzel, Jimmy Lee, Fan Ye, Stephen E. Borst and Joshua F. Yarrow
Int. J. Mol. Sci. 2018, 19(6), 1701; https://doi.org/10.3390/ijms19061701 - 07 Jun 2018
Cited by 26 | Viewed by 8187
Abstract
Neuromuscular impairment and reduced musculoskeletal integrity are hallmarks of spinal cord injury (SCI) that hinder locomotor recovery. These impairments are precipitated by the neurological insult and resulting disuse, which has stimulated interest in activity-based physical rehabilitation therapies (ABTs) that promote neuromuscular plasticity after [...] Read more.
Neuromuscular impairment and reduced musculoskeletal integrity are hallmarks of spinal cord injury (SCI) that hinder locomotor recovery. These impairments are precipitated by the neurological insult and resulting disuse, which has stimulated interest in activity-based physical rehabilitation therapies (ABTs) that promote neuromuscular plasticity after SCI. However, ABT efficacy declines as SCI severity increases. Additionally, many men with SCI exhibit low testosterone, which may exacerbate neuromusculoskeletal impairment. Incorporating testosterone adjuvant to ABTs may improve musculoskeletal recovery and neuroplasticity because androgens attenuate muscle loss and the slow-to-fast muscle fiber-type transition after SCI, in a manner independent from mechanical strain, and promote motoneuron survival. These neuromusculoskeletal benefits are promising, although testosterone alone produces only limited functional improvement in rodent SCI models. In this review, we discuss the (1) molecular deficits underlying muscle loss after SCI; (2) independent influences of testosterone and locomotor training on neuromuscular function and musculoskeletal integrity post-SCI; (3) hormonal and molecular mechanisms underlying the therapeutic efficacy of these strategies; and (4) evidence supporting a multimodal strategy involving ABT with adjuvant testosterone, as a potential means to promote more comprehensive neuromusculoskeletal recovery than either strategy alone. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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14 pages, 947 KiB  
Review
Stem Cells Therapy for Spinal Cord Injury
by Marina Gazdic, Vladislav Volarevic, C. Randall Harrell, Crissy Fellabaum, Nemanja Jovicic, Nebojsa Arsenijevic and Miodrag Stojkovic
Int. J. Mol. Sci. 2018, 19(4), 1039; https://doi.org/10.3390/ijms19041039 - 30 Mar 2018
Cited by 84 | Viewed by 15818
Abstract
Spinal cord injury (SCI), a serious public health issue, most likely occurs in previously healthy young adults. Current therapeutic strategies for SCI includes surgical decompression and pharmacotherapy, however, there is still no gold standard for the treatment of this devastating condition. Inefficiency and [...] Read more.
Spinal cord injury (SCI), a serious public health issue, most likely occurs in previously healthy young adults. Current therapeutic strategies for SCI includes surgical decompression and pharmacotherapy, however, there is still no gold standard for the treatment of this devastating condition. Inefficiency and adverse effects of standard therapy indicate that novel therapeutic strategies are required. Because of their neuroregenerative and neuroprotective properties, stem cells are a promising tool for the treatment of SCI. Herein, we summarize and discuss the promising therapeutic potential of human embryonic stem cells (hESC), induced pluripotent stem cells (iPSC) and ependymal stem/progenitor cells (epSPC) for SCI. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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15 pages, 860 KiB  
Review
Stress-Activated Protein Kinases in Spinal Cord Injury: Focus on Roles of p38
by Yoshitoshi Kasuya, Hiroki Umezawa and Masahiko Hatano
Int. J. Mol. Sci. 2018, 19(3), 867; https://doi.org/10.3390/ijms19030867 - 15 Mar 2018
Cited by 39 | Viewed by 5942
Abstract
Spinal cord injury (SCI) consists of three phases—acute, secondary, and chronic damages—and limiting the development of secondary damage possibly improves functional recovery after SCI. A major component of the secondary phase of SCI is regarded as inflammation-triggered events: induction of cytokines, edema, microglial [...] Read more.
Spinal cord injury (SCI) consists of three phases—acute, secondary, and chronic damages—and limiting the development of secondary damage possibly improves functional recovery after SCI. A major component of the secondary phase of SCI is regarded as inflammation-triggered events: induction of cytokines, edema, microglial activation, apoptosis of cells including oligodendrocytes and neurons, demyelination, formation of the astrocytic scar, and so on. Two major stress-activated protein kinases (SAPKs)—c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK)—are activated in various types of cells in response to cellular stresses such as apoptotic stimuli and inflammatory waves. In animal models of SCI, inhibition of either JNK or p38 has been shown to promote neuroprotection-associated functional recovery. Here, we provide an overview on the roles of SAPKs in SCI and, in particular, the pathological role of p38 will be discussed as a promising target for therapeutic intervention in SCI. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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Other

2 pages, 2075 KiB  
Correction
Correction: Cizkova, D., et al. Localized Intrathecal Delivery of Mesenchymal Stromal Cells Conditioned Media Improves Functional Recovery in A Rat Model of Contusive Spinal Cord Injury. Int. J. Mol. Sci. 2018, 19, 870
by Dasa Cizkova, Veronika Cubinkova, Tomas Smolek, Adriana-Natalia Murgoci, Jan Danko, Katarina Vdoviakova, Filip Humenik, Milan Cizek, Jusal Quanico, Isabelle Fournier and Michel Salzet
Int. J. Mol. Sci. 2018, 19(7), 1942; https://doi.org/10.3390/ijms19071942 - 02 Jul 2018
Cited by 2 | Viewed by 2777
Abstract
In lieu of an abstract, this is an excerpt from the first page. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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