Genetic Ablation of Soluble TNF Does Not Affect Lesion Size and Functional Recovery after Moderate Spinal Cord Injury in Mice

Traumatic spinal cord injury (SCI) is followed by an instant increase in expression of the microglial-derived proinflammatory cytokine tumor necrosis factor (TNF) within the lesioned cord. TNF exists both as membrane-anchored TNF (mTNF) and as cleaved soluble TNF (solTNF). We previously demonstrated that epidural administration of a dominant-negative inhibitor of solTNF, XPro1595, to the contused spinal cord resulted in changes in Iba1 protein expression in microglia/macrophages, decreased lesion volume, and improved locomotor function. Here, we extend our studies using mice expressing mTNF, but no solTNF (mTNFΔ/Δ), to study the effect of genetic ablation of solTNF on SCI. We demonstrate that TNF levels were significantly decreased within the lesioned spinal cord 3 days after SCI inmTNFΔ/Δmice compared to littermates. This decrease did, however, not translate into significant changes in other pro- and anti-inflammatory cytokines (IL-10, IL-1β, IL-6, IL-5, IL-2, CXCL1, CCL2, or CCL5), despite a tendency towards increased IL-10 and decreased IL-1β, TNFR1, and TNFR2 levels inmTNFΔ/Δmice. In addition, microglial and leukocyte infiltration, activation state (Iba1, CD11b, CD11c, CD45, and MHCII), lesion size, and functional outcome after moderate SCI were comparable between genotypes. Collectively, our data demonstrate that genetic ablation of solTNF does not significantly modulate postlesion outcome after SCI.

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Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in Mice

Cells ◽

10.3390/cells9112407 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2407

Author(s):

Ditte Gry Ellman ◽

Minna Christiansen Lund ◽

Maiken Nissen ◽

Pernille Sveistrup Nielsen ◽

Charlotte Sørensen ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Outcome ◽

Myeloid Cells ◽

Myeloid Cell ◽

Lesion Size ◽

Signaling Cascades ◽

Lesion Volume ◽

Cord Injury ◽

Cytokine Tumor Necrosis Factor

Spinal cord injury (SCI) is a devastating condition consisting of an instant primary mechanical injury followed by a secondary injury that progresses for weeks to months. The cytokine tumor necrosis factor (TNF) plays an important role in the pathophysiology of SCI. We investigated the effect of myeloid TNF ablation (peripheral myeloid cells (macrophages and neutrophils) and microglia) versus central myeloid TNF ablation (microglia) in a SCI contusion model. We show that TNF ablation in macrophages and neutrophils leads to reduced lesion volume and improved functional outcome after SCI. In contrast, TNF ablation in microglia only or TNF deficiency in all cells had no effect. TNF levels tended to be decreased 3 h post-SCI in mice with peripheral myeloid TNF ablation and was significantly decreased 3 days after SCI. Leukocyte and microglia populations and all other cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and IFNγ) and chemokines (CCL2, CCL5, and CXCL1) investigated, in addition to TNFR1 and TNFR2, were comparable between genotypes. Analysis of post-SCI signaling cascades demonstrated that the MAPK kinase SAPK/JNK decreased and neuronal Bcl-XL levels increased post-SCI in mice with ablation of TNF in peripheral myeloid cells. These findings demonstrate that peripheral myeloid cell-derived TNF is pathogenic in SCI.

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Inhibition of astroglial nuclear factor κB reduces inflammation and improves functional recovery after spinal cord injury

Journal of Experimental Medicine ◽

10.1084/jem.20041918 ◽

2005 ◽

Vol 202 (1) ◽

pp. 145-156 ◽

Cited By ~ 316

Author(s):

Roberta Brambilla ◽

Valerie Bracchi-Ricard ◽

Wen-Hui Hu ◽

Beata Frydel ◽

Annmarie Bramwell ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Transforming Growth Factor ◽

Dominant Negative ◽

Dramatic Improvement ◽

Lesion Volume ◽

Nuclear Factor ◽

Protective Effects ◽

Cord Injury

In the central nervous system (CNS), the transcription factor nuclear factor (NF)-κB is a key regulator of inflammation and secondary injury processes. After trauma or disease, the expression of NF-κB–dependent genes is highly activated, leading to both protective and detrimental effects on CNS recovery. We demonstrate that selective inactivation of astroglial NF-κB in transgenic mice expressing a dominant negative (dn) form of the inhibitor of κBα under the control of an astrocyte-specific promoter (glial fibrillary acidic protein [GFAP]–dn mice) leads to a dramatic improvement in functional recovery 8 wk after contusive spinal cord injury (SCI). Histologically, GFAP mice exhibit reduced lesion volume and substantially increased white matter preservation. In parallel, they show reduced expression of proinflammatory chemokines and cytokines, such as CXCL10, CCL2, and transforming growth factor–β2, and of chondroitin sulfate proteoglycans participating in the formation of the glial scar. We conclude that selective inhibition of NF-κB signaling in astrocytes results in protective effects after SCI and propose the NF-κB pathway as a possible new target for the development of therapeutic strategies for the treatment of SCI.

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Genetic Ablation of Transcription Repressor Bach1 Reduces Neural Tissue Damage and Improves Locomotor Function after Spinal Cord Injury in Mice

Journal of Neurotrauma ◽

10.1089/neu.2008.0667 ◽

2009 ◽

Vol 26 (1) ◽

pp. 31-39 ◽

Cited By ~ 33

Author(s):

Haruo Kanno ◽

Hiroshi Ozawa ◽

Yoshihiro Dohi ◽

Akira Sekiguchi ◽

Kazuhiko Igarashi ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Tissue Damage ◽

Neural Tissue ◽

Locomotor Function ◽

Genetic Ablation ◽

Cord Injury

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Beneficial Effect of the Traditional Chinese Drug Shu-Xue-Tong on Recovery of Spinal Cord Injury in the Rat

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2011/862197 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Li-Yun Jia ◽

An-Hui Yao ◽

Fang Kuang ◽

Yu-Kai Zhang ◽

Xue-Feng Shen ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Blood Flow ◽

Histological Analysis ◽

Lesion Size ◽

Chinese Drug ◽

Sprague Dawley ◽

Spinal Cord Blood Flow ◽

Doppler Flowmetry ◽

Cord Injury

Shu-Xue-Tong (SXT) is a traditional Chinese drug widely used to ameliorate stagnation of blood flow, such as brain or myocardial infarction. Whether SXT may have therapeutic value for spinal cord injury (SCI), during which ischemia plays an important role in its pathology, remains to be elucidated. We hypothesized that SXT may promote SCI healing by improving spinal cord blood flow (SCBF), and a study was thus designed to explore this possibility. Twenty-five male Sprague-Dawley rats were used. SCI was induced by compression, and SXT was administrated 24 h postinjury for 14 successive days. The effects of SXT were assessed by means of laser-Doppler flowmetry, motor functional analysis (open-field walking and footprint analysis), and histological analysis (hematoxylin-eosin and thionin staining and NeuN immunohistochemistry). SXT significantly promoted SCBF of the contused spinal cord and enhanced the recovery of motor function. Histological analysis indicated that the lesion size was reduced, the pathological changes were ameliorated, and more neurons were preserved. Based on these results we conclude that SXT can effectively improve SCI.

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Galantamine improves functional recovery and reduces lesion size in a rat model of spinal cord injury

Brain Research ◽

10.1016/j.brainres.2019.146424 ◽

2019 ◽

Vol 1724 ◽

pp. 146424 ◽

Cited By ~ 1

Author(s):

Laura E. Sperling ◽

Karina Pires Reis ◽

Fabricio Nicola ◽

Cristian Euzebio Teixeira ◽

Gabriele Gulielmin Didó ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Rat Model ◽

Lesion Size ◽

Cord Injury

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CCL3 contributes to secondary damage after spinal cord injury

Journal of Neuroinflammation ◽

10.1186/s12974-020-02037-3 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Nicolas Pelisch ◽

Jose Rosas Almanza ◽

Kyle E. Stehlik ◽

Brandy V. Aperi ◽

Antje Kroner

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Lesion Size ◽

Secondary Injury ◽

Wild Type ◽

Locomotor Recovery ◽

Secondary Damage ◽

Cord Injury

Abstract Background Secondary damage after spinal cord injury (SCI) is characterized by a cascade of events including hemorrhage, apoptosis, oxidative stress, and inflammation which increase the lesion size which can influence the functional impairment. Thus, identifying specific mechanisms attributed to secondary injury is critical in minimizing tissue damage and improving neurological outcome. In this work, we are investigating the role of CCL3 (macrophage inflammatory protein 1-α, MIP-1α), a chemokine involved in the recruitment of inflammatory cells, which plays an important role in inflammatory conditions of the central and peripheral nervous system. Methods A mouse model of lower thoracic (T11) spinal cord contusion injury was used. We assessed expression levels of CCL3 and its receptors on the mRNA and protein level and analyzed changes in locomotor recovery and the inflammatory response in the injured spinal cord of wild-type and CCL3−/− mice. Results The expression of CCL3 and its receptors was increased after thoracic contusion SCI in mice. We then examined the role of CCL3 after SCI and its direct influence on the inflammatory response, locomotor recovery and lesion size using CCL3−/− mice. CCL3−/− mice showed mild but significant improvement of locomotor recovery, a smaller lesion size and reduced neuronal damage compared to wild-type controls. In addition, neutrophil numbers as well as the pro-inflammatory cytokines and chemokines, known to play a deleterious role after SCI, were markedly reduced in the absence of CCL3. Conclusion We have identified CCL3 as a potential target to modulate the inflammatory response and secondary damage after SCI. Collectively, this study shows that CCL3 contributes to progressive tissue damage and functional impairment during secondary injury after SCI.

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Mesenchymal stem cells overexpressing IL-13 decrease lesion size and demyelination after spinal cord injury

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2014.08.429 ◽

2014 ◽

Vol 275 (1-2) ◽

pp. 160

Author(s):

Dearbhaile Dooley ◽

Evi Lemmens ◽

Tim Vangansewinkel ◽

Stefanie Lemmens ◽

Nathalie De Vocht ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Lesion Size ◽

Cord Injury

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Magnetic resonance imaging versus histological assessment for estimation of lesion volume after experimental spinal cord injury

Journal of Neurosurgery Spine ◽

10.3171/spi/2008/9/9/301 ◽

2008 ◽

Vol 9 (3) ◽

pp. 301-306 ◽

Cited By ~ 14

Author(s):

David S. Ditor ◽

Sunil John ◽

Jason Cakiroglu ◽

Colin Kittmer ◽

Paula J. Foster ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Mr Imaging ◽

Mean Difference ◽

Lesion Volume ◽

Perfect Agreement ◽

Experimental Spinal Cord Injury ◽

Cord Injury ◽

The Mean ◽

The Difference

Object The purpose of this study was to compare measures of lesion volume obtained by means of 1.5-T MR imaging to those obtained by the Cavalieri method, 6 weeks after experimental spinal cord injury. Methods Nine male Wistar rats were subjected to spinal cord injury by clip compression (50 g) at the T-4 level. Six weeks postinjury, the rats were sacrificed, and spinal cords were analyzed ex vivo for lesion volume by means of 1.5-T MR imaging and subsequently, by the Cavalieri method. In the latter method, cords were cut longitudinally in 25-μm sections and stained with solochrome cyanin for myelin. The area of the lesion was determined for each serial section, and the distance-weighted sum of all area measures was then calculated to estimate the total lesion volume. Results Bland–Altman analysis showed that the 2 methods had an acceptable level of agreement for lesion volume estimation, but the Cavalieri method was prone to an overestimation bias. The MR imaging estimates of lesion volume were greater than the Cavalieri method estimates in 3 spinal cords, but the difference between measures was within 1 standard deviation of perfect agreement in these 3 lesions, and the mean difference between measures was 18.3%. In contrast, in those lesions in which the Cavalieri method yielded larger lesion volumes (5 lesions), the difference between measures was 2 standard deviations away from perfect agreement for 2 animals and the mean difference between measures was 72.4%. Conclusions The results illustrate that the overestimation bias of the Cavalieri method is due, in part, to artifacts produced during processing of the spinal cord tissue.

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Mechanisms of Behavioral Changes After Spinal Cord Injury

Oxford Research Encyclopedia of Neuroscience ◽

10.1093/acrefore/9780190264086.013.245 ◽

2019 ◽

Cited By ~ 3

Author(s):

Karim Fouad ◽

Abel Torres-Espín ◽

Keith K. Fenrich

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Motor Function ◽

Lesion Size ◽

Behavioral Changes ◽

Sensory Function ◽

Wide Range ◽

Cord Injury ◽

New Treatment ◽

Recovery Of Motor Function

Spinal cord injury results in a wide range of behavioral changes including impaired motor and sensory function, autonomic dysfunction, spasticity, and depression. Currently, restoring lost motor function is the most actively studied and sought-after goal of spinal cord injury research. This research is rooted in the fact that although self-repair following spinal cord injury in adult mammals is very limited, there can be some recovery of motor function. This recovery is strongly dependent on the lesion size and location as well as on neural activity of denervated networks activated mainly through physical activity (i.e., rehabilitative training). Recovery of motor function is largely due to neuroplasticity, which includes adaptive changes in spared and injured neural circuitry. Neuroplasticity after spinal cord injury is extensive and includes mechanisms such as moderate axonal sprouting, the formation of new synaptic connections, network remapping, and changes to neuron cell properties. Neuroplasticity after spinal cord injury has been described at various physiological and anatomical levels of the central nervous system including the brain, brainstem, and spinal cord, both above and below injury sites. The growing number of mechanisms underlying postinjury plasticity indicate the vast complexity of injury-induced plasticity. This poses important opportunities to further enhance and harness plasticity in order to promote recovery. However, the diversity of neuroplasticity also creates challenges for research, which is frequently based on mechanistically driven approaches. The appreciation of the complexity of neuronal plasticity and the findings that recovery is based on a multitude and interlinked adaptations will be essential in developing meaningful new treatment avenues.

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