Surgical intervention combined with weight-bearing walking training promotes recovery in patients with chronic spinal cord injury:a randomized controlled study

For patients with chronic spinal cord injury,the co nventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection,pressure sores,osteoporosis,and deep vein thrombosis.Surgery is rarely perfo rmed on spinal co rd injury in the chronic phase,and few treatments have been proven effective in chronic spinal cord injury patients.Development of effective therapies fo r chronic spinal co rd injury patients is needed.We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal co rd injury to compare intensive rehabilitation(weight-bearing walking training)alone with surgical intervention plus intensive rehabilitation.This clinical trial was registered at ClinicalTrials.gov(NCT02663310).The goal of surgical intervention was spinal cord detethering,restoration of cerebrospinal fluid flow,and elimination of residual spinal cord compression.We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement,reduced spasticity,and more rapid bowel and bladder functional recovery than weight-bearing walking training alone.Overall,the surgical procedures and intensive rehabilitation were safe.American Spinal Injury Association Impairment Scale improvement was more common in T7-T11 injuries than in T2-T6 injuries.Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.

Data and subject heterogeneity and data sharing:keys to translational success in spinal cord injury research?

Spinal cord injury(SCI)is a highly devastating and com plex inj u ry with many seconda ry consequences.Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys.As a matter of fact,there are still no robust and reliable clinical treatments to minimize or repair spinal cord damage.

GDNF-Enhanced Axonal Regeneration and Myelination Following Spinal Cord Injury is Mediated by Primary Effects on Neurons

我们先前研究表明胶质细胞源性神经营养因子(GDNF)联合施万细胞移植能促进脊髓损伤后轴突再生和髓鞘形成。然而,GDNF介导这一过程的细胞靶点尚不清楚。在此,我们报道了GDNF可增加在体再生轴突的数目和直径,并促进体外背根神经节神经元的轴突向外生长,提示GDNF对神经元有直接作用。在施万细胞-背根神经节神经元共培养下,GDNF显著增加施万细胞生成的髓鞘数目;GDNF处理对孤立培养的施万细胞增殖无作用,但可促进已与神经轴突有突触联系的施万细胞增殖;GDNF可增加孤立施万细胞中分子量为140kDa的神经细胞黏附分子(NCAM)的表达,但对黏附分子L1表达或神经营养因子NGF、NT3及BDNF分泌没有影响。总之,这些结果支持假设:GDNF提高轴突再生和施万细胞髓鞘形成主要是通过GDNF对神经元的直接作用介导的,并且提示GDNF联合施万细胞移植可能是促进脊髓损伤后轴突再生和髓鞘形成的有效策略之一。

Interactions of primary insult biomechanics and secondary cascades in spinal cord injury： implications for therapy

The complex and variable nature of traumatic spinal cord inju- ry （SCI） presents a unique challenge for translational research. SCI is not bound by any demographic nor is it limited to specific injury biomechanics.

Commentary on:“Facilitating transparency in spinal cord injury studies using data standards and ontologies”

Commentary Most would agree that providing comprehensive detail in scientific reporting is critical for the development of mean- ingful therapies and treatments for diseases. Such stellar practices 1） allow for reproduction of experiments to con- firm results, 2） promote thorough analyses of data, and 3） foster the incremental advancement of valid approaches. Unfortunately, most would also agree we have far to go to reach this vital goal （Hackam and Redelmeier, 2006; Prinz et al., 2011; Baker et al., 2014）.

Continued development of azithromycin as a neuroprotective therapeutic for the treatment of spinal cord injury and other neurological conditions

Spinal cord injury(SCI)induces a robust inflammatory response largely mediated by resident microglia and infiltrating macrophages across the blood-brain barrier.While these cell populations are capable of promoting repair and regenerative responses,in the days and weeks after SCI they predominately adopt pro-inflammatory profiles known to inhibit recovery and potentiate secondary injury pathways.

Temporal changes in inflammatory mitochondria-enriched microRNAs following traumatic brain injury and effects of miR-146a nanoparticle delivery

MicroRNAs(miRNAs)are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function.We previously reported that the activities of several mitochondria-enriched miRNAs regulating inflammation(i.e.,miR-142-3p,miR-142-5p,and miR-146a)are altered in the hippocampus at 3–12 hours following a severe traumatic brain injury.In the present study,we investigated the temporal expression profile of these inflammatory miRNAs in mitochondria and cytosol fractions at more chronic post-injury times following severe controlled cortical impact injury in rats.In addition,several inflammatory genes were analyzed in the cytosol fractions.The analysis showed that while elevated levels were observed in cytoplasm,the mitochondria-enriched miRNAs,miR-142-3p and miR-142-5p continued to be significantly reduced in mitochondria from injured hippocampi for at least 3 days and returned to near normal levels at 7 days post-injury.Although not statistically significant,miR-146a also remained at reduced levels for up to 3 days following controlled cortical impact injury,and recovered by 7 days.In contrast,miRNAs that are not enriched in mitochondria,including miR-124a,miR-150,miR-19b,miR-155,and miR-223 were either increased or demonstrated no change in their levels in mitochondrial fractions for 7 days.The one exception was that miR-223 levels were reduced in mitochondria at 1 day following injury.No major alterations were observed in sham operated animals.This temporal pattern was unique to mitochondria-enriched miRNAs and correlated with injury-induced changes in mitochondrial bioenergetics as well as expression levels of several inflammatory markers.These observations suggested a potential compartmental re-distribution of the mitochondria-enriched inflammatory miRNAs and may reflect an intracellular mechanism by which specific miRNAs regulate injury-induced inflammatory signaling.To test this,we utilized a novel peptide-based nanoparticle strategy for in vitro and in vivo delivery of a miR-146a mimic as a potential therapeutic strategy for targeting nuclear factor-kappa B inflammatory modulators in the injured brain.Nanoparticle delivery of miR-146a to BV-2 or SH-SY5Y cells significantly reduced expression of TNF receptor-associated factor 6(TRAF6)and interleukin-1 receptor-associated kinase 1(IRAK1),two important modulators of the nuclear factor-kappa B(NF-κB)pro-inflammatory pathway.Moreover,injections of miR-146a containing nanoparticles into the brain immediately following controlled cortical impact injury significantly reduced hippocampal TNF receptor-associated factor 6 and interleukin-1 receptor-associated kinase 1 levels.Taken together,our studies demonstrate the subcellular alteration of inflammatory miRNAs after traumatic brain injury and establish proof of principle that nanoparticle delivery of miR-146a has therapeutic potential for modulating pro-inflammatory effectors in the injured brain.All of the studies performed were approved by the University of Kentucky Institutional Animal Care and Usage Committee(IACUC protocol#2014-1300)on August 17,2017.

Targeting mitoNEET with pioglitazone for therapeutic neuroprotection after spinal cord injury

There is mounting evidence that targeting mitochondrial dysfunction following neurotrauma could be key in developing effective therapeutic strategies since mitochondria are known to play a major role in cellular bioenergetics, function, and survival following traumatic spinal cord injury （SCI） （Rabchevsky et al., 2011）. Our research group is one of the pioneers in targeting mitochondrial dysfunction to foster functional neuroprotection, having documented that phar- macological maintenance of mitochondrial function acutely results in long-term neuroprotection and improved function- al recover. We have recently reported that treatment with the pleiotropic drug, pioglitazone, maintains acute mitochondrial integrity correlated with chronic tissue sparing and functional recovery after contusion SCI, but that this was not correlated with altered neuroinflammation （Patel et al., 2017）. We herein propose that the mechanism（s） by which pioglitazone confers neuroprotection may not be entirely dependent upon its activation of peroxisome proliferator activated receptor （PPAR）,

Therapeutic implications of advanced age at time of spinal cord injury

A recent demographic shift towards increased age at time of spinal cord injury (SCI), as well as decreased functional recovery following SCI in older populations, create the need to investigate how age effects SCI pathology and repair (Scivoletto et al., 2003). While decreased neuroplasticity or physical strength with age may contribute to functional deficits, work from our lab and others have identified exacerbated acute inflammatory events as contributors to age-dependent secondary injury. Specifically, our recent paper identified that increased production of reactive oxygen species (ROS) from macrophage nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) with age exacerbates secondary injury after SCI (Zhang et al., 2019).

Therapeutic potential of natural compounds from Chinese medicine in acute and subacute phases of ischemic stroke

Stroke is one of the leading causes of death and disability in adults worldwide,resulting in huge social and financial burdens.Extracts from herbs,especially those used in Chinese medicine,have emerged as new pharmaceuticals for stroke treatment.Here we review the evidence from preclinical studies investigating neuroprotective properties of Chinese medicinal compounds through their application in acute and subacute phases of ischemic stroke,and highlight potential mechanisms underlying their therapeutic effects.It is noteworthy that many herbal compounds have been shown to target multiple mechanisms and in combinations may exert synergistic effects on signaling pathways,thereby attenuating multiple aspects of ischemic pathology.We conclude the paper with a general discussion of the prospects for novel natural compound-based regimens against stroke.

Role of mitochondria in regulating micro RNA activity and its relevance to the central nervous system

Mitochondria serve as the powerhouse of cells,respond to cellular demands and stressors,and play an essential role in cell signaling,differentiation,and survival.Aberrant mitochondria function has been linked to diverse and complex human diseases such as neurodegenerative diseases,cancers,myopathies,premature aging,and metabolic syndromes（Nunnari and Suomalainen,2012）.

Targeting ERK1/2-calpain 1-NF-κB signal transduction in secondary tissue damage and astrogliosis after spinal cord injury

Neuronal damage, glial inflammation, and astrogliosis/astroglial scar formation are major secondary injury mechanisms that are significant contributors to functional deficits after spinal cord injury （SCI）. The objectives of the study were to evaluate the distinct roles of ERK2 vs. ERK1/2 and ERK1/2-calpain 1 -NF-r,B signal transduction in the tissue damage and astrogliosis/astroglial scar formation following SCI in rats. RNAi approaches, pharmacological intervention （U0126）, Western blot analysis, immunofluorescence analysis, and histological assessment were used to target ERK1/2-calpain 1-NF-KB signal transduction pathway for neuroprotection. Histological staining analysis demonstrated that selectively reducing pERK2 using ERK2 siRNA, but not inhibition of pERK1/2 with U0126, significantly reduced lesion volume and improved total tissue sparing, white matter sparing, and gray matter sparing in spinal cord two weeks after contusive SCI. An ERK1/2-calpain 1-NF-KB signal transduction pathway was involved in the astroglial scar formation after SCI. Blockade of ERK1/2 by U0126 decreased calpain 1 expression 4 h following SCI. Selective calpain 1 reduction by lentiviral shRNA attenuated astroglial NF-κB activity and astroglial scar formation after SCI in rats. Taken together, these results demonstrate the involvement of individual ERK2 and caipain 1 signaling pathways in tissue damage and astrogliosis/astroglial scar formation in animal models of SCI. Therefore, targeting individual ERK and its downstream signal transduction of calpain 1-NF-κB may provide greater potential as novel therapeutics for minimizing tissue damage and astroglial scar formation following SCI.

Neuronal growth cones and regeneration: gridlock within th extracellular matrix

The extracellular matrix is a diverse composition of glycoproteins and proteoglycans found in all cellular systems. The extracellular matrix, abundant in the mammalian central nervous system, is temporally and spatially regulated and is a dynamic ＂living＂ entity that is reshaped and redesigned on a continuous basis in response to changing needs. Some modifications are adaptive and some are maladaptive. It is the maladaptive responses that pose a significant threat to successful axonal regeneration and/or sprouting following traumatic and spinal cord injuries, and has been the focus of a myriad of research laboratories for many years. This review focuses largely on the extracellular matrix component, chondroitin sulfate proteoglycans, with certain comparisons to heparan sulfate proteoglycans, which tend to serve opposite functions in the central nervous system. Although about equally as well characterized as some of the other proteoglycans such as hyaluronan and dermatan sulfate proteoglycan, chondroitin sulfate proteoglycans are the most widely researched and discussed proteoglycans in the field of axonal injury and regeneration. Four laboratories discuss various aspects of chondroitin sulfate proteoglycans and proteoglycans in general with respect to their structure and function （Beller and Snow）, the recent discovery of specific chondroitin sulfate proteoglycan receptors and what this may mean the field （Shen）, extracellular for increased advancements in matrix degradation by matrix metalloproteinases, which sculpt and resculpt to provide support for outgrowth, synapse formation, and synapse stability （Phillips et al.）, and the perilesion microenvironment with respect to immune system function in response to proteoglycans and central nervous system injuries （Jakeman et al.）.

Proteoglycans: Road Signs for Neurite Outgrowth

Proteoglycans in the central nervous system play integral roles as ＂traffic signals＂ for the direction of neurite outgrowth. This attribute of proteoglycans is a major factor in regeneration of the injured central nervous system. In this review, the structures of proteoglycans and the evidence suggesting their involvement in the response following spinal cord injury are presented. The review further describes the methods routinely used to determine the effect proteoglycans have on neurite outgrowth. The effects of proteoglycans on neurite outgrowth are not completely understood as there is disagreement on what component of the molecule is interacting with growing neurites and this ambiguity is chronicled in an historical context. Finally, the most recent findings suggesting possible receptors, interactions, and sulfation patterns that may be important in eliciting the effect of proteoglycans on neurite outgrowth are discussed. A greater understanding of the proteoglycan-neurite interaction is necessary for successfully promoting regeneration in the iniured central nervous system.

Distinct roles for ERK1 and ERK2 in pathophysiology of CNS

Mitogen-activated protein kinases ERK1 and ERK2 have been implicated in various pathophysiological events of the CNS, but their specific roles in cell processes under physiologic and pathological conditions remain to be determined. ERK1/2 was originally identified as a kinase activity that mediates neuronal survival and neuroprotection, but it was subsequently found that ERK1/2 also plays a critical role in neurodegeneration. This dichotomy makes it difficult to target ERK1/2 for neuroprotection. Accumulating evidence suggests that ERK1 and ERK2 may play distinct functions in a variety of cell fate decisions. In this review, I summarize recent evidence for distinct roles for individual ERK isoforms in pathophysiology of the CNS.